Clinical and Experimental Hypertension. Part A: Theory and Practice
ISSN: 0730-0077 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/iceh19
Patterns of Renal Function in Hypertension Due to Unilateral Renal Artery Occlusion Yuji Tsuji, David A. Goldfarb, Zenjiro Masaki & Carlos M. Ferrario To cite this article: Yuji Tsuji, David A. Goldfarb, Zenjiro Masaki & Carlos M. Ferrario (1992) Patterns of Renal Function in Hypertension Due to Unilateral Renal Artery Occlusion, Clinical and Experimental Hypertension. Part A: Theory and Practice, 14:6, 1067-1081, DOI: 10.3109/10641969209038193 To link to this article: http://dx.doi.org/10.3109/10641969209038193
Published online: 03 Jul 2009.
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CLIN. AND EXPER. HYPER.-THEORY AND PRACTICE, A14(6), 1067-1081 (1992)
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PATTERNS OF RENAL FUNCTION IN HYPERTENSION DUE TO UNILATERAL RENAL ARTERY OCCLUSION
YUJITSUJI, DAVID A. GOLDFARB, ZENJIROMASAKI, AND CARLOS M. FERRARIO
Department of Brain and Vascular Research Research Institute The Cleveland Clinic Foundation Cleveland, Ohio 44195 KEYWORDS:angiotensin converting enzyme, blood pressure, 2-kidney l-clip hypertension, renovascular hypertension, renal function, CGS 16,617
ABSTRACT We performed renal function studies in dogs with chronic renovascular hypertension produced by complete occlusion of a renal artery. In addition, we evaluated in anesthetized dogs the acute effects of a novel angiotensin converting enzyme inhibitor, CGS 16,617, on renal function and plasma neurohormones (epinephrine, norepinephrine and vasopressin) 4 weeks after initiation of 2 kidney, 1 clip hypertension. CGS 16,617 effectively decreased blood pressure in renal hypertensive animals. This response was associated with suppression of angiotensin I1
Address for Correspondence: Carlos M. Ferrario, M.D. Chairman Department of Brain and Vascular Research Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, Ohio 44195 1067 Copyright 0 1992 by Marcel Dekker, Inc.
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indicating effective converting enzyme inhibition. In the non-clipped kidney, acute administration of CGS 16,617 increased effective renal plasma flow but not glomerular filtration rate and urinary sodium excretion. In the clipped kidney, CGS 16,617 caused no change in any parameter of renal function. Plasma norepinephrine, epinephrine and vasopressin were unaffected by administration of CGS 16,617. These studies showed that chronic occlusion of a renal artery does not result in renal infarction because of a compensatory increase in the amount of blood provided through capsular collateral vessels. The collateral circulation which has developed in the clipped kidney explains the lack of a converting enzyme inhibitor effect.
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I " The frequency of renovascular hypertension in the setting of diffuse abdominal atherosclerosis is receiving increased attention (1) as advances in medicine lead to a steady increase in the number of elderly persons in industrialized countries. The threat to renal function imposed by atherosclerotic renal artery disease is now a wellrecognized and important clinical issue (2). Patients with renal artery stenosis which affects the entire renal mass may be at risk for development of renal failure when their hypertension is treated with angiotensin converting enzyme inhibitors (3). Gradual occlusion of a renal artery may stimulate development of collateral circulation but the effectiveness of this compensatory response to renal ischemia in terms of preserving renal function or in response to reductions in renal perfusion pressure remains to be established. The effects of angiotensin converting enzyme (ACE) inhibitors on individual kidney function have been reported in rats (4) and acute canine models of renovascular hypertension (5). Less information is available regarding the effects of ACE inhibition on renal function in chronically ischemic kidneys. Inhibition of ACE augments renal blood flow (RBF), glomerular filtration rate (GFR) and urinary sodium excretion (UNa+) in the non-clipped kidney (4,6) but the action of these drugs on the clipped kidney are more complex and depend upon the seventy and duration of the stenosis (7).Because studies indicate that angiotensin I1 (Ang 11) plays a key role in maintaining clipped kidney GFR by preserving efferent arteriolar resistance, blocbde of Ang I1 may decrease GFR even though RBF remains stable (5). Given the importance of this subject we have revisited a further characterization of an experimental model for the production of unilateral renal hypertension in the dog. The technique used by us in the early 70s (8) to produce two kidney, one clip (2K,1C) hypertension relied on the growth of renal collateral vessels to supplant the surgical interruption of blood flow to a kidney. In these studies a renal artery was occluded via a two step clamping procedure that was spaced 14 days apart. This experimental model of hypertension seemed to us best suited to evaluate the degree of renal function that may be maintained in the presence of a chronic obstruction of the renal artery and
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the response of the ischemic kidney to inhibition of ACE. With this in mind we evaluated the effects of acute administration of a structurally novel ACE inhibitor, CGS 16,617 on blood pressure, individual kidney function and plasma neurohormones in dogs with chronic 2K, 1C renovascular hypertension.
METHODS
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Experiments were performed in 16 trained male mongrel dogs weighing 18-25
kg. Animals were fed a pellet diet (Purina Dog Chow) containing 65 mEqNa+/day. Water was given ad libitum. All surgical procedures were performed with halothane anesthesia (Fluothane, Ayerst Laboratories, New York, NY) following an intravenous (i.v.1 injection of sodium thiamyl(25 mg/kg, Surital? Parke-Davis, Morris Plains, NJ). After surgery, dogs convalesced for at least 1 week in individual pens and were monitored daily by a full-time veterinarian. Post-operative care included prophylactic antibiotics, analgesics, and measurements of body temperature, weight and food intake. Dogs were instrumented with a plastic catheter placed into an iliac artery (9). The free end of the catheter was tunneled through the subcutaneous tissue to the back of the dog's neck. In 11 of 16 dogs, 2K, 1C hypertension was produced according to the technique described by Masaki et al. (8). Briefly, the left renal artery was first constricted to 50% of its original diameter with an externally adjustable clamp. Two weeks later, the previously constricted renal artery was totally occluded from the outside. This two step procedure causes a form of renovascular hypertension that endures in dogs for many months. Arterial blood pressure and heart rate were recorded continuously for 30 min to 1 hr in dogs that were trained to rest quietly in a holding pen. A sample of arterial blood (14 ml) was taken during the control period (before renal artery clipping) and again on days 7,14,21 and 28 after renal artery occlusion. Renal Function Studies: In six of 11 renal hypertensive and five normal dogs, split renal function studies were performed after anesthesia with sodium pentobarbital (25 mg/kg, i.v., Nembutal@ Abbott Laboratories, North Chicago, IL). Animals were intubated and respired mechanically. The ureters were exposed through a small lower midline incision and individually catheterized with polyethylene tubing. The abdomen was closed, then dogs were given an i.v. infusion of 0.45% sodium chloride, 5% dextrose and 2% mannitol in water at a rate of 0.25ml/kg/min throughout the study. Split renal function studies were performed as described by Masaki et al. (4). 1251-iothalamate (Glofil, Iso-Tex Diagnostics, Friendswood, TX) and 1311-hippuran
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(Hippuran, CIS Radiopharmaceuticals, Bedford, MA) were infused at a rate based on 0.0025 pCi/ml x effective renal plasma flow (ERPF, ml/min), respectively. These infusions followed a priming dose of 0.5 pCi/kg (i.v.1 of each isotope. An initial 60-min equilibrium period achieved steady state levels of each indicator in plasma. Six consecutive 20-min clearance periods were obtained in each dog. After two 20-min control clearance periods, 0.02 mg/kg of the nonsulfhydryl ACE inhibitor CGS 16,617 (Ciba-Geigy, Summit, NJ) was infused i.v. and two clearances were then obtained. Then a larger dose of CGS 16,617 (0.2 mg/kg) was given i.v. followed by two 20-min clearance periods. Samples of arterial blood were collected at the midpoint of each clearance period for measurement of 1251-iothalamateand 1311-hippuran. GFR and ERPF were calculated as the clearance of 1251-iothalamate and 1311-hippuran, respectively. CGS 16,617 (3-[(5-amino-l-carboxy-lS-pentyl)amino],2,3,4,5-tetrahydro-2oxo-3S1H-l-benzazepine-l-aceticacid) is a novel inhibitor with a potency comparable to those found for other carboxyl ACE inhibitors (10). Neurohormonal Studies: In five of 11 renal hypertensive dogs, we determined the hormonal response to systemic administration of CGS 16,617. Animals were surgically prepared and given 2 doses of CGS 16,617 using protocols identical to those described above. On the other hand, 1251-iothalamateor 1311-hippuranwere not given because the label interfered with measurement of hormones by radioimmunoassay (RIA). Samples of arterial blood were drawn at the midpoint of each clearance period and analyzed for plasma renin activity (PRA),Ang 11, epinephrine (EPI),norepinephrine (NE) and arginine vasopressin (AVP). Biochemical Assays: Techniques for determination of plasma concentrations of Ang 11, PRA, EPI, NE, and AVP have been describe previously (11-14).Serum concentration of sodium (Na+), potassium (K+),creatinine and blood urea nitrogen (BUN) were measured using an auto-analyzer. Normal values and indices of intra- and inter-assay variability are described elsewhere (11-14). The concentrations of 1251-iothalamateand 1311-hippuran from aliquots of plasma and urine were counted in a gamma scintillation counter with a dualchannel pulse-height analysis system for the discrimination and simultaneous counting of 125I-and 1311. Data Analysis: All data are expressed as means
standard error of the mean. One-way and
two-way analysis of variance (ANOVA)for repeated measures were performed and changes were considered statistically significant at p < 0.05.
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RESULTS s of 2K.1C Hypertensior?;
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Table 1 shows average hemodynamic and laboratory values obtained before and during the 4 weeks that followed complete occlusion of a renal artery. Hypertension was associated with modest decreases in heart rate that attained statistical significance on days 7 and 24 after renal artery occlusion. Development of 2K, 1C hypertension was accompanied by a gradual rise in PRA that reached statistical significance (p c 0.05) on the last three weeks of the experiment. Plasma Ang I1 also increased gradually above baseline values but the angiotensinemia was statistically significant only at day 28 after renal artery occlusion. The established form of renovascular hypertension was also accompanied by mild hypokalemia but no changes in plasma Na+, creatinine and BUN concentrations (Table 1). Plasma levels of AVP, NE and EPI remained unchanged for the duration of the study. Table 2 shows the effects of acute inhibition of ACE activity on hormonal values. CGS 16,617 effectively inhibited the conversion of endogenous Ang I into Ang I1 as plasma levels of the active peptide were reduced by 93% within 20 min after administration of the ACE inhibitor at the lowest dose. Plasma levels of Ang I1 remained markedly suppressed during the period that corresponded to the second renal clearance and not further modified following delivery of CGS 16,617 at a 10-fold higher dose. Suppression of plasma Ang I1 was associated with increases in PRA but no significant changes in plasma catecholamines or vasopressin.
Effect 0f CGS 16.617 on Renal Hemodvnamics: Renal function data were obtained from both the clipped and nonclipped kidneys of six anesthetized hypertensive dogs. Baseline MAP averaged 162 f 9 mm Hg during the two clearance periods that precede administration of the drug. Infusion of the ACE inhibitor at a dose of 0.02 mg/kg reduced MAP to an average of 143 f 8 mm Hg during the 1st and 141 f 7 mm Hg during the 2nd clearance periods. These changes were statistically significant (p < 0.05) when compared with the values of blood pressure obtained before ACE blockade. Infusion of a larger dose of CGS 16,617 caused no further changes in MAP. Average values of MAP during administration of the 0.20 mg/kg dose were 139 f 7 mm Hg and 142 f7 mm Hg, respectively. Figure 1 summarizes the effects of CGS 16,617 on renal hemodynamics in both the clipped and non-clipped kidneys. Clearance studies showed significant differences in the baseline renal function between both kidneys. Urinary volume in the kidneys subjected to chronic occlusion of their renal artery was 29%of the values obtained in the
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TABLE 1. Laboratory Findings During the Evolution of Two-Kidney, One Clip Hypertension
Variable
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Before
7th Day
After Renal Artery Occlusion 14th Day 21st Day
28th Day
Mean Arterial Pressure (mm Hgj
88 2 2
Heart Rate (bpn)
83 * 2
76 * 4*
79 2 5
73 2 5*
76 2 5
Plasma Renin Activity (nglmllhr)
1.7 2 0.1
2.62 0.5
3.62 0.7*
6.3+1.6*
5.42 1.4*
Plasma Angiotensin I1 (pglml
13 2 2.
16%5
2225
49220
39212*
Plasma Vasopressin (pglml)
1.2 2 0.4
2.52 0.9
1.32 0.3
1.8 0.4
2.02 0.5
Plasma Norepinephrine (pglml)
162 2 21
133 2 16
126 2 13
108 2 20
101 2 18
Plasma Epinephrine (pglml
41 2 7
422 10
582 11
702 18
56%17
Serum Na+ (mEqll)
145 2 2
143+2
1452 1
141 2 1
1452 1
Serum K+ (mEqll)
4.2 2 0.2
3.920.1
4.020.1
3.720.1*
3.720.1*
Serum Creatinine (mgldl)
0.7 2 0.1
0.8rtO.1
0.8kO.1
0.820.1
0.8kO.1
24 * 2
24 % 2
27%1
262 2
23 % 2
Blood Urea Nitrogen (mgldl)
Values are means 2 SE from 11 conscious dogs developing renal hypertension. * = p < 0.05 compared to before production of 2K, 1C hypertension.
Variable
2.50 -+ 0.60
45 6
198 2 34
49.80 2 17.60
7.24 2 2.35
Baseline
3.20 2 1.00
101 2 45
215 2 52
3.40 -c 2.50 *
10.82 f 5.36
1st Period
3.40 2 1.30
682 11
205 2 16
4.10 2 2.50 *
10.89 f 5.55
2nd Period
3.40 2 1.20
63221
217 2 23
2.30 2 0.90
11.94 f 5.41
1st Period
2.30 2 0
43 2 1
208 2
1.20 2 0
11.68 f
2nd Per
CGS 16,617 (0.20 mglkg)
es are means f SE from five anesthetized dogs with renal hypertension of five week duration. * = p < 0.05vs control per
d
a Vasopressin
d
a Epinephrine
in)
a Norepinephrine
a Angiotensin I1 l)
llhr)
a Renin Activity
CGS 16,617 (0.02 mglkg)
TABLE 2. Effect of CGS 16,617 on The Blood Pressure and Plasma Neurohormone Values of 2K, 1 C Hypertension
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Control
CGS 16,617 (0.02 mglkg)
4
A = p < 0.05
CGS 16,617 (0.2 mglkg)
vs clipped kidney
-Ea- 3
si
$3
.-c5
1
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0
; a
60 50
c
.-0
cn
40
E .c = E 30 &=: 'E sc
2
20
0)
g
10
G
o
1st
2nd
1st
2nd
1st
2nd
1st
2nd
Ecn
O n
h.E 100
-E
gg
K-
.-ct
50
0
300 I
"
I
I
1st
2nd
I
1st
2nd
FIG.1: Comparative actions of acute systemic inhibition of angiotensin converting enzyme or renal function variables of the clipped (open bars) and non-clipped (hatched bars) kidneys of six dogs with chronic renovascular hypertension. Abbreviations are: 1st and 2nd, first and second clearance periods, respectively.
Variable
13f4
Values are means f SE from five anesthetized normal dogs. * = p c 0.05 vs control period.
14f4
10+3
Urinary K+Excretion (PEqlml)
12+4
36 2 20
40*20
1224
47 2 25
972 12
942 11
32 -t 4 9 2 2 11
33 2 3
33 2 3
322 3
0.74 2 0.12
94 f 9*
1st Period
92fll
0.78 2 0.15
102 k T*
2nd Period
0.74 2 0.13
94fF
1st Period
0.54 f0.04
110 f 6
Baseline
2 100 f 9*
12k4
47 2 30
9 3 2 11
32 2 4
0.85 2 0.17
"i
3 cl
m
v3
$
v3
Ez * r E
2nd Period
(0.20mglkg)
(0.02mglkg)
Urinary Volume (ml/min) Glomerular Filtration Rate (mllmin) Effective Renal Plasma Flow (mllmin) Urinary Na+ Excretion (~Eqlrnl)
(mm Hg)
Mean Arterial Pressure
CGS 16,617
CGS 16,617
TABLE 3. Effect of CGS 16,617 on The Blood Pressure and Renal Function of Normotensive Dogs.
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contralateral non-clipped kidneys. The reduced diuresis was associated with a marked reduction in urinary excretion of both Na+ (Figure 1) and K+. Kaliuresis averaged 25 f 5 pEq/min in the non-clipped kidneys and 4 f 1 pEq/min in the opposite counterpart (p < 0.05). These changes were associated with significant reductions of GFR and ERPF in the kidneys with an occluded renal artery. Administration of the ACE inhibitor caused no significant changes in renal function of the clipped kidneys both at the low and higher doses of CGS 16,617 (Figure 1). On the other hand, ACE inhibition caused a significant increase in ERPF of the non-clipped kidney that was sustained for all clearance periods and at both doses of the drug. To determine how the renal function in the occluded and non-occluded kidneys of hypertensive dogs compared to normal values, additional studies were done in normotensive dogs. Table 3 shows renal function variables in a group of normotensive anesthetized animals before and during inhibition of ACE. In normal dogs baseline values of urinary volume, urinary Na+ and K+ excretion and ERPF were not different from those measured in the clipped kidney of hypertensive animals. On the other hand, baseline GFR in normotensive dogs was 39%greater (p c 0.05) than in the clipped kidney of hypertensive dogs (Table 3 and Figure 1). In contrast, the untouched kidney of hypertensive animals showed enhanced excretory function because baseline values of urinary volume and urinary Na+ and K+ excretion averaged 211%, 1,092%and 150% above the values recorded in normotensive dogs, respectively (Figure 1 and Table 3). These differences were statistically significant (p c 0.05). The untouched kidneys of normotensive and hypertensive animals showed similar baseline values for ERPF, whereas GFR values were 22% higher (p < 0.05) in the non-clipped kidney of hypertensive dogs (Figure 1 and Table 3). Table 3 also shows that inhibition of ACE significantly decreased the blood pressure of normal anesthetized animals but had no effect on renal excretory and hemodynamic function.
DISCUSSlON The purpose of the present study was to investigate the effect of complete chronic occlusion of a renal artery on the renal function of the ischemic kidney before and following acute systemic inhibition of ACE. This model of renovascular hypertension afforded us the opportunity to evaluate the comparative function of the ischemic and non-ischemic kidneys in an experimental situation that bears similarities with the syndrome of chronic renal ischemia produced by severe atherosclerotic renal
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artery disease in humans (15). Our studies showed that chronic occlusion of a renal artery causes hypertension that is associated with significant reduction but not cessation
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of function in the occluded kidney. This possibility had been suspected in previous studies that used angiography (8) or histological examination (16)of the canine ischemic kidney. The decrease in renal function was primarily evidenced by a marked decrease in urine volume and electrolyte excretion when compared with the non-clipped kidney. Less profound decreases in GFR and ERPF were noted. On the other hand, urinary excretion of Na+ and K+ and ERPF were not different from those obtained from single measures of kidney function in normotensive animals. These data illustrate the remarkable capacity of renal collateral vessels to compensate for the suppression of blood flow through the main renal artery. In addition, we confirmed that the reduced excretory capacity of the ischemic kidney was associated with a marked increase in the function of the contralateral kidney both in terms of blood flow, production of urine and increased excretion of Na+ and K+. The changes in blood pressure and heart rate recorded in dogs developing a chronic form of 2K, 1C hypertension agree with previous findings obtained by this laboratory (8). This form of renovascular hypertension is accompanied by overactivity of the RAS as indicated by the increases in PRA and plasma Ang I1 concentrations. The use of anesthesia in the performance of split renal function studies did not mask the presence of hypertension or alter biochemical markers of Ang I1 hyperactivity. In addition, inhibition of ACE caused a depressor response that was associated with an almost complete elimination of circulating Ang 11. The magnitude of the depressor effect of CGS 16,617 is comparable to that reported elsewhere in anesthetized normotensive dogs (17). On the other hand, this is the first observation that CGS 16,617 Other decreases the blood pressure in a canine model of 2K, 1C hypertension. investigators (18,191 showed an antihypertensive effect of CGS 16,617 in conscious spontaneously hypertensive rats . In conscious 2K, 1C hypertensive dogs, we found that Sar1,Thfi-Ang I1 has a depressor effect in the acute but not the chronic phase of renovascular hypertension (8). A diminished depressor response to captopril has been reported also in the chronic phase of 2K, 1C hypertension in conscious dogs (20). The data obtained in the current experiments thus agree with the concept that the renal pressor system participates but does not entirely account for the increases in blood pressure found in the maintenance phase of renovascular hypertension. Our studies also showed that acute inhibition of ACE causes no changes in plasma levels of catecholamines or vasopressin. Ben and colleagues (21)noted that administration of captopril failed to elicit changes in plasma AVP. In contrast, studies
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in hypertensive patients have shown that chronic, but not acute, administration of captopril decreases plasma AVP (22). Previous experiments in our laboratory confirmed that this form of hypertension stimulates the development of compensatory hypertrophy in the kidney contralateral to the occluded one (8). Values for both GFR and ERPF were significantly greater in the non clipped kidney when compared to either the ischemic or normal kidneys from hypertensive and normotensive dogs, respectively. Therefore, the total renal mass available for filtration in both the ischemic and non-ischemic kidneys accounts for the absence of laboratory evidence of impaired renal function. The normal values of BUN and serum creatinine found in this model of renovascular hypertension are in keeping with this interpretation. The major renal hemodynamic effect of CGS 16,617 in the non-clipped kidney of hypertensive animals was to induce a significant rise in ERPF that was associated with a non statistically significant increase in GFR. These data agree with findings from past experiments performed in 2K, 1C hypertensive dogs (6). The renal vasodilator response of the non-clipped kidney to inhibition of ACE is due to a fall in post-glomerular resistance (6). Since ACE inhibitors block degradation of bradykinin, higher concentrations of circulating kinins may contribute to the vasodilator response (23). ACE inhibition had no effect on renal function parameters in the ischemic kidney. Prevailing concepts suggest that elevated intrarenal levels of Ang I1 maintain GFR in stenosed kidneys (5,7).In keeping with this interpretation it has been found that ACE inhibitors can reduced GFR in patients with bilateral renal artery stenosis (3) It is possible that the hemodynamic requirements of a kidney that is solely dependent on collateral circulation to maintain its function did not render GFR dependent on the intrarenal actions of Ang 11. Consistent with this explanation is.the observation by Ernst et al. (24) that renal vein renin from the clipped kidney of chronic 2K, 1C dogs returned toward normal with development of collateral circulation . An exaggerated Na+ excretion was observed for non-clipped kidneys compared to either the clipped or normotensive kidneys. This pressure related natriuresis in the unclipped kidney of 2K, 1C hypertensive dogs has been characterized by us previously (6). CGS 16,617 did not cause a statistically significant increase in Na+ excretion in any of our experimental groups, however, modest increases in Na+ excretion were noted in the non-clipped kidneys from both normal and hypertensive dogs. Na+ excretion is dependent upon blood pressure, GFR (filtered load of Na+) and tubular reabsorption. The lack of a significant response in the non-clipped kidneys may be explained by the counterbalancing effect of the fall in blood pressure. We have previously shown that
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Na+ excretion in the non-clipped kidney of this model is linearly dependent upon blood pressure and that the slope of this response is steep (6). Small decreases in blood pressure caused large decreases in Na+ excretion in 2K, 1C hypertensive dogs. In contrast, Huang et al. found increased Na+ excretion in the non-clipped kidney 2K, 1C rats given teprotide despite significant decreases in blood pressure (4). In their experiments teprotide caused a significant increase in the GFR of unclipped kidneys resulting in an increase in the filtered load of Na+. Ang I1 can also increase reabsorption of Na+ by a direct effect on proximal tubules (25,261. The increased Na+ excretion of the non-clipped kidney in response to ACE inhibitor treatment has been explained in part by reduced tubular Na+ reabsorption (26). In the present study CGS 16,617 resulted in a 20 mm Hg drop in blood pressure and no change in GFR. Together, these factors would decrease Na+ excretion. The modest but statistically insignificant increases in Na+ excretion observed for the non-clipped kidneys may result from decreased tubular reabsorption of Na+. Since the fractional excretion of Na+ was not measured, the contribution of tubular reabsorption of Na+ to the mild natriuresis cannot be precisely determined. In summary, our experiments showed that the collateral circulation of a kidney with a chronic complete occlusion of its renal artery is able to maintain a considerable degree of renal function. CGS 16,617 can effectively decrease blood pressure in 2K, 1C renal hypertensive and normotensive anesthetized dogs. In the renal hypertensive dogs blood pressure changes were associated with significant suppression of circulating Ang I1 indicating effective inhibition of converting enzyme. In the non-clipped kidney CGS 16,617 caused an increase in ERPF, no change in GFR and a modest non significant increase in sodium excretion. The response of the clipped kidney to CGS 16,617 is not consistent with the previously reported effects of ACE inhibitors on clipped kidney hemodynamics. We postulate that the collateral circulation found in this chronic model of renal ischemia maintains renal function.
ACKNOWLEDGEMENTS This work is supported in part by Grant HL-6835 from the NHLBI of the NIH and an educational grant provided by CIBA-GEIGY Company, Summit, New Jersey. We thank Dr. Mark Zimmerman, formerly of the CIBA-GEIGY Co. for his contributions in the design of the experiments.
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Bridle PA, Brosnihan KB, Speth RC, Goormastic M, Ferrario CM: Basal levels of plasma epinephrine and norepinephrine in the dog. Hyuertension 1983;5:(Suppl V):V-128-V-133
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Scheft P, Novick AC, Stewart BH, Straffon RA: Renal revascularization in patients with total occlusion of the renal artery. J Urol1980;124184187
16.
Ferrario CM, Helmchen UM, McCubbin JW:On the differences and similarities between the benign and malignant phases of renal hypertension. In: Recent Advances in Hypertension, Vol. 2. PL Milliez and M Safar (eds). Reims, France: Boehringer Ingelheim, 1975, pp 159-169.
17.
Levens NR Renal actions of the new angiotensin converting enzyme inhibitor CGS 16,617. Arch Int Pharmacodvn 1988;292266-280
18.
Zimmerman MB, Barclay BW, Lehmann M, Normal JA: Effects of chronic administration angiotensin converting enzyme (ACE) inhibitors on blood pressure and tissue ACE activity in theSHR.- Clin Exp Hvpertens (Theory and Practice) 1987;A9:473-476
19.
Levens NR, Ksander GM, Zimmerman MB, Mullane KM: Thromboxane synthase inhibition enhances action of converting enzyme inhibitors. HvDertension 1989;13:51-62
20.
Zimmerman BG, Mommsen C, Kraft C: Renal vasodilatation caused by captopril in conscious normotensive and Goldblatt hypertensive dogs (40896). Proc SOCEXDBiol Med 1980;164:459-465
21.
Ben LK, Maselli J, Keil LC, Reid IA: Role of renin-angiotensin system in control of vasopressin and ACTH secretons during the development of renal hypertension in dogs. HvDertension 1984;635-41
22.
Thibonnier M, Soto ME, Menard J, Aldiger JC, Corvol P, Milliez P: Reduction of plasma and urinary vasopressin during treatment of severe hypertension by captopril. Eur 1 Clin Invest 1981;11:449-453
23.
Hajj-ali AF, Zimmerman BG: Kinin contribution to renal vasodilator effect of captopril in rabbit. HvDertension 1991;17504509
24.
Ernst CB, Daugherty ME, Kotchen TA: Relationship between collateral development and renin in experimental renal artery stenosis. Sureery 1976;80:252-258
25.
Huang WC, Ploth DW, Navar LG: Angiotensin-mediated alterations in nephron function in Goldblatt hypertensive rats. Am 1 Phvsiol1982;243F553-F560
26.
Huang WC, Jackson CA, Navar LG: Nephron responses to converting enzyme inhibition in non-clipped kidney of Goldblatt hypertensive rat at normotensive pressures. Kidnev Internatll985; 28:128-134
Submission d a t e : 10/28/91 Date a c c e p t e d : 03/24/92
ISSN: 0730-0077 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/iceh19
Patterns of Renal Function in Hypertension Due to Unilateral Renal Artery Occlusion Yuji Tsuji, David A. Goldfarb, Zenjiro Masaki & Carlos M. Ferrario To cite this article: Yuji Tsuji, David A. Goldfarb, Zenjiro Masaki & Carlos M. Ferrario (1992) Patterns of Renal Function in Hypertension Due to Unilateral Renal Artery Occlusion, Clinical and Experimental Hypertension. Part A: Theory and Practice, 14:6, 1067-1081, DOI: 10.3109/10641969209038193 To link to this article: http://dx.doi.org/10.3109/10641969209038193
Published online: 03 Jul 2009.
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Date: 07 April 2016, At: 23:02
CLIN. AND EXPER. HYPER.-THEORY AND PRACTICE, A14(6), 1067-1081 (1992)
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PATTERNS OF RENAL FUNCTION IN HYPERTENSION DUE TO UNILATERAL RENAL ARTERY OCCLUSION
YUJITSUJI, DAVID A. GOLDFARB, ZENJIROMASAKI, AND CARLOS M. FERRARIO
Department of Brain and Vascular Research Research Institute The Cleveland Clinic Foundation Cleveland, Ohio 44195 KEYWORDS:angiotensin converting enzyme, blood pressure, 2-kidney l-clip hypertension, renovascular hypertension, renal function, CGS 16,617
ABSTRACT We performed renal function studies in dogs with chronic renovascular hypertension produced by complete occlusion of a renal artery. In addition, we evaluated in anesthetized dogs the acute effects of a novel angiotensin converting enzyme inhibitor, CGS 16,617, on renal function and plasma neurohormones (epinephrine, norepinephrine and vasopressin) 4 weeks after initiation of 2 kidney, 1 clip hypertension. CGS 16,617 effectively decreased blood pressure in renal hypertensive animals. This response was associated with suppression of angiotensin I1
Address for Correspondence: Carlos M. Ferrario, M.D. Chairman Department of Brain and Vascular Research Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, Ohio 44195 1067 Copyright 0 1992 by Marcel Dekker, Inc.
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indicating effective converting enzyme inhibition. In the non-clipped kidney, acute administration of CGS 16,617 increased effective renal plasma flow but not glomerular filtration rate and urinary sodium excretion. In the clipped kidney, CGS 16,617 caused no change in any parameter of renal function. Plasma norepinephrine, epinephrine and vasopressin were unaffected by administration of CGS 16,617. These studies showed that chronic occlusion of a renal artery does not result in renal infarction because of a compensatory increase in the amount of blood provided through capsular collateral vessels. The collateral circulation which has developed in the clipped kidney explains the lack of a converting enzyme inhibitor effect.
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I " The frequency of renovascular hypertension in the setting of diffuse abdominal atherosclerosis is receiving increased attention (1) as advances in medicine lead to a steady increase in the number of elderly persons in industrialized countries. The threat to renal function imposed by atherosclerotic renal artery disease is now a wellrecognized and important clinical issue (2). Patients with renal artery stenosis which affects the entire renal mass may be at risk for development of renal failure when their hypertension is treated with angiotensin converting enzyme inhibitors (3). Gradual occlusion of a renal artery may stimulate development of collateral circulation but the effectiveness of this compensatory response to renal ischemia in terms of preserving renal function or in response to reductions in renal perfusion pressure remains to be established. The effects of angiotensin converting enzyme (ACE) inhibitors on individual kidney function have been reported in rats (4) and acute canine models of renovascular hypertension (5). Less information is available regarding the effects of ACE inhibition on renal function in chronically ischemic kidneys. Inhibition of ACE augments renal blood flow (RBF), glomerular filtration rate (GFR) and urinary sodium excretion (UNa+) in the non-clipped kidney (4,6) but the action of these drugs on the clipped kidney are more complex and depend upon the seventy and duration of the stenosis (7).Because studies indicate that angiotensin I1 (Ang 11) plays a key role in maintaining clipped kidney GFR by preserving efferent arteriolar resistance, blocbde of Ang I1 may decrease GFR even though RBF remains stable (5). Given the importance of this subject we have revisited a further characterization of an experimental model for the production of unilateral renal hypertension in the dog. The technique used by us in the early 70s (8) to produce two kidney, one clip (2K,1C) hypertension relied on the growth of renal collateral vessels to supplant the surgical interruption of blood flow to a kidney. In these studies a renal artery was occluded via a two step clamping procedure that was spaced 14 days apart. This experimental model of hypertension seemed to us best suited to evaluate the degree of renal function that may be maintained in the presence of a chronic obstruction of the renal artery and
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the response of the ischemic kidney to inhibition of ACE. With this in mind we evaluated the effects of acute administration of a structurally novel ACE inhibitor, CGS 16,617 on blood pressure, individual kidney function and plasma neurohormones in dogs with chronic 2K, 1C renovascular hypertension.
METHODS
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Experiments were performed in 16 trained male mongrel dogs weighing 18-25
kg. Animals were fed a pellet diet (Purina Dog Chow) containing 65 mEqNa+/day. Water was given ad libitum. All surgical procedures were performed with halothane anesthesia (Fluothane, Ayerst Laboratories, New York, NY) following an intravenous (i.v.1 injection of sodium thiamyl(25 mg/kg, Surital? Parke-Davis, Morris Plains, NJ). After surgery, dogs convalesced for at least 1 week in individual pens and were monitored daily by a full-time veterinarian. Post-operative care included prophylactic antibiotics, analgesics, and measurements of body temperature, weight and food intake. Dogs were instrumented with a plastic catheter placed into an iliac artery (9). The free end of the catheter was tunneled through the subcutaneous tissue to the back of the dog's neck. In 11 of 16 dogs, 2K, 1C hypertension was produced according to the technique described by Masaki et al. (8). Briefly, the left renal artery was first constricted to 50% of its original diameter with an externally adjustable clamp. Two weeks later, the previously constricted renal artery was totally occluded from the outside. This two step procedure causes a form of renovascular hypertension that endures in dogs for many months. Arterial blood pressure and heart rate were recorded continuously for 30 min to 1 hr in dogs that were trained to rest quietly in a holding pen. A sample of arterial blood (14 ml) was taken during the control period (before renal artery clipping) and again on days 7,14,21 and 28 after renal artery occlusion. Renal Function Studies: In six of 11 renal hypertensive and five normal dogs, split renal function studies were performed after anesthesia with sodium pentobarbital (25 mg/kg, i.v., Nembutal@ Abbott Laboratories, North Chicago, IL). Animals were intubated and respired mechanically. The ureters were exposed through a small lower midline incision and individually catheterized with polyethylene tubing. The abdomen was closed, then dogs were given an i.v. infusion of 0.45% sodium chloride, 5% dextrose and 2% mannitol in water at a rate of 0.25ml/kg/min throughout the study. Split renal function studies were performed as described by Masaki et al. (4). 1251-iothalamate (Glofil, Iso-Tex Diagnostics, Friendswood, TX) and 1311-hippuran
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(Hippuran, CIS Radiopharmaceuticals, Bedford, MA) were infused at a rate based on 0.0025 pCi/ml x effective renal plasma flow (ERPF, ml/min), respectively. These infusions followed a priming dose of 0.5 pCi/kg (i.v.1 of each isotope. An initial 60-min equilibrium period achieved steady state levels of each indicator in plasma. Six consecutive 20-min clearance periods were obtained in each dog. After two 20-min control clearance periods, 0.02 mg/kg of the nonsulfhydryl ACE inhibitor CGS 16,617 (Ciba-Geigy, Summit, NJ) was infused i.v. and two clearances were then obtained. Then a larger dose of CGS 16,617 (0.2 mg/kg) was given i.v. followed by two 20-min clearance periods. Samples of arterial blood were collected at the midpoint of each clearance period for measurement of 1251-iothalamateand 1311-hippuran. GFR and ERPF were calculated as the clearance of 1251-iothalamate and 1311-hippuran, respectively. CGS 16,617 (3-[(5-amino-l-carboxy-lS-pentyl)amino],2,3,4,5-tetrahydro-2oxo-3S1H-l-benzazepine-l-aceticacid) is a novel inhibitor with a potency comparable to those found for other carboxyl ACE inhibitors (10). Neurohormonal Studies: In five of 11 renal hypertensive dogs, we determined the hormonal response to systemic administration of CGS 16,617. Animals were surgically prepared and given 2 doses of CGS 16,617 using protocols identical to those described above. On the other hand, 1251-iothalamateor 1311-hippuranwere not given because the label interfered with measurement of hormones by radioimmunoassay (RIA). Samples of arterial blood were drawn at the midpoint of each clearance period and analyzed for plasma renin activity (PRA),Ang 11, epinephrine (EPI),norepinephrine (NE) and arginine vasopressin (AVP). Biochemical Assays: Techniques for determination of plasma concentrations of Ang 11, PRA, EPI, NE, and AVP have been describe previously (11-14).Serum concentration of sodium (Na+), potassium (K+),creatinine and blood urea nitrogen (BUN) were measured using an auto-analyzer. Normal values and indices of intra- and inter-assay variability are described elsewhere (11-14). The concentrations of 1251-iothalamateand 1311-hippuran from aliquots of plasma and urine were counted in a gamma scintillation counter with a dualchannel pulse-height analysis system for the discrimination and simultaneous counting of 125I-and 1311. Data Analysis: All data are expressed as means
standard error of the mean. One-way and
two-way analysis of variance (ANOVA)for repeated measures were performed and changes were considered statistically significant at p < 0.05.
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RESULTS s of 2K.1C Hypertensior?;
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Table 1 shows average hemodynamic and laboratory values obtained before and during the 4 weeks that followed complete occlusion of a renal artery. Hypertension was associated with modest decreases in heart rate that attained statistical significance on days 7 and 24 after renal artery occlusion. Development of 2K, 1C hypertension was accompanied by a gradual rise in PRA that reached statistical significance (p c 0.05) on the last three weeks of the experiment. Plasma Ang I1 also increased gradually above baseline values but the angiotensinemia was statistically significant only at day 28 after renal artery occlusion. The established form of renovascular hypertension was also accompanied by mild hypokalemia but no changes in plasma Na+, creatinine and BUN concentrations (Table 1). Plasma levels of AVP, NE and EPI remained unchanged for the duration of the study. Table 2 shows the effects of acute inhibition of ACE activity on hormonal values. CGS 16,617 effectively inhibited the conversion of endogenous Ang I into Ang I1 as plasma levels of the active peptide were reduced by 93% within 20 min after administration of the ACE inhibitor at the lowest dose. Plasma levels of Ang I1 remained markedly suppressed during the period that corresponded to the second renal clearance and not further modified following delivery of CGS 16,617 at a 10-fold higher dose. Suppression of plasma Ang I1 was associated with increases in PRA but no significant changes in plasma catecholamines or vasopressin.
Effect 0f CGS 16.617 on Renal Hemodvnamics: Renal function data were obtained from both the clipped and nonclipped kidneys of six anesthetized hypertensive dogs. Baseline MAP averaged 162 f 9 mm Hg during the two clearance periods that precede administration of the drug. Infusion of the ACE inhibitor at a dose of 0.02 mg/kg reduced MAP to an average of 143 f 8 mm Hg during the 1st and 141 f 7 mm Hg during the 2nd clearance periods. These changes were statistically significant (p < 0.05) when compared with the values of blood pressure obtained before ACE blockade. Infusion of a larger dose of CGS 16,617 caused no further changes in MAP. Average values of MAP during administration of the 0.20 mg/kg dose were 139 f 7 mm Hg and 142 f7 mm Hg, respectively. Figure 1 summarizes the effects of CGS 16,617 on renal hemodynamics in both the clipped and non-clipped kidneys. Clearance studies showed significant differences in the baseline renal function between both kidneys. Urinary volume in the kidneys subjected to chronic occlusion of their renal artery was 29%of the values obtained in the
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TABLE 1. Laboratory Findings During the Evolution of Two-Kidney, One Clip Hypertension
Variable
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Before
7th Day
After Renal Artery Occlusion 14th Day 21st Day
28th Day
Mean Arterial Pressure (mm Hgj
88 2 2
Heart Rate (bpn)
83 * 2
76 * 4*
79 2 5
73 2 5*
76 2 5
Plasma Renin Activity (nglmllhr)
1.7 2 0.1
2.62 0.5
3.62 0.7*
6.3+1.6*
5.42 1.4*
Plasma Angiotensin I1 (pglml
13 2 2.
16%5
2225
49220
39212*
Plasma Vasopressin (pglml)
1.2 2 0.4
2.52 0.9
1.32 0.3
1.8 0.4
2.02 0.5
Plasma Norepinephrine (pglml)
162 2 21
133 2 16
126 2 13
108 2 20
101 2 18
Plasma Epinephrine (pglml
41 2 7
422 10
582 11
702 18
56%17
Serum Na+ (mEqll)
145 2 2
143+2
1452 1
141 2 1
1452 1
Serum K+ (mEqll)
4.2 2 0.2
3.920.1
4.020.1
3.720.1*
3.720.1*
Serum Creatinine (mgldl)
0.7 2 0.1
0.8rtO.1
0.8kO.1
0.820.1
0.8kO.1
24 * 2
24 % 2
27%1
262 2
23 % 2
Blood Urea Nitrogen (mgldl)
Values are means 2 SE from 11 conscious dogs developing renal hypertension. * = p < 0.05 compared to before production of 2K, 1C hypertension.
Variable
2.50 -+ 0.60
45 6
198 2 34
49.80 2 17.60
7.24 2 2.35
Baseline
3.20 2 1.00
101 2 45
215 2 52
3.40 -c 2.50 *
10.82 f 5.36
1st Period
3.40 2 1.30
682 11
205 2 16
4.10 2 2.50 *
10.89 f 5.55
2nd Period
3.40 2 1.20
63221
217 2 23
2.30 2 0.90
11.94 f 5.41
1st Period
2.30 2 0
43 2 1
208 2
1.20 2 0
11.68 f
2nd Per
CGS 16,617 (0.20 mglkg)
es are means f SE from five anesthetized dogs with renal hypertension of five week duration. * = p < 0.05vs control per
d
a Vasopressin
d
a Epinephrine
in)
a Norepinephrine
a Angiotensin I1 l)
llhr)
a Renin Activity
CGS 16,617 (0.02 mglkg)
TABLE 2. Effect of CGS 16,617 on The Blood Pressure and Plasma Neurohormone Values of 2K, 1 C Hypertension
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Control
CGS 16,617 (0.02 mglkg)
4
A = p < 0.05
CGS 16,617 (0.2 mglkg)
vs clipped kidney
-Ea- 3
si
$3
.-c5
1
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0
; a
60 50
c
.-0
cn
40
E .c = E 30 &=: 'E sc
2
20
0)
g
10
G
o
1st
2nd
1st
2nd
1st
2nd
1st
2nd
Ecn
O n
h.E 100
-E
gg
K-
.-ct
50
0
300 I
"
I
I
1st
2nd
I
1st
2nd
FIG.1: Comparative actions of acute systemic inhibition of angiotensin converting enzyme or renal function variables of the clipped (open bars) and non-clipped (hatched bars) kidneys of six dogs with chronic renovascular hypertension. Abbreviations are: 1st and 2nd, first and second clearance periods, respectively.
Variable
13f4
Values are means f SE from five anesthetized normal dogs. * = p c 0.05 vs control period.
14f4
10+3
Urinary K+Excretion (PEqlml)
12+4
36 2 20
40*20
1224
47 2 25
972 12
942 11
32 -t 4 9 2 2 11
33 2 3
33 2 3
322 3
0.74 2 0.12
94 f 9*
1st Period
92fll
0.78 2 0.15
102 k T*
2nd Period
0.74 2 0.13
94fF
1st Period
0.54 f0.04
110 f 6
Baseline
2 100 f 9*
12k4
47 2 30
9 3 2 11
32 2 4
0.85 2 0.17
"i
3 cl
m
v3
$
v3
Ez * r E
2nd Period
(0.20mglkg)
(0.02mglkg)
Urinary Volume (ml/min) Glomerular Filtration Rate (mllmin) Effective Renal Plasma Flow (mllmin) Urinary Na+ Excretion (~Eqlrnl)
(mm Hg)
Mean Arterial Pressure
CGS 16,617
CGS 16,617
TABLE 3. Effect of CGS 16,617 on The Blood Pressure and Renal Function of Normotensive Dogs.
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contralateral non-clipped kidneys. The reduced diuresis was associated with a marked reduction in urinary excretion of both Na+ (Figure 1) and K+. Kaliuresis averaged 25 f 5 pEq/min in the non-clipped kidneys and 4 f 1 pEq/min in the opposite counterpart (p < 0.05). These changes were associated with significant reductions of GFR and ERPF in the kidneys with an occluded renal artery. Administration of the ACE inhibitor caused no significant changes in renal function of the clipped kidneys both at the low and higher doses of CGS 16,617 (Figure 1). On the other hand, ACE inhibition caused a significant increase in ERPF of the non-clipped kidney that was sustained for all clearance periods and at both doses of the drug. To determine how the renal function in the occluded and non-occluded kidneys of hypertensive dogs compared to normal values, additional studies were done in normotensive dogs. Table 3 shows renal function variables in a group of normotensive anesthetized animals before and during inhibition of ACE. In normal dogs baseline values of urinary volume, urinary Na+ and K+ excretion and ERPF were not different from those measured in the clipped kidney of hypertensive animals. On the other hand, baseline GFR in normotensive dogs was 39%greater (p c 0.05) than in the clipped kidney of hypertensive dogs (Table 3 and Figure 1). In contrast, the untouched kidney of hypertensive animals showed enhanced excretory function because baseline values of urinary volume and urinary Na+ and K+ excretion averaged 211%, 1,092%and 150% above the values recorded in normotensive dogs, respectively (Figure 1 and Table 3). These differences were statistically significant (p c 0.05). The untouched kidneys of normotensive and hypertensive animals showed similar baseline values for ERPF, whereas GFR values were 22% higher (p < 0.05) in the non-clipped kidney of hypertensive dogs (Figure 1 and Table 3). Table 3 also shows that inhibition of ACE significantly decreased the blood pressure of normal anesthetized animals but had no effect on renal excretory and hemodynamic function.
DISCUSSlON The purpose of the present study was to investigate the effect of complete chronic occlusion of a renal artery on the renal function of the ischemic kidney before and following acute systemic inhibition of ACE. This model of renovascular hypertension afforded us the opportunity to evaluate the comparative function of the ischemic and non-ischemic kidneys in an experimental situation that bears similarities with the syndrome of chronic renal ischemia produced by severe atherosclerotic renal
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artery disease in humans (15). Our studies showed that chronic occlusion of a renal artery causes hypertension that is associated with significant reduction but not cessation
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of function in the occluded kidney. This possibility had been suspected in previous studies that used angiography (8) or histological examination (16)of the canine ischemic kidney. The decrease in renal function was primarily evidenced by a marked decrease in urine volume and electrolyte excretion when compared with the non-clipped kidney. Less profound decreases in GFR and ERPF were noted. On the other hand, urinary excretion of Na+ and K+ and ERPF were not different from those obtained from single measures of kidney function in normotensive animals. These data illustrate the remarkable capacity of renal collateral vessels to compensate for the suppression of blood flow through the main renal artery. In addition, we confirmed that the reduced excretory capacity of the ischemic kidney was associated with a marked increase in the function of the contralateral kidney both in terms of blood flow, production of urine and increased excretion of Na+ and K+. The changes in blood pressure and heart rate recorded in dogs developing a chronic form of 2K, 1C hypertension agree with previous findings obtained by this laboratory (8). This form of renovascular hypertension is accompanied by overactivity of the RAS as indicated by the increases in PRA and plasma Ang I1 concentrations. The use of anesthesia in the performance of split renal function studies did not mask the presence of hypertension or alter biochemical markers of Ang I1 hyperactivity. In addition, inhibition of ACE caused a depressor response that was associated with an almost complete elimination of circulating Ang 11. The magnitude of the depressor effect of CGS 16,617 is comparable to that reported elsewhere in anesthetized normotensive dogs (17). On the other hand, this is the first observation that CGS 16,617 Other decreases the blood pressure in a canine model of 2K, 1C hypertension. investigators (18,191 showed an antihypertensive effect of CGS 16,617 in conscious spontaneously hypertensive rats . In conscious 2K, 1C hypertensive dogs, we found that Sar1,Thfi-Ang I1 has a depressor effect in the acute but not the chronic phase of renovascular hypertension (8). A diminished depressor response to captopril has been reported also in the chronic phase of 2K, 1C hypertension in conscious dogs (20). The data obtained in the current experiments thus agree with the concept that the renal pressor system participates but does not entirely account for the increases in blood pressure found in the maintenance phase of renovascular hypertension. Our studies also showed that acute inhibition of ACE causes no changes in plasma levels of catecholamines or vasopressin. Ben and colleagues (21)noted that administration of captopril failed to elicit changes in plasma AVP. In contrast, studies
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in hypertensive patients have shown that chronic, but not acute, administration of captopril decreases plasma AVP (22). Previous experiments in our laboratory confirmed that this form of hypertension stimulates the development of compensatory hypertrophy in the kidney contralateral to the occluded one (8). Values for both GFR and ERPF were significantly greater in the non clipped kidney when compared to either the ischemic or normal kidneys from hypertensive and normotensive dogs, respectively. Therefore, the total renal mass available for filtration in both the ischemic and non-ischemic kidneys accounts for the absence of laboratory evidence of impaired renal function. The normal values of BUN and serum creatinine found in this model of renovascular hypertension are in keeping with this interpretation. The major renal hemodynamic effect of CGS 16,617 in the non-clipped kidney of hypertensive animals was to induce a significant rise in ERPF that was associated with a non statistically significant increase in GFR. These data agree with findings from past experiments performed in 2K, 1C hypertensive dogs (6). The renal vasodilator response of the non-clipped kidney to inhibition of ACE is due to a fall in post-glomerular resistance (6). Since ACE inhibitors block degradation of bradykinin, higher concentrations of circulating kinins may contribute to the vasodilator response (23). ACE inhibition had no effect on renal function parameters in the ischemic kidney. Prevailing concepts suggest that elevated intrarenal levels of Ang I1 maintain GFR in stenosed kidneys (5,7).In keeping with this interpretation it has been found that ACE inhibitors can reduced GFR in patients with bilateral renal artery stenosis (3) It is possible that the hemodynamic requirements of a kidney that is solely dependent on collateral circulation to maintain its function did not render GFR dependent on the intrarenal actions of Ang 11. Consistent with this explanation is.the observation by Ernst et al. (24) that renal vein renin from the clipped kidney of chronic 2K, 1C dogs returned toward normal with development of collateral circulation . An exaggerated Na+ excretion was observed for non-clipped kidneys compared to either the clipped or normotensive kidneys. This pressure related natriuresis in the unclipped kidney of 2K, 1C hypertensive dogs has been characterized by us previously (6). CGS 16,617 did not cause a statistically significant increase in Na+ excretion in any of our experimental groups, however, modest increases in Na+ excretion were noted in the non-clipped kidneys from both normal and hypertensive dogs. Na+ excretion is dependent upon blood pressure, GFR (filtered load of Na+) and tubular reabsorption. The lack of a significant response in the non-clipped kidneys may be explained by the counterbalancing effect of the fall in blood pressure. We have previously shown that
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Na+ excretion in the non-clipped kidney of this model is linearly dependent upon blood pressure and that the slope of this response is steep (6). Small decreases in blood pressure caused large decreases in Na+ excretion in 2K, 1C hypertensive dogs. In contrast, Huang et al. found increased Na+ excretion in the non-clipped kidney 2K, 1C rats given teprotide despite significant decreases in blood pressure (4). In their experiments teprotide caused a significant increase in the GFR of unclipped kidneys resulting in an increase in the filtered load of Na+. Ang I1 can also increase reabsorption of Na+ by a direct effect on proximal tubules (25,261. The increased Na+ excretion of the non-clipped kidney in response to ACE inhibitor treatment has been explained in part by reduced tubular Na+ reabsorption (26). In the present study CGS 16,617 resulted in a 20 mm Hg drop in blood pressure and no change in GFR. Together, these factors would decrease Na+ excretion. The modest but statistically insignificant increases in Na+ excretion observed for the non-clipped kidneys may result from decreased tubular reabsorption of Na+. Since the fractional excretion of Na+ was not measured, the contribution of tubular reabsorption of Na+ to the mild natriuresis cannot be precisely determined. In summary, our experiments showed that the collateral circulation of a kidney with a chronic complete occlusion of its renal artery is able to maintain a considerable degree of renal function. CGS 16,617 can effectively decrease blood pressure in 2K, 1C renal hypertensive and normotensive anesthetized dogs. In the renal hypertensive dogs blood pressure changes were associated with significant suppression of circulating Ang I1 indicating effective inhibition of converting enzyme. In the non-clipped kidney CGS 16,617 caused an increase in ERPF, no change in GFR and a modest non significant increase in sodium excretion. The response of the clipped kidney to CGS 16,617 is not consistent with the previously reported effects of ACE inhibitors on clipped kidney hemodynamics. We postulate that the collateral circulation found in this chronic model of renal ischemia maintains renal function.
ACKNOWLEDGEMENTS This work is supported in part by Grant HL-6835 from the NHLBI of the NIH and an educational grant provided by CIBA-GEIGY Company, Summit, New Jersey. We thank Dr. Mark Zimmerman, formerly of the CIBA-GEIGY Co. for his contributions in the design of the experiments.
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Olin JW, Vidt DG, Gifford RW Jr, Novick AC. Renovascular diseases in the elderly: an analysis of 50 patients. JACC 1985;5:1232-1238
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2.
Vidt DG, Eisele G, Gephardt GN, Tubbs R, Novick AC. Atheroembolic renal disease: association with renal arterial stenosis. Cleve Clin I Med 1989;56:407413
3.
Bender W, LaFrance N, Walker WG: Mechanism of deterioration in renal function in patients with renovascular hypertension treated with enalapril. Hvuertension 1984;6(SupplI):I-193-1-197
4.
Huang WC, Plotz DW, Bell PD, Work J, Navar LG: Bilateral renal function responses to converting enzyme inhibitor (SQ 20,881) in two-kidney, one clip Goldblatt hypertensive rats. Hvuertension 1981;3:285-293
5.
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Submission d a t e : 10/28/91 Date a c c e p t e d : 03/24/92
