ANNUAL REVIEWS
Annu. Rev. Med. 1990. 41:289�302 Copyright © 1990 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
EFFECTS OF CALCIUM CHANNEL BLOCKERS ON
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
RENAL FUNCTION Laurence Chan, M.D., and Robert W. Schrier, M.D.
Department of Medicine, University of Colorado School of Medicine, Denver, Colorado 80262 KEY WORDS:
kidney, transplantation, renal failure, cytoprotection.
ABSTRACT Calcium channel or entry blockers (CEBs) exert important vascular and tubular effects on the kidney. These renal effects include an enhancement of glomerular filtration rate (GFR), renal blood flow (RBF), and electrolyte excretion. Experimental studies in animals and humans indicate the poten tial therapeutic use of CEBs in several important clinical situations, for example attenuating the course of acute renal failure and slowing the progression of chronic renal failure. The latter effect appears to involve both the agent's antihypertensive effect and an additional cytoprotective effect. That CEBs help preserve renal function in renal transplantation has been shown in both animals and humans. In this setting, the effects of cyclosporine ( CsA) and CEB on the immune system and on CsA hepatic metabolism are areas of importance for future research. INTRODUCTION
Since the pioneering work of Fleckenstein in the 1960s (1), substantial progress has been made in elucidating the mechanisms of action and physiological effects of CEBs. These drugs have been widely used in the treatment of hypertension, angina pectoris, and cardiac arrhythmias (2). There is also recent evidencc that these CEBs may affect renal function (3). In this article we review the effects of eEBs on renal hemodynamics, glomerular filtration, and sodium and water excretion. The role of these 289 0066-4219/90/0401--0289$02.00
290
CHAN & SCHRIER
agents in experimental and human renal transplantation, and in acute and chronic renal failure, is also discussed.
ROLE OF Ca2+ AND CALCIUM CHANNEL
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
BLOCKERS
Cytosolic calcium (CaH) acts as a second messenger in a host of biological processes, including maintenance of tone in smooth muscle, release of hormone and neurotransmitters, and the transport of ions across .cell membrane (3,4). The nQrmal cell membrane is relatively impermeable to Ca2+ so that a steep calcium gradient is maintained. The calcium concentration outside cells is about 5,000 to 10,000 times greater than that within cells; which allows calcium ions to enter through voltage"dependent channels in the cell membranes (3-5). Intracellular CaH levels:·a.re through energy"dependent membrane pumps that promote CaH efflux. In' the renal tubular cells, at least two effective mechanisms in the basolateral membranes mediate Ca2+ efflux from.the cells ( Figure I); (a) a Ca"ATPase that is involved'ii1:ATP-dependent CaH effiux;and (b) a Na/ Ca exchange mechanism that is indirectly dep(mdent on A TP, since cellular sodium concentration is predominantly determined by Na/K-ATPase (3). In addition, intracellular organelles, namely mitochondria and endoplasmic reticulum, actively increase their calcium uptake in response-to-an.increase- in cytosolic CaH. Cytosolic CaH levels may rise because of an increase in cellular membrane permeability to CaH, a diminution in Ca2+ effiux, or a combination of both processes. The calcium channel blockers are a chemically heterogeneous group of drugs capable of influencing the movement of calcium into the cytosol; they have numerous pharmacologic effects (6, 7). The commonly used CEBs are (a) verapamil, a papaverine derivative; (b) diltiazem, a benzo thiazapine; and (c) nifedipine, the prototype of dihydropyridine group ( Figure 2). Several other dihydropyridine derivatives-including niludi pine, nimoldipine, nisodipine, nitrendipine, nicardipine, and felodipine are still under investigation. Other verapamil congeners under active inves tigation are gallopamil, anipamil, and tiopamil. All these agents impede the transmembrane influx of Ca2+ in cardiac and vascular smooth muscle,'. which in turn depresses both myocardial contraction and smooth muscle vasoconstriction. These overall hemodynamic effects may differ among the CEBs dependirig on the specific drug and dosage: Verapamil and diltiazem have both cardiac and vasodilatof,y� actions" while nifedipine is primarily an arterial. vasodilator.. Unlike other vasodilators, CEBs cause little activation of sympathetio inervous and renin-angiotensin-aldosterone
CALCIUM CHANNEL BLOCKERS
291
3 Na
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
Na-K ATPase
\ Figure 1
Brush border membrane
Mechanism of cellular calcium regulation (from Ref.
3).
systems. The comparative effects and pharmacokinetic properties of the three main CEBs (verapamil, diltiazem, and nifedipine) are summarized in Table I. Each of these CEBs differs in apparent mode of action, time and course of action, and pharmacologic action in different tissues. EFFECT ON NORMAL KIDNEY FUNCTION Renal Hemodynamics and Glomerular Filtration
In animal experiments, CEBs increase renal blood flow ( RBF) and glom erular filtration rate ( GF R), and they augment urine flow and electrolyte excretion (8-15). Several mechanisms have been proposed for the observed increase in GFR and RBF following CEB therapy ( Figure 3). A direct effect of CEBs to decrease afferent arteriolar resistance, however, may be the primary mechanism. Angiotensin II-induced vasoconstriction (mesan gium and/or afferent arteriolar tone) and norepinephrine-induced vaso-
292
CHAN & SCHRIER
~ ::,.... I
H)COOC H3C I
I
N J
H
N02
C ()()()-f:3 CH)
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
H
Nifedipine
Diltiazem
Verapamil
Figure 2
Molecular structure of the three major calcium channel blockers: nifedipine
(a dihydropyridine derivative), diltiazem (a benzothiazepine derivative), and verapamil (a papaverine derivative).
constnctlOn (afferent arteriolar tone) may also be reversed. Diltiazem, nifedipine, nitrendipine, and verapamil have all been reported to attenuate the intrarenal effects of exogenously administered angiotensin I I and of norepinephrine, and thereby to increase renal perfusion and GFR (lO15). In human acute studies, administration of eEBs similarly enhanced renal hemodynamic and diuretic effects ( 16--19). With CEBs, RBF and GFR are maintained in spite of a fall in blood pressure. Among the currently studied CEBs, diltiazem, nifedipine, and nicardipine are reported to increase acutelyGFR and/or effective renal plasma flow. For example, intravenous administration of nifedipine to patients with essential hyper tension increased both GFR (maximum 24%), as measured by inulin clearance, and effective renal plasma flow (maximum 30%), as measured by p-aminohippurate clearance (17).
293
CALCIUM CHANNEL BLOCKERS
Table 1
Phannacokinetic properties and comparative effects' Verapamil
Diltiazem
Nifedipine
+ +
+ +
++ ++
!
0
0
Myocardial oxygen consumption
! ! l
l
r l
Heart rate
0
0
0
RBF
0
r
GFR
0
V
0
t t t t t t
Peripheral vasodilatation Coronary vasodilatation A-V nodal conduction
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
Myocardial contractility
UNa V
0
r r t
PRA
0
0
Angiotensin II
0
0
Aldosterone
0
0
0
3-7
2-6
1.5-5
Elimination half-life (hr)
Excretion (% ren a l) Daily doses (mg) •
o
=
70
40
80
240-480
120-360
30-150
Symbols used: V � urine volume; UN,V - urinary sodium secretion; PRA no effect; i
=
increase; !
=
�
Plasma renin activity;
decrease.
Clinical studies on the renal effects of long-term treatment with CEBs are still lacking. Several investigators, using open-label study designs, evaluated the effects of CEB on renal vascular resistance, RBF, effective renal plasma flow, and glomerular filtration. Bauer and his colleagues (2022) reported on the renal effects of diltiazem and the dihydropyridine CEB amlodipine as well as nifedipine. These studies suggested that CEBs have the potential to enhance effective renal plasma flow and RBF, to preserve or improve GFR, and to lower renal vascular resistance. However, these effects are not consistent in studies from other investigators (23-25). Che1lingsworth et al did not find any increase in GFR of healthy volunteers in a randomized, single-blind, placebo-controlled study designed to evaluate the effects of diltiazem, nifedipine, and verapamil (24). Clinical results may vary because the renal response to CEB depends on the resting vascular tone of the kidney. Therefore, essential hypertension favors a renal vaso dilatory response to these agents, since it is generally associated with baseline renal vasoconstriction (20-22). This interpretation is supported by studies in isolated perfused rat kidneys from Dahl saIt-sensitive hyper tensive rats, which exhibited an exaggerated increase in GFR when their kidneys were constricted with norepinephrine and then treated with ver apamil or nitrendipine (26). Even though CEBs effectively lower systemic, and thus renal, blood pressure, adverse effects on renal function are rare. Nevertheless, Diamond
294
CHAN & SCHRIER
l
�
Decreaw
f
�
I ""rease
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
Mesa�ial cell contraction
t
Figure 3
I PG� t PGE2 Renin re-lease
'-:;;t
t
Afferent
arteriolar tone
Possible intrarenal mechanisms whereby calcium entry blockers may influence
GFR are summarized. Prevailing evidence indicates that CEBs tend to increast: GFR, probably by preferentially attenuating afferent arteriolar tone. They may also influence GFR through direct nonvascular actions (e.g. by increasing the glomerular ultrafiltration coefficient, Kr) as well as indirect actions (e.g. through decreased prostaglandin production, increased All production, or induction of natriuresis). [Modified with permission from Ref.
(12)].
et al (27) reported that nifedipine administration was associated with an acute, reversible deterioration in renal function in four patients with chronic renal insufficiency. They tentatively attributed the renal dys function to blockade of angiotensin II-mediated efferent arteriolar vaso constriction in association with impaired renal autoregulation. Since GFR is a function of the pressure created by afferent arteriolar dilatation and efferent arteriolar constriction, either constriction of the afferent arteriole or dilatation of the efferent arteriole results in a loss of glomerular pressure and a decrease in GFR. It is important to point out, however, that in this report ( 27) the patients were hemodynamically unstable and were receiving
CALCIUM CHANNEL BLOCKERS
295
a variety of cardiovascular drugs prior to CEB treatment. Diltiazem has also been reported to cause acute renal insufficiency (28). Only one clinical study reported the effects of diltiazem on intraglomerular pressure as well as on afferent and efferent arteriolar resistances (29). This study calculated intraglomerular pressure and afferent and efferent arteriolar resistances via indirect methods; diltiazem significantly reduced mean afferent and efferent arteriolar resistances by 38% and 67% respectively.
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
Water and Electrolyte Excretion
All of the CEBs induce an acute natriuresis and diuresis. Acute studies in isolated pcrfuscd kidneys and in experimental animals, as well as in humans, consistently demonstrate diuresis, natriuresis, calciuresis, and kaliuresis, even in the face of arterial blood pressure reduction (13, 15, 30). CEBs may exert their natriuretic response via a combination of hemo dynamic effects and/or direct tubular action. In clinical studies, the natri uretic effect of CEBs appears to be independent of any hemodynamic action and is most likely due to a direct effect on both the proximal tubule and the loop of Henle. None of the CEBs, however, have any clinically sustained effect on salt and water excretion. Thus, serum electrolytes, urinary sodium and potassium excretion, body fluid composition, and body weight of patients maintained on CEBs are not altered (30). Because CEB administration generally lowers blood pressure without producing salt and water retention, these drugs are likely to assume an important role as first-step therapy in the treatment of some hypertensive disorders. Renin-Angiotensin and Aldosterone System
The renin-angiotensin-aldosterone system plays a central role in electrolyte homeostasis and in the regulation of arterial pressure. Since calcium may inhibit renin secretion by a direct action on juxtaglomerular cells, the administration of a CEB might be expected to stimulate renin secretion and thus increase the circulatory angiotensin II concentrations (9, 13, 31). It is known, however, that the vasoconstricting action of exogenously administered angiotensin II is attenuated by a concurrent intravenous infusion of verapamil, diltiazem, nifedipine, or nitrendipine. Thus, while CEBs may increase circulating angiotensin, they inhibit the sensitivity of the vasculature to angiotensin II, probably by preventing the angiotensin II-mediated increase in cytosolic calcium. PROTECTION AGAINST ACUTE RENAL FAILURE
Animal studies suggest that cellular calcium accumulation represents a major pathophysiologic event in the development of ischemic and toxic
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
296
CHAN & SCHRIER
cell injury (3,32). During the past several years, several studies performed in our laboratories have confirmed these important observations and have examined the protective effect of CEBs both in the ischemic and nephro toxic models of acute renal failure (3, 33, 34). Other supportive studies have demonstrated improvement in renal function following CEB admin istration in the renal artery clamp models (35-38) as well as in the nephro toxic models (39, 40) of acute renal failure. However, these studies do not clearly document whether the protective effect of CEB is primarily expressed on vascular, epithelial, or both types of renal tissues. Specifically, consequences of an ischemic renal insult including renal vasoconstriction, diminished glomerular capillary permeability, loss of autoregulation, and hypersensitivity to renal nerve stimulation may relate to increased cellular Ca2+ concentration in the renal afferent arteriole and glomerular mesangial cells. In addition, injury to the tubular plasma membrane may be associ ated with increased calcium uptake (3, 33). In the norepinephrine model of acute renal failure in the dog, verapamil infused in the renal artery either 30 minutes before the ischemic injury or for two hours after the ischemic insult afforded significant functional protection as assessed by the recovery ofGFR (34).GFR recovered better when verapamil was administered before the injury. Protection against mitochondrial calcium accumulation or respiratory dysfunction was observed with both verapamil and nifedipine administration after the ischemic insult. Further studies designed to evaluate the time course of mitochondrial respiratory failure and calcium overload were conducted subsequently in rats with bilateral renal pedicle clamping for 45-50 minutes (41--43). These data demonstrated that during the first 3--4 hours of reflow after ischemia, mitochondrial respiration improved rapidly in parallel with a modest but steady increase in mitochondrial calcium content. In the next 20 hours, however, mitochondrial respiration declined precipitously, in parallel with a further large and linear increase in mitochondrial calcium content. Thus, between 3--4 and 24 hours after ischemia, parallel events (i.e. declining mitochondrial respiration and increasing mitochondrial calcium content) were observed. These data suggested a potential role for cellular and mitochondrial calcium overload during reperfusion as a possible cause for mitochondrial respiratory injury_ To substantiate this relationship, mitochondria from normal rat kidneys were harvested and suspended in media with varying amounts of calcium. These otherwise normal mitochondria also exhibited the same type of decline in respiratory function when exposed to extra mitochondrial calcium concentrations estimated to mimic the cytosolic concentrations to which the mitochondria from ischemic kidneys are
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
CALCIUM CHANNEL BLOCKERS
297
exposed in vivo (42). These results strongly suggest that postischemic renal tissue, presumably exposed to a constant supply of extracellular calcium during reflow secondary to damaged plasma membranes, can accumulate excessive calcium, particularly in the mitochondria (43). Since mito chondria are the source of energy production (ATP) needed to reestablish ionic homeostasis and synthetic and repair processes that were temporarily arrested during ischemia, their dysfunction due to calcium overload com promises many aspects of cellular recovery from the original insult. In order to achieve higher renal tissue concentrations and fewer systemic effects, clinical studies are under way with intrarenal infusions of CEBs in acute renal failure. It should also be mentioned that forms of acute renal failure involving a profound renal vasoconstriction effect, such as occurs with radiocontrast-induced acute renal failure (39), may be particularly amenable to prevention by CEB administration. EFFECT ON RENAL TRANSPLANTATION
Organ preservation prior to transplantation provides an ideal setting for the use of CEBs. We have studied the beneficial effect of CEBs in cold and warm ischemia in the isolated perfused rat kidney. Following either warm or cold ischemia, isolated rat kidneys, when placed in the perfused kidney preparation, exhibited higher inulin clearances and restoration of renal cortical tissue A TP if the original flushing solution contained verapamil or emopamil (44,45). Similar protection was observed in a cold perfusion model (46). These studies in the isolated perfused rat kidney confirm the unique ability of CEBs to protect against ischemic injury in the absence of any systemic manifestations of the drug. Clinical studies demonstrating the beneficial effect of CEBs to prevent acute renal failure during renal transplantation are emerging. Because of their vasodilatory action, CEBs are under study via the arterial route in patients with acute renal failure. Duggan et al (47) suggest that verapamil improves the early function of graft in renal transplant patients when administered to the donors before harvesting the kidneys. Moreover, the patients who received the verapamil-treated kidney had a lower incidence of acute rejection episodes (47,48). A similar observation was made by Wagner et al (49) using diltiazem in transplant patients receiving cyclo sporine (esA) and prednisone. In this study, better graft function was observed despite higher esA levels in the kidneys that were treated with diltiazem, which suggests that in this setting eEBs may also prevent esA nephrotoxicity (49,50). This potential interaction between esA and eEB is important since esA is now commonly used in renal transplant patients
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
298
CHAN & SCHRIER
who are also receiving a CEB to treat their hypertension. In this regard, both the nephrotoxic and hypertensive effects of CsA may involve increased cellular calcium ( 51 ). Because of this effect of CsA on cellular calcium; CEBs may be useful in protecting the transplanted kidney from CsA toxicity. Additional comment about the interaction between CEB and CsA is worthwhile. Because they inhibit hepatic microsomal drug metabolism ( 52), CEBs exert a marked effect on CsA blood levels, as determined by the polyclonal radioimmunoassay, and on CsA dose requirements in transplant patients (53, 54). Both verapamil and diltiazem cause a sig nificant elevation in CsA blood levels in renal transplant patients. Thus, in renal transplant patients receiving CEBs, reduction of the CsA dosage by 20-30% is possible without compromising graft function ( 50). Since calcium and its carrier protein, calmodulin, may be involved in various T-cell functions, CEBs and CsA may be directly additive with regard to the Ca2+ -dependent cellular immune mechanism (55). In studies in experimental transplantation (56), others have suggested that verapamil potentiates CsA by inhibiting protein kinase C-mediated events in acti vation of lymphocytes and diminishing calcium efflux, which thereby increases its therapeutic effectiveness.
EFFECT ON THE PROGRESSION OF CHRONIC RENAL FAILURE
In contrast to their potential beneficial effects in acute renal injury, CEBs were originally thought to have adverse effects, namely dilating the afferent arteriole and increasing glomerular pressure in the reduced number of functioning nephrons ( 57). However, in studies by Goligorsky et al ( 58), the chronic administration of verapamil prevented calcium accumulation in tubular cells and basement membrane, corrected abnormal cellular calcium kinetics, and prevented mitochondrial and tubular basement mem brane ultrastructural changes. The observations of GQligorsky et al were made over just three weeks, however, a time period too short for functional deterioration in this remnant model of chronic renal failure. Harris et al (59) extended the observations of Goligorsky et ai, with the intent of examining the long-term effect of chronic verapamil administration on renal functional deterioration and survival in this model of experimental chronic renal failure. Chronic verapamil significantly attenuated the rate of deterioration of renal function. Renal function was protected despite the absence of any observable effect of verapamil on proteinuria, which
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
CALCIUM CHANNEL BLOCKERS
299
suggests that proteinuria and progressive deterioration of renal function are not necessarily directly related in this model of chronic renal disease. The protective effect of verapamil was also dissociated from the anti hypertensive effect of the drug. In addition, the protective effect of chronic verapamil treatment was associated with a significant decrease in· calcium content of the kidney and improved renal histology. The effect of CEB on the progression of chronic renal failure has also been explored by Eliahou et al in humans (60). Patients with stable renal insufficiency were randomized to receive either the CEB nisoldipine or placebo. The monthly progression of their renal failure was assessed by calculating the'reciprocal of serum creatinine versus time in months. The CEB-treated group showed a significant decrease in their slopes of pro gression, whereas the placebo-treated group showed no significant change in their slopes after 17 (range 6-30) months of follow-up. It is interesting to note that the changes in slope of progression did not correlate with the changes in blood pressure. Therefore, the beneficial effect of eEB, both in humans and in experimental animals with chronic renal failure, appears to be additive to any effect on blood pressure. In this regard, a long-acting CEB, anipamil, was recently studied in our laboratory (61). The beneficial effects of this agent in retarding the progression of chronic renal failure in the remnant i-kidney involved both its antihypertensive effect and an additional blood pressure-independent cytoprotective effect .
SUMMARY
Calcium entry blockers are a heterogeneous group of compounds with diverse chemical structures and pharmacologic actions. Studies in intact animals and humans indicate that the renal hemodynamic response to CEBs depends on the neural and hormonal determinants of renal vascular resistance. The effects of CEBs on renal hemodynamics and tubular func tion suggest several new renal therapeutic applications for these agents. In addition to their use in the treatment of hypertension, CEBs may have a role in the prophylaxis of acute renal insufficiency in clinical settings such as renal transplantation, organ preservation during harvesting of kidneys for transplantation, and the administration of radiocontrast agents to high-risk patients; they may also shorten the recovery time for ischemic acute renal failure. The interaction of CsA and CEB on CsA metabolism and immune function is also an important area for research. Finally, evidence is emerging that chronic administration of CEBs may afford an additional cytoprotective effect in preventing the progression of chronic renal failure over and above the agents' important antihypertensive effects.
300
CHAN & SCHRIER
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
Literature Cited I. Fleckenstein, A. 1983. Calcium Antag onism in Heart and Smooth Muscle Experimental Facts and Therapeutic Aspects. New York: Wiley 2. Braunwald, E. 1983. Mechanism of action of calcium channel-blocking agents. N. Engl. J. Med. 307: 1618-22 3. Schrier, R. W., Arnold, P. E., Van Putten, V. l., Burke, T.l. 1987. Cellular calcium in ischemic acute renal failure: role of calcium entry blocker. Kidney Int. 32: 312-21 4. Borle, A. B. 1981. Control, modulation, regulation of cell calcium. Rev. Physiol. Biochem. Pharmacol. 90: 13-153 5. Cheung, 1. Y., Constantine, 1. M., Bon ventre, 1. V. 1986. Regulation of cyto solie free calcium concentration in cul tured renal epithelial cells. Am. J. Physiol. 251: F690--701 6. Godfreind, T. 1987. Classification of cal cium antagonist. Am. J. Cardiol. 59: IIB-23B 7. Fleckenstein, A. , Fleckenstein-Grun, G., Frey, M., Zorn, J. 1987. Future direction in the use of calcium antag onists. Am. J. Cardiol. 59: 177B-87B 8. Barrett, R. J., Wright, K. P., Taylor, D. R., Proakis, A. G. 1988.Cardiovascular and renal action of calcium channel blocker chemical subgroup: a search for renal specificity. J. Pharm. Pharmacal. 40:408-14 9. Abe, Y., Komori, T., Miura, K., et a!. 1983. Effects of the calcium antagonist nicardipine on renal function and renin release in dogs. J. Cardiovasc. Phar macol. 5: 254-59 10. Bell, A. J., Lindner, A. 1984. Effects of verapamil on nifedipine on renal func tion and hemodynamics in the dog. Renal Physiol. 7: 329-43 II. Dietz, J. R., Davis, J. 0., Freeman, R. H., Villarrell, D., Echtenkamp, S. F. 1983. Effects of intrarenal infusion of calcium entry blockers in anesthetized dogs. Hypertension 5: 482-88 12. Loutzenhiser, R., Epstein, M. 1985. Effects of calcium antagonists on renal hemodynamics. Am. J. Physiol. 249: F6 I 6-29 13. Goldberg, J. P., Schrier, R. W. 1984. Effect of calcium membrane blockers on in vivo vasoconstrictor properties of norepinephrine, angiotensin II and vasopressin. Miner. Electro!. Metab. 10: 178-83 14. Loutzenhiser, R., Epstein, M. 1987. Renal hemodynamic effects of calcium antagonists. Am. J. Med. 82 (Supp!. 3): 23-28
15. Steele, T., Challoner-Hue, L. 1984. Renal interactions between norepin ephrine and calcium antagonists. Kidney Int. 26: 79-4 16. Christcnsen, C. K. , Ledcrballe, P. , Mikkelsen, E. 1982. Renal cffccts of acute calcium channel blockade with nifedipine in hypertensive patients. Clin. Pharmacal. Ther. 32: 572-76 17. Klutsch, K., Schmidt, P., Grosswendt, 1. 1972. Der Einftuss von Bay a 1040 an die Nierenfunktion des Hypertonikers. Arzneim-Florsch. Drug Res. 22: 377-80 18. Leonetti, G., Cuspid, c., Sampieri, L., Terzoli, L., Zanchetti, A. 1982. Com parison of cardiovascular, renal and humoral effects of acute administration of two calcium channel blockers in nor motensive and hypertensive subjects. J. Cardiovasc. Pharmacol. 4: S319-24 19. Yokoyama, S., Kaburagi, T. 1983. Clini cal effects of intravenous nifedipine on renal function. J. Cardiovasc. Pharma col. 5: 67-71 20. Reams, G., Hamory, A., Lau, A., Bauer, J. H. 1988. Effect of nifedipine on renal function in patients with essential hyper tension. Hypertension II: 425-456 21. Sunderrajan, S., Reams, G., Bauer, J. H. 1987. Long-term renal effects of dilti azem in essential hypertension. Am. Heart J: 114: 383-88 22. Bauer, J. H., Reams, G. 1987. Short and long-term effects of calcium entry blockers on the kidney. Am. J. Cardiol. 59: 66A-71A 23. Romero, J. C. , Raij, L., Granger, J. P., Ruilope, l. M., Rodicio, 1. L. 1987. Mul tiple effects of calcium entry blockers on renal function in hypertension. Hyper tension 10: 140--51 24. Chellingsworth, M. c., Kendall, M. 1. 1988. Effects of nifedipine, verapamil and diltiazem on renal function. Br. J. Clin. Pharmacal. 25: 599-602 25. Van Schaik, B. A. M., Van Nistelrooy, A. E. J., Geyskes, G. G. 1984 Anti hypertensive and renal effects of nitren dipine. Br. J. c/in. Pharmacol. 18: 5763 26. Steele, T. H. 1987. Calcium entry modu lation and renal hemodynamics in the hypertensive kidney. Am. J. Nephrol. 7 (Supp!. I): 17-23 27. Diamond, 1. R., Cheung, 1. Y., Fang, L. S. 1984. Nifedipine-induced renal dys function. Am. J. Med. 77: 905-8 28. Ter Wee, P. M., Ro sma n, 1. R., Van Der Geest, S. 1984. Acute renal failure due to diltiazem. Lancet 2:1337-38 29. Jsshike, T., Amodeo, c., Messerli, F. H.,
CALCIUM CHANNEL BLOCKERS
30.
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
31.
32. 33.
Pegram, 8. L., Frohlich, E. D. 1987. Diltiazem maintains renal vasodilata tion without hyperfiltration in hyperten sion: studies on essential hypertensive man and the spontaneous hypertensive rat. Cardiovasc. Drugs Ther. 1: 359-66 Bauer, J. H., Sunderrajan, S., Reams, G. 1985. Effect of calcium entry blockers on renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion and body fluid com position. Am. J. Cardiol. 56: 62H-67H Roy, M. W., Gurthrie, G. P. Jr., Holla day, F. P., Kotchen, T. A. 1983. Effects of verapamil on renin and aldosterone in the dog and rat. Am. J. Physiol . 245: E410-16 Farber, J. L. 1981. The role of calcium in cell death. Life Sci. 29: 1289-95 Conger, J. D., Robinette, J. 8., Schrier, R. W. 1989. Smooth muscle calcium and endothelium-derived relaxing factor in the abnormal vascular responses of acute renal failure.
532-37
35.
36.
37.
38.
39.
40.
41.
42.
43.
44. .
45.
J. Clin. Invest. 82:
34. Burke, T. J., Arnold, P. E., Gordon, J .
A., Bulger, R. E., Dobyan, D. C., Schrier, R. W. 1984. Protective effect of intrarenal calcium mcmbrane blockers before or after renal ischemia. 1. Clin. Invest. 74: 1830-41 Malis, C. D., Cheung, J. Y., Leaf, A., Bonventre, J. V. 1983. Effects of ver apamil in models of ischemic acute renal failure in the rat. Am. J. Physiol. 245: F735-42 Cheung, J. Y., Bonventre, J. V., Malis, C. D., Leaf, A. 1986. Calcium and isch emic injury. N. Engl. J. Med. 314: 167076 Goldfarb, D., Iaina, A., Serban, I., Gavendo, S., Kapuler, S., Eliahou, H. E. 1983. Beneficial effect of verapamil in ischemic acute renal failure in the rat. Proc. Soc. Exp. Bioi. Med. 172: 38992 Rose, H., Philipson, J., Puschett, J. B. 1987. Effects of nitrendipine in a rat model of ischemic acute renal failure. J. Cardiovasc. Pharmacol. 9 (Supp!. I): 5759 Bakris, G. I., Burnett, J. C. 1985. A role for calcium in radiocontrast-induced reductions in renal hemodynamics. Kid ney Int. 27: 465-68 Lee, S. M., Hillman, 8. J ., Clark, R. L., Michael, V. F. 1985. The effects of diltiazem and captopril on glycerol induced acute renal failure in the rat: functional, pathologic and microangio graphic studies. Invest. Radiol. 20: 96170 Wilson, D. R., Arnold, P. E., Burke, T.
301
J., Schrier, R. W. 1984. Mitochondrial
calcium accumulation and respiration in ischemic acute renal failure in the rat. Kidney Int. 25: 519-26 Arnold, P. E., Lumlertgul, D., Burke, T. J., Schrier, R. W. 1985. In vitro versus in vivo mitochondrial calcium loading in ischemic acute renal failure. Am. J. Physiol. 248: F845-51 Arnold, P. E., Van Putten, V. J., Lum lertgul, D., Burke, T. J., Schrier, R. W. 1986. Adenine nucleotide metabolism and mitochondrial Ca2+ transport fol lowing renal ischemia. Am. J. Physiol. 250: F357-63 Shapiro, J. I., Cheun�. c., Itabashi. A., Schrier, R. W.,Chan, L. 1986. The effect of verapamil on renal function after warm and cold ischemia in the isolated perfused rat kidney. Tran splantation 40: 596-600. Mills, S., Chan, L., Schwertschlag, V., Shapiro, J. I., Schrier, R. W. 1987. Pro tective effect of emopamil on renal func
46.
47.
48.
49.
50.
51.
52.
53.
tion following warm and cold ischemia. Transp lan tation 43: 928-30 Nakamoto, M., Shapiro, J. I., Mills, S., Schrier, R. W., Chan, L. 1988. Yer apamil improves renal preservation by cold perfusion in the isolated rat kidney. Transplantation 45: 313-15 Duggan, G. A., MacDonald, G. J., Charlesworth, J. A., Pussel, B. A. 1985. Verapamil prevents post-transplant oli guric renal failure. Clin. Nephrol. 24: 289 Korb, S., Albornoz, G., Brems, W., Ali, A., Light, J. A. 1989. Verapamil pre treatment of hemodynamically unstable donors prevent delayed graft function post-transplant. Transplant. Proc. 21: 1236-38 Wagner, K., Albrecht, S., Neumayer, H. H. 1986. Prevention of delayed graft function in cadaveric kidney trans plantation by a calcium antagonist. Pre liniinary results of two prospective ran domized trials. Transplant. Proc. 18: 510 Wagner, K., Henkel, M., Heinemeyer, G., Neumayer, H. H. 1988. Interaction of calcium blockers and cyc1osporine. Transplant. Proc. 20: 561 68 Meyer-Lehnert, H., Schrier, R. W. 1988. Cyclosporine A enhances vasopressin induced Ca2+ mobilization and con traction in mesengiaJ cells: a potential mechani&,m of nephrotoxicity. Kidney Tnt. 34: lW-97 Renton, K. W. 1985. Inhibition of hep atic microsomal drug metabolism by cal cium channel blockers diltiazem and ver apamil. Biochem. Pharmacol. 34: 54953 Grino, J. M., Sebate, I., Castelao, A. M.,
302
CHAN & SCHRIER
Alsina, J. 1986. Influence of diltiazem on cyclosporinc clearancc. Lancet I: 136 54. Howard, R., Shapiro, 1. I., Babcock, S., Chan, L. 1990. The effect of calcium
55.
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
56.
57.
58.
channel blockers on cyclosporine dose requirement in renal transplant recipi ents. 1. Renal Failure. In press Weir, M. R., Peppler, R., Gomolka, D ., Handwerger, B. S. 1989. Additive inhibi tory effect of cyclosporine and verapamil may occur through different mech anisms that may be dependent or inde pendent of the slow calcium channel. Transplant. Proc. 2 1: 866-70 Wells, M. S., Vogelsang, G. B., Col ombani, P. M., Hess, A. D. 1989. Cyclo sporin A binding to calmodulin. Tra ns plant. Proc. 21: 850--52 Brenner, B. M. 1985. Nephron adap tation to renal injury or ablation. Am. 1. Physiol. 249: F324-37 Goligorsky, M. S., Chaimovitz, C.,
Rapaport, J., Goldstein, J., Kot, R. 1985. Calcium metabolism in uremic nephrocalcinosis: Preventivc effect of verapamil. Kidney Int. 27: 774-79 59. Harris, D. C. H., Hammond, W. S., Burke, T. J., Schrier, R. W. 1986. Ver apamil protects against progression of experimental chronic acute renal failure. Kidney Int. 31: 41-46 60. E1iahou, H. E., Cohen, D., Hellberg, B., Ben-David, A., Herzog, D., et al. 1988. Effect of the calcium channel blocker nisoldipine on the progression of chronic renal failure in man. Am. 1. Nephrol. 8: 285-90 61. larusiripipat, c., Zhou, H. Z., Shapiro, 1. I., Chan, L., Schrier, R. W. 1989. Effect of long-acting calcium channel blocker on blood pressure, renal func tion and survival of uremic rats. Pre sented at the Am. Soc. Nephrol., 22nd Annu. Meet., Dec. 1989
Annu. Rev. Med. 1990. 41:289�302 Copyright © 1990 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
EFFECTS OF CALCIUM CHANNEL BLOCKERS ON
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
RENAL FUNCTION Laurence Chan, M.D., and Robert W. Schrier, M.D.
Department of Medicine, University of Colorado School of Medicine, Denver, Colorado 80262 KEY WORDS:
kidney, transplantation, renal failure, cytoprotection.
ABSTRACT Calcium channel or entry blockers (CEBs) exert important vascular and tubular effects on the kidney. These renal effects include an enhancement of glomerular filtration rate (GFR), renal blood flow (RBF), and electrolyte excretion. Experimental studies in animals and humans indicate the poten tial therapeutic use of CEBs in several important clinical situations, for example attenuating the course of acute renal failure and slowing the progression of chronic renal failure. The latter effect appears to involve both the agent's antihypertensive effect and an additional cytoprotective effect. That CEBs help preserve renal function in renal transplantation has been shown in both animals and humans. In this setting, the effects of cyclosporine ( CsA) and CEB on the immune system and on CsA hepatic metabolism are areas of importance for future research. INTRODUCTION
Since the pioneering work of Fleckenstein in the 1960s (1), substantial progress has been made in elucidating the mechanisms of action and physiological effects of CEBs. These drugs have been widely used in the treatment of hypertension, angina pectoris, and cardiac arrhythmias (2). There is also recent evidencc that these CEBs may affect renal function (3). In this article we review the effects of eEBs on renal hemodynamics, glomerular filtration, and sodium and water excretion. The role of these 289 0066-4219/90/0401--0289$02.00
290
CHAN & SCHRIER
agents in experimental and human renal transplantation, and in acute and chronic renal failure, is also discussed.
ROLE OF Ca2+ AND CALCIUM CHANNEL
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
BLOCKERS
Cytosolic calcium (CaH) acts as a second messenger in a host of biological processes, including maintenance of tone in smooth muscle, release of hormone and neurotransmitters, and the transport of ions across .cell membrane (3,4). The nQrmal cell membrane is relatively impermeable to Ca2+ so that a steep calcium gradient is maintained. The calcium concentration outside cells is about 5,000 to 10,000 times greater than that within cells; which allows calcium ions to enter through voltage"dependent channels in the cell membranes (3-5). Intracellular CaH levels:·a.re through energy"dependent membrane pumps that promote CaH efflux. In' the renal tubular cells, at least two effective mechanisms in the basolateral membranes mediate Ca2+ efflux from.the cells ( Figure I); (a) a Ca"ATPase that is involved'ii1:ATP-dependent CaH effiux;and (b) a Na/ Ca exchange mechanism that is indirectly dep(mdent on A TP, since cellular sodium concentration is predominantly determined by Na/K-ATPase (3). In addition, intracellular organelles, namely mitochondria and endoplasmic reticulum, actively increase their calcium uptake in response-to-an.increase- in cytosolic CaH. Cytosolic CaH levels may rise because of an increase in cellular membrane permeability to CaH, a diminution in Ca2+ effiux, or a combination of both processes. The calcium channel blockers are a chemically heterogeneous group of drugs capable of influencing the movement of calcium into the cytosol; they have numerous pharmacologic effects (6, 7). The commonly used CEBs are (a) verapamil, a papaverine derivative; (b) diltiazem, a benzo thiazapine; and (c) nifedipine, the prototype of dihydropyridine group ( Figure 2). Several other dihydropyridine derivatives-including niludi pine, nimoldipine, nisodipine, nitrendipine, nicardipine, and felodipine are still under investigation. Other verapamil congeners under active inves tigation are gallopamil, anipamil, and tiopamil. All these agents impede the transmembrane influx of Ca2+ in cardiac and vascular smooth muscle,'. which in turn depresses both myocardial contraction and smooth muscle vasoconstriction. These overall hemodynamic effects may differ among the CEBs dependirig on the specific drug and dosage: Verapamil and diltiazem have both cardiac and vasodilatof,y� actions" while nifedipine is primarily an arterial. vasodilator.. Unlike other vasodilators, CEBs cause little activation of sympathetio inervous and renin-angiotensin-aldosterone
CALCIUM CHANNEL BLOCKERS
291
3 Na
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
Na-K ATPase
\ Figure 1
Brush border membrane
Mechanism of cellular calcium regulation (from Ref.
3).
systems. The comparative effects and pharmacokinetic properties of the three main CEBs (verapamil, diltiazem, and nifedipine) are summarized in Table I. Each of these CEBs differs in apparent mode of action, time and course of action, and pharmacologic action in different tissues. EFFECT ON NORMAL KIDNEY FUNCTION Renal Hemodynamics and Glomerular Filtration
In animal experiments, CEBs increase renal blood flow ( RBF) and glom erular filtration rate ( GF R), and they augment urine flow and electrolyte excretion (8-15). Several mechanisms have been proposed for the observed increase in GFR and RBF following CEB therapy ( Figure 3). A direct effect of CEBs to decrease afferent arteriolar resistance, however, may be the primary mechanism. Angiotensin II-induced vasoconstriction (mesan gium and/or afferent arteriolar tone) and norepinephrine-induced vaso-
292
CHAN & SCHRIER
~ ::,.... I
H)COOC H3C I
I
N J
H
N02
C ()()()-f:3 CH)
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
H
Nifedipine
Diltiazem
Verapamil
Figure 2
Molecular structure of the three major calcium channel blockers: nifedipine
(a dihydropyridine derivative), diltiazem (a benzothiazepine derivative), and verapamil (a papaverine derivative).
constnctlOn (afferent arteriolar tone) may also be reversed. Diltiazem, nifedipine, nitrendipine, and verapamil have all been reported to attenuate the intrarenal effects of exogenously administered angiotensin I I and of norepinephrine, and thereby to increase renal perfusion and GFR (lO15). In human acute studies, administration of eEBs similarly enhanced renal hemodynamic and diuretic effects ( 16--19). With CEBs, RBF and GFR are maintained in spite of a fall in blood pressure. Among the currently studied CEBs, diltiazem, nifedipine, and nicardipine are reported to increase acutelyGFR and/or effective renal plasma flow. For example, intravenous administration of nifedipine to patients with essential hyper tension increased both GFR (maximum 24%), as measured by inulin clearance, and effective renal plasma flow (maximum 30%), as measured by p-aminohippurate clearance (17).
293
CALCIUM CHANNEL BLOCKERS
Table 1
Phannacokinetic properties and comparative effects' Verapamil
Diltiazem
Nifedipine
+ +
+ +
++ ++
!
0
0
Myocardial oxygen consumption
! ! l
l
r l
Heart rate
0
0
0
RBF
0
r
GFR
0
V
0
t t t t t t
Peripheral vasodilatation Coronary vasodilatation A-V nodal conduction
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
Myocardial contractility
UNa V
0
r r t
PRA
0
0
Angiotensin II
0
0
Aldosterone
0
0
0
3-7
2-6
1.5-5
Elimination half-life (hr)
Excretion (% ren a l) Daily doses (mg) •
o
=
70
40
80
240-480
120-360
30-150
Symbols used: V � urine volume; UN,V - urinary sodium secretion; PRA no effect; i
=
increase; !
=
�
Plasma renin activity;
decrease.
Clinical studies on the renal effects of long-term treatment with CEBs are still lacking. Several investigators, using open-label study designs, evaluated the effects of CEB on renal vascular resistance, RBF, effective renal plasma flow, and glomerular filtration. Bauer and his colleagues (2022) reported on the renal effects of diltiazem and the dihydropyridine CEB amlodipine as well as nifedipine. These studies suggested that CEBs have the potential to enhance effective renal plasma flow and RBF, to preserve or improve GFR, and to lower renal vascular resistance. However, these effects are not consistent in studies from other investigators (23-25). Che1lingsworth et al did not find any increase in GFR of healthy volunteers in a randomized, single-blind, placebo-controlled study designed to evaluate the effects of diltiazem, nifedipine, and verapamil (24). Clinical results may vary because the renal response to CEB depends on the resting vascular tone of the kidney. Therefore, essential hypertension favors a renal vaso dilatory response to these agents, since it is generally associated with baseline renal vasoconstriction (20-22). This interpretation is supported by studies in isolated perfused rat kidneys from Dahl saIt-sensitive hyper tensive rats, which exhibited an exaggerated increase in GFR when their kidneys were constricted with norepinephrine and then treated with ver apamil or nitrendipine (26). Even though CEBs effectively lower systemic, and thus renal, blood pressure, adverse effects on renal function are rare. Nevertheless, Diamond
294
CHAN & SCHRIER
l
�
Decreaw
f
�
I ""rease
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
Mesa�ial cell contraction
t
Figure 3
I PG� t PGE2 Renin re-lease
'-:;;t
t
Afferent
arteriolar tone
Possible intrarenal mechanisms whereby calcium entry blockers may influence
GFR are summarized. Prevailing evidence indicates that CEBs tend to increast: GFR, probably by preferentially attenuating afferent arteriolar tone. They may also influence GFR through direct nonvascular actions (e.g. by increasing the glomerular ultrafiltration coefficient, Kr) as well as indirect actions (e.g. through decreased prostaglandin production, increased All production, or induction of natriuresis). [Modified with permission from Ref.
(12)].
et al (27) reported that nifedipine administration was associated with an acute, reversible deterioration in renal function in four patients with chronic renal insufficiency. They tentatively attributed the renal dys function to blockade of angiotensin II-mediated efferent arteriolar vaso constriction in association with impaired renal autoregulation. Since GFR is a function of the pressure created by afferent arteriolar dilatation and efferent arteriolar constriction, either constriction of the afferent arteriole or dilatation of the efferent arteriole results in a loss of glomerular pressure and a decrease in GFR. It is important to point out, however, that in this report ( 27) the patients were hemodynamically unstable and were receiving
CALCIUM CHANNEL BLOCKERS
295
a variety of cardiovascular drugs prior to CEB treatment. Diltiazem has also been reported to cause acute renal insufficiency (28). Only one clinical study reported the effects of diltiazem on intraglomerular pressure as well as on afferent and efferent arteriolar resistances (29). This study calculated intraglomerular pressure and afferent and efferent arteriolar resistances via indirect methods; diltiazem significantly reduced mean afferent and efferent arteriolar resistances by 38% and 67% respectively.
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
Water and Electrolyte Excretion
All of the CEBs induce an acute natriuresis and diuresis. Acute studies in isolated pcrfuscd kidneys and in experimental animals, as well as in humans, consistently demonstrate diuresis, natriuresis, calciuresis, and kaliuresis, even in the face of arterial blood pressure reduction (13, 15, 30). CEBs may exert their natriuretic response via a combination of hemo dynamic effects and/or direct tubular action. In clinical studies, the natri uretic effect of CEBs appears to be independent of any hemodynamic action and is most likely due to a direct effect on both the proximal tubule and the loop of Henle. None of the CEBs, however, have any clinically sustained effect on salt and water excretion. Thus, serum electrolytes, urinary sodium and potassium excretion, body fluid composition, and body weight of patients maintained on CEBs are not altered (30). Because CEB administration generally lowers blood pressure without producing salt and water retention, these drugs are likely to assume an important role as first-step therapy in the treatment of some hypertensive disorders. Renin-Angiotensin and Aldosterone System
The renin-angiotensin-aldosterone system plays a central role in electrolyte homeostasis and in the regulation of arterial pressure. Since calcium may inhibit renin secretion by a direct action on juxtaglomerular cells, the administration of a CEB might be expected to stimulate renin secretion and thus increase the circulatory angiotensin II concentrations (9, 13, 31). It is known, however, that the vasoconstricting action of exogenously administered angiotensin II is attenuated by a concurrent intravenous infusion of verapamil, diltiazem, nifedipine, or nitrendipine. Thus, while CEBs may increase circulating angiotensin, they inhibit the sensitivity of the vasculature to angiotensin II, probably by preventing the angiotensin II-mediated increase in cytosolic calcium. PROTECTION AGAINST ACUTE RENAL FAILURE
Animal studies suggest that cellular calcium accumulation represents a major pathophysiologic event in the development of ischemic and toxic
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
296
CHAN & SCHRIER
cell injury (3,32). During the past several years, several studies performed in our laboratories have confirmed these important observations and have examined the protective effect of CEBs both in the ischemic and nephro toxic models of acute renal failure (3, 33, 34). Other supportive studies have demonstrated improvement in renal function following CEB admin istration in the renal artery clamp models (35-38) as well as in the nephro toxic models (39, 40) of acute renal failure. However, these studies do not clearly document whether the protective effect of CEB is primarily expressed on vascular, epithelial, or both types of renal tissues. Specifically, consequences of an ischemic renal insult including renal vasoconstriction, diminished glomerular capillary permeability, loss of autoregulation, and hypersensitivity to renal nerve stimulation may relate to increased cellular Ca2+ concentration in the renal afferent arteriole and glomerular mesangial cells. In addition, injury to the tubular plasma membrane may be associ ated with increased calcium uptake (3, 33). In the norepinephrine model of acute renal failure in the dog, verapamil infused in the renal artery either 30 minutes before the ischemic injury or for two hours after the ischemic insult afforded significant functional protection as assessed by the recovery ofGFR (34).GFR recovered better when verapamil was administered before the injury. Protection against mitochondrial calcium accumulation or respiratory dysfunction was observed with both verapamil and nifedipine administration after the ischemic insult. Further studies designed to evaluate the time course of mitochondrial respiratory failure and calcium overload were conducted subsequently in rats with bilateral renal pedicle clamping for 45-50 minutes (41--43). These data demonstrated that during the first 3--4 hours of reflow after ischemia, mitochondrial respiration improved rapidly in parallel with a modest but steady increase in mitochondrial calcium content. In the next 20 hours, however, mitochondrial respiration declined precipitously, in parallel with a further large and linear increase in mitochondrial calcium content. Thus, between 3--4 and 24 hours after ischemia, parallel events (i.e. declining mitochondrial respiration and increasing mitochondrial calcium content) were observed. These data suggested a potential role for cellular and mitochondrial calcium overload during reperfusion as a possible cause for mitochondrial respiratory injury_ To substantiate this relationship, mitochondria from normal rat kidneys were harvested and suspended in media with varying amounts of calcium. These otherwise normal mitochondria also exhibited the same type of decline in respiratory function when exposed to extra mitochondrial calcium concentrations estimated to mimic the cytosolic concentrations to which the mitochondria from ischemic kidneys are
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
CALCIUM CHANNEL BLOCKERS
297
exposed in vivo (42). These results strongly suggest that postischemic renal tissue, presumably exposed to a constant supply of extracellular calcium during reflow secondary to damaged plasma membranes, can accumulate excessive calcium, particularly in the mitochondria (43). Since mito chondria are the source of energy production (ATP) needed to reestablish ionic homeostasis and synthetic and repair processes that were temporarily arrested during ischemia, their dysfunction due to calcium overload com promises many aspects of cellular recovery from the original insult. In order to achieve higher renal tissue concentrations and fewer systemic effects, clinical studies are under way with intrarenal infusions of CEBs in acute renal failure. It should also be mentioned that forms of acute renal failure involving a profound renal vasoconstriction effect, such as occurs with radiocontrast-induced acute renal failure (39), may be particularly amenable to prevention by CEB administration. EFFECT ON RENAL TRANSPLANTATION
Organ preservation prior to transplantation provides an ideal setting for the use of CEBs. We have studied the beneficial effect of CEBs in cold and warm ischemia in the isolated perfused rat kidney. Following either warm or cold ischemia, isolated rat kidneys, when placed in the perfused kidney preparation, exhibited higher inulin clearances and restoration of renal cortical tissue A TP if the original flushing solution contained verapamil or emopamil (44,45). Similar protection was observed in a cold perfusion model (46). These studies in the isolated perfused rat kidney confirm the unique ability of CEBs to protect against ischemic injury in the absence of any systemic manifestations of the drug. Clinical studies demonstrating the beneficial effect of CEBs to prevent acute renal failure during renal transplantation are emerging. Because of their vasodilatory action, CEBs are under study via the arterial route in patients with acute renal failure. Duggan et al (47) suggest that verapamil improves the early function of graft in renal transplant patients when administered to the donors before harvesting the kidneys. Moreover, the patients who received the verapamil-treated kidney had a lower incidence of acute rejection episodes (47,48). A similar observation was made by Wagner et al (49) using diltiazem in transplant patients receiving cyclo sporine (esA) and prednisone. In this study, better graft function was observed despite higher esA levels in the kidneys that were treated with diltiazem, which suggests that in this setting eEBs may also prevent esA nephrotoxicity (49,50). This potential interaction between esA and eEB is important since esA is now commonly used in renal transplant patients
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
298
CHAN & SCHRIER
who are also receiving a CEB to treat their hypertension. In this regard, both the nephrotoxic and hypertensive effects of CsA may involve increased cellular calcium ( 51 ). Because of this effect of CsA on cellular calcium; CEBs may be useful in protecting the transplanted kidney from CsA toxicity. Additional comment about the interaction between CEB and CsA is worthwhile. Because they inhibit hepatic microsomal drug metabolism ( 52), CEBs exert a marked effect on CsA blood levels, as determined by the polyclonal radioimmunoassay, and on CsA dose requirements in transplant patients (53, 54). Both verapamil and diltiazem cause a sig nificant elevation in CsA blood levels in renal transplant patients. Thus, in renal transplant patients receiving CEBs, reduction of the CsA dosage by 20-30% is possible without compromising graft function ( 50). Since calcium and its carrier protein, calmodulin, may be involved in various T-cell functions, CEBs and CsA may be directly additive with regard to the Ca2+ -dependent cellular immune mechanism (55). In studies in experimental transplantation (56), others have suggested that verapamil potentiates CsA by inhibiting protein kinase C-mediated events in acti vation of lymphocytes and diminishing calcium efflux, which thereby increases its therapeutic effectiveness.
EFFECT ON THE PROGRESSION OF CHRONIC RENAL FAILURE
In contrast to their potential beneficial effects in acute renal injury, CEBs were originally thought to have adverse effects, namely dilating the afferent arteriole and increasing glomerular pressure in the reduced number of functioning nephrons ( 57). However, in studies by Goligorsky et al ( 58), the chronic administration of verapamil prevented calcium accumulation in tubular cells and basement membrane, corrected abnormal cellular calcium kinetics, and prevented mitochondrial and tubular basement mem brane ultrastructural changes. The observations of GQligorsky et al were made over just three weeks, however, a time period too short for functional deterioration in this remnant model of chronic renal failure. Harris et al (59) extended the observations of Goligorsky et ai, with the intent of examining the long-term effect of chronic verapamil administration on renal functional deterioration and survival in this model of experimental chronic renal failure. Chronic verapamil significantly attenuated the rate of deterioration of renal function. Renal function was protected despite the absence of any observable effect of verapamil on proteinuria, which
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
CALCIUM CHANNEL BLOCKERS
299
suggests that proteinuria and progressive deterioration of renal function are not necessarily directly related in this model of chronic renal disease. The protective effect of verapamil was also dissociated from the anti hypertensive effect of the drug. In addition, the protective effect of chronic verapamil treatment was associated with a significant decrease in· calcium content of the kidney and improved renal histology. The effect of CEB on the progression of chronic renal failure has also been explored by Eliahou et al in humans (60). Patients with stable renal insufficiency were randomized to receive either the CEB nisoldipine or placebo. The monthly progression of their renal failure was assessed by calculating the'reciprocal of serum creatinine versus time in months. The CEB-treated group showed a significant decrease in their slopes of pro gression, whereas the placebo-treated group showed no significant change in their slopes after 17 (range 6-30) months of follow-up. It is interesting to note that the changes in slope of progression did not correlate with the changes in blood pressure. Therefore, the beneficial effect of eEB, both in humans and in experimental animals with chronic renal failure, appears to be additive to any effect on blood pressure. In this regard, a long-acting CEB, anipamil, was recently studied in our laboratory (61). The beneficial effects of this agent in retarding the progression of chronic renal failure in the remnant i-kidney involved both its antihypertensive effect and an additional blood pressure-independent cytoprotective effect .
SUMMARY
Calcium entry blockers are a heterogeneous group of compounds with diverse chemical structures and pharmacologic actions. Studies in intact animals and humans indicate that the renal hemodynamic response to CEBs depends on the neural and hormonal determinants of renal vascular resistance. The effects of CEBs on renal hemodynamics and tubular func tion suggest several new renal therapeutic applications for these agents. In addition to their use in the treatment of hypertension, CEBs may have a role in the prophylaxis of acute renal insufficiency in clinical settings such as renal transplantation, organ preservation during harvesting of kidneys for transplantation, and the administration of radiocontrast agents to high-risk patients; they may also shorten the recovery time for ischemic acute renal failure. The interaction of CsA and CEB on CsA metabolism and immune function is also an important area for research. Finally, evidence is emerging that chronic administration of CEBs may afford an additional cytoprotective effect in preventing the progression of chronic renal failure over and above the agents' important antihypertensive effects.
300
CHAN & SCHRIER
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
Literature Cited I. Fleckenstein, A. 1983. Calcium Antag onism in Heart and Smooth Muscle Experimental Facts and Therapeutic Aspects. New York: Wiley 2. Braunwald, E. 1983. Mechanism of action of calcium channel-blocking agents. N. Engl. J. Med. 307: 1618-22 3. Schrier, R. W., Arnold, P. E., Van Putten, V. l., Burke, T.l. 1987. Cellular calcium in ischemic acute renal failure: role of calcium entry blocker. Kidney Int. 32: 312-21 4. Borle, A. B. 1981. Control, modulation, regulation of cell calcium. Rev. Physiol. Biochem. Pharmacol. 90: 13-153 5. Cheung, 1. Y., Constantine, 1. M., Bon ventre, 1. V. 1986. Regulation of cyto solie free calcium concentration in cul tured renal epithelial cells. Am. J. Physiol. 251: F690--701 6. Godfreind, T. 1987. Classification of cal cium antagonist. Am. J. Cardiol. 59: IIB-23B 7. Fleckenstein, A. , Fleckenstein-Grun, G., Frey, M., Zorn, J. 1987. Future direction in the use of calcium antag onists. Am. J. Cardiol. 59: 177B-87B 8. Barrett, R. J., Wright, K. P., Taylor, D. R., Proakis, A. G. 1988.Cardiovascular and renal action of calcium channel blocker chemical subgroup: a search for renal specificity. J. Pharm. Pharmacal. 40:408-14 9. Abe, Y., Komori, T., Miura, K., et a!. 1983. Effects of the calcium antagonist nicardipine on renal function and renin release in dogs. J. Cardiovasc. Phar macol. 5: 254-59 10. Bell, A. J., Lindner, A. 1984. Effects of verapamil on nifedipine on renal func tion and hemodynamics in the dog. Renal Physiol. 7: 329-43 II. Dietz, J. R., Davis, J. 0., Freeman, R. H., Villarrell, D., Echtenkamp, S. F. 1983. Effects of intrarenal infusion of calcium entry blockers in anesthetized dogs. Hypertension 5: 482-88 12. Loutzenhiser, R., Epstein, M. 1985. Effects of calcium antagonists on renal hemodynamics. Am. J. Physiol. 249: F6 I 6-29 13. Goldberg, J. P., Schrier, R. W. 1984. Effect of calcium membrane blockers on in vivo vasoconstrictor properties of norepinephrine, angiotensin II and vasopressin. Miner. Electro!. Metab. 10: 178-83 14. Loutzenhiser, R., Epstein, M. 1987. Renal hemodynamic effects of calcium antagonists. Am. J. Med. 82 (Supp!. 3): 23-28
15. Steele, T., Challoner-Hue, L. 1984. Renal interactions between norepin ephrine and calcium antagonists. Kidney Int. 26: 79-4 16. Christcnsen, C. K. , Ledcrballe, P. , Mikkelsen, E. 1982. Renal cffccts of acute calcium channel blockade with nifedipine in hypertensive patients. Clin. Pharmacal. Ther. 32: 572-76 17. Klutsch, K., Schmidt, P., Grosswendt, 1. 1972. Der Einftuss von Bay a 1040 an die Nierenfunktion des Hypertonikers. Arzneim-Florsch. Drug Res. 22: 377-80 18. Leonetti, G., Cuspid, c., Sampieri, L., Terzoli, L., Zanchetti, A. 1982. Com parison of cardiovascular, renal and humoral effects of acute administration of two calcium channel blockers in nor motensive and hypertensive subjects. J. Cardiovasc. Pharmacol. 4: S319-24 19. Yokoyama, S., Kaburagi, T. 1983. Clini cal effects of intravenous nifedipine on renal function. J. Cardiovasc. Pharma col. 5: 67-71 20. Reams, G., Hamory, A., Lau, A., Bauer, J. H. 1988. Effect of nifedipine on renal function in patients with essential hyper tension. Hypertension II: 425-456 21. Sunderrajan, S., Reams, G., Bauer, J. H. 1987. Long-term renal effects of dilti azem in essential hypertension. Am. Heart J: 114: 383-88 22. Bauer, J. H., Reams, G. 1987. Short and long-term effects of calcium entry blockers on the kidney. Am. J. Cardiol. 59: 66A-71A 23. Romero, J. C. , Raij, L., Granger, J. P., Ruilope, l. M., Rodicio, 1. L. 1987. Mul tiple effects of calcium entry blockers on renal function in hypertension. Hyper tension 10: 140--51 24. Chellingsworth, M. c., Kendall, M. 1. 1988. Effects of nifedipine, verapamil and diltiazem on renal function. Br. J. Clin. Pharmacal. 25: 599-602 25. Van Schaik, B. A. M., Van Nistelrooy, A. E. J., Geyskes, G. G. 1984 Anti hypertensive and renal effects of nitren dipine. Br. J. c/in. Pharmacol. 18: 5763 26. Steele, T. H. 1987. Calcium entry modu lation and renal hemodynamics in the hypertensive kidney. Am. J. Nephrol. 7 (Supp!. I): 17-23 27. Diamond, 1. R., Cheung, 1. Y., Fang, L. S. 1984. Nifedipine-induced renal dys function. Am. J. Med. 77: 905-8 28. Ter Wee, P. M., Ro sma n, 1. R., Van Der Geest, S. 1984. Acute renal failure due to diltiazem. Lancet 2:1337-38 29. Jsshike, T., Amodeo, c., Messerli, F. H.,
CALCIUM CHANNEL BLOCKERS
30.
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
31.
32. 33.
Pegram, 8. L., Frohlich, E. D. 1987. Diltiazem maintains renal vasodilata tion without hyperfiltration in hyperten sion: studies on essential hypertensive man and the spontaneous hypertensive rat. Cardiovasc. Drugs Ther. 1: 359-66 Bauer, J. H., Sunderrajan, S., Reams, G. 1985. Effect of calcium entry blockers on renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion and body fluid com position. Am. J. Cardiol. 56: 62H-67H Roy, M. W., Gurthrie, G. P. Jr., Holla day, F. P., Kotchen, T. A. 1983. Effects of verapamil on renin and aldosterone in the dog and rat. Am. J. Physiol . 245: E410-16 Farber, J. L. 1981. The role of calcium in cell death. Life Sci. 29: 1289-95 Conger, J. D., Robinette, J. 8., Schrier, R. W. 1989. Smooth muscle calcium and endothelium-derived relaxing factor in the abnormal vascular responses of acute renal failure.
532-37
35.
36.
37.
38.
39.
40.
41.
42.
43.
44. .
45.
J. Clin. Invest. 82:
34. Burke, T. J., Arnold, P. E., Gordon, J .
A., Bulger, R. E., Dobyan, D. C., Schrier, R. W. 1984. Protective effect of intrarenal calcium mcmbrane blockers before or after renal ischemia. 1. Clin. Invest. 74: 1830-41 Malis, C. D., Cheung, J. Y., Leaf, A., Bonventre, J. V. 1983. Effects of ver apamil in models of ischemic acute renal failure in the rat. Am. J. Physiol. 245: F735-42 Cheung, J. Y., Bonventre, J. V., Malis, C. D., Leaf, A. 1986. Calcium and isch emic injury. N. Engl. J. Med. 314: 167076 Goldfarb, D., Iaina, A., Serban, I., Gavendo, S., Kapuler, S., Eliahou, H. E. 1983. Beneficial effect of verapamil in ischemic acute renal failure in the rat. Proc. Soc. Exp. Bioi. Med. 172: 38992 Rose, H., Philipson, J., Puschett, J. B. 1987. Effects of nitrendipine in a rat model of ischemic acute renal failure. J. Cardiovasc. Pharmacol. 9 (Supp!. I): 5759 Bakris, G. I., Burnett, J. C. 1985. A role for calcium in radiocontrast-induced reductions in renal hemodynamics. Kid ney Int. 27: 465-68 Lee, S. M., Hillman, 8. J ., Clark, R. L., Michael, V. F. 1985. The effects of diltiazem and captopril on glycerol induced acute renal failure in the rat: functional, pathologic and microangio graphic studies. Invest. Radiol. 20: 96170 Wilson, D. R., Arnold, P. E., Burke, T.
301
J., Schrier, R. W. 1984. Mitochondrial
calcium accumulation and respiration in ischemic acute renal failure in the rat. Kidney Int. 25: 519-26 Arnold, P. E., Lumlertgul, D., Burke, T. J., Schrier, R. W. 1985. In vitro versus in vivo mitochondrial calcium loading in ischemic acute renal failure. Am. J. Physiol. 248: F845-51 Arnold, P. E., Van Putten, V. J., Lum lertgul, D., Burke, T. J., Schrier, R. W. 1986. Adenine nucleotide metabolism and mitochondrial Ca2+ transport fol lowing renal ischemia. Am. J. Physiol. 250: F357-63 Shapiro, J. I., Cheun�. c., Itabashi. A., Schrier, R. W.,Chan, L. 1986. The effect of verapamil on renal function after warm and cold ischemia in the isolated perfused rat kidney. Tran splantation 40: 596-600. Mills, S., Chan, L., Schwertschlag, V., Shapiro, J. I., Schrier, R. W. 1987. Pro tective effect of emopamil on renal func
46.
47.
48.
49.
50.
51.
52.
53.
tion following warm and cold ischemia. Transp lan tation 43: 928-30 Nakamoto, M., Shapiro, J. I., Mills, S., Schrier, R. W., Chan, L. 1988. Yer apamil improves renal preservation by cold perfusion in the isolated rat kidney. Transplantation 45: 313-15 Duggan, G. A., MacDonald, G. J., Charlesworth, J. A., Pussel, B. A. 1985. Verapamil prevents post-transplant oli guric renal failure. Clin. Nephrol. 24: 289 Korb, S., Albornoz, G., Brems, W., Ali, A., Light, J. A. 1989. Verapamil pre treatment of hemodynamically unstable donors prevent delayed graft function post-transplant. Transplant. Proc. 21: 1236-38 Wagner, K., Albrecht, S., Neumayer, H. H. 1986. Prevention of delayed graft function in cadaveric kidney trans plantation by a calcium antagonist. Pre liniinary results of two prospective ran domized trials. Transplant. Proc. 18: 510 Wagner, K., Henkel, M., Heinemeyer, G., Neumayer, H. H. 1988. Interaction of calcium blockers and cyc1osporine. Transplant. Proc. 20: 561 68 Meyer-Lehnert, H., Schrier, R. W. 1988. Cyclosporine A enhances vasopressin induced Ca2+ mobilization and con traction in mesengiaJ cells: a potential mechani&,m of nephrotoxicity. Kidney Tnt. 34: lW-97 Renton, K. W. 1985. Inhibition of hep atic microsomal drug metabolism by cal cium channel blockers diltiazem and ver apamil. Biochem. Pharmacol. 34: 54953 Grino, J. M., Sebate, I., Castelao, A. M.,
302
CHAN & SCHRIER
Alsina, J. 1986. Influence of diltiazem on cyclosporinc clearancc. Lancet I: 136 54. Howard, R., Shapiro, 1. I., Babcock, S., Chan, L. 1990. The effect of calcium
55.
Annu. Rev. Med. 1990.41:289-302. Downloaded from www.annualreviews.org by North Carolina State University on 03/27/13. For personal use only.
56.
57.
58.
channel blockers on cyclosporine dose requirement in renal transplant recipi ents. 1. Renal Failure. In press Weir, M. R., Peppler, R., Gomolka, D ., Handwerger, B. S. 1989. Additive inhibi tory effect of cyclosporine and verapamil may occur through different mech anisms that may be dependent or inde pendent of the slow calcium channel. Transplant. Proc. 2 1: 866-70 Wells, M. S., Vogelsang, G. B., Col ombani, P. M., Hess, A. D. 1989. Cyclo sporin A binding to calmodulin. Tra ns plant. Proc. 21: 850--52 Brenner, B. M. 1985. Nephron adap tation to renal injury or ablation. Am. 1. Physiol. 249: F324-37 Goligorsky, M. S., Chaimovitz, C.,
Rapaport, J., Goldstein, J., Kot, R. 1985. Calcium metabolism in uremic nephrocalcinosis: Preventivc effect of verapamil. Kidney Int. 27: 774-79 59. Harris, D. C. H., Hammond, W. S., Burke, T. J., Schrier, R. W. 1986. Ver apamil protects against progression of experimental chronic acute renal failure. Kidney Int. 31: 41-46 60. E1iahou, H. E., Cohen, D., Hellberg, B., Ben-David, A., Herzog, D., et al. 1988. Effect of the calcium channel blocker nisoldipine on the progression of chronic renal failure in man. Am. 1. Nephrol. 8: 285-90 61. larusiripipat, c., Zhou, H. Z., Shapiro, 1. I., Chan, L., Schrier, R. W. 1989. Effect of long-acting calcium channel blocker on blood pressure, renal func tion and survival of uremic rats. Pre sented at the Am. Soc. Nephrol., 22nd Annu. Meet., Dec. 1989
