AJH

1991;4:90-96

Synergistic Intrarenal Actions of Angiotensin on Tubular Reabsorption and Renal Hemodynamics L Gabriel Navar, Gaetano Saccomani, and Kenneth D. Mitchell

There is a g r o w i n g awareness that the direct intrare­ enhanced TGF sensitivity serves to m i n i m i z e or prevent TGF mediated increases in glomerular fil­ nal actions of angiotensin II (ANG II) on both tu­ tration rate in the face of reduced distal delivery. bular and vascular structures contribute to s o d i u m conservation. Even very l o w concentrations of A N G With greater increases i n interstitial A N G II con­ centration, reductions in glomerular pressure h a v e II ( 1 0 ) m o l / L ) stimulate proximal reabsorption b e e n observed, demonstrating a powerful action o n rate. Recent studies indicate that this stimulatory preglomerular arterioles that predominates over the action is d u e to an enhanced activity of the so­ w e l l k n o w n effects on efferent arterioles. At these d i u m / h y d r o g e n exchanger of the l u m i n a l m e m ­ brane. Elevated A N G II l e v e l s in the renal intersti- higher doses, the direct h e m o d y n a m i c actions of A N G II, plus the effects on the glomerular filtration tium, effected either through increased delivery of coefficient, w i l l directly reduce filtered s o d i u m A N G II via the circulation or as a consequence of load. Through these synergistic effects on both tu­ conversion of angiotensin I (ANG I) generated l o ­ bular reabsorptive and h e m o d y n a m i c function, cally, can also enhance proximal reabsorption rate. A N G II can elicit sustained decreases in distal O n e consequence of enhanced proximal reabsorp­ nephron s o d i u m delivery w h i c h contribute greatly tion rate is reduced distal v o l u m e delivery, w h i c h to its efficacy as a regulator of s o d i u m excretion. A m w o u l d be expected to elicit arteriolar vasodilation J Hypertens 1991;4:90-96 mediated b y the tubuloglomerular feedback (TGF) mechanism. It has b e e n observed, h o w e v e r , that peritubular capillary infusions of either A N G I or A N G II, at doses sufficiently l o w to be w i t h o u t ob­ KEY WORDS: Tubuloglomerular feedback, proximal v i o u s direct effects on glomerular dynamics, can reabsorption, sodium excretion, s o d i u m / h y d r o g e n increase the sensitivity of the TGF mechanism. This exchange, angiotensin conversion. -1

A

lthough it is clearly recognized that the renin - angiotensin system is of major impor­ tance in the control of sodium homeostasis and extracellular fluid volume, the contribu1

From the Department of Physiology, Tulane University School of Medicine, N e w Orleans, Louisiana (LGN, KDM), and the Department of Physiology and Biophysics, University of Alabama at Birmingham (GS). This research was supported by National Institutes of Health grants HL-35051, DK-39258, HL-18426, and HL-26371. Address correspondence and reprint requests to L. Gabriel Navar, PhD, Department of Physiology, Tulane University School of Medi­ cine, N e w Orleans, LA 70112.

© 1991 by the American Journal of Hypertension,

Inc.

tions of the various actions of A N G II to this overall process have not been clearly delineated. In addition to its effects on the peripheral circulation, the adrenal glands, and the nervous system, w e n o w know that A N G II can directly influence renal hemodynamics and tubular reabsorptive function. ' Interestingly, the ulti­ mate sodium conserving effect of A N G II appears to be orchestrated by a sequence of synergistic actions that include direct effects on tubular reabsorption rate as well as the more generally recognized actions on the micro vasculature. There is a growing awareness that these direct actions of A N G II on the kidney serve as a 2

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ANGIOTENSIN O N TUBULAR REABSORPTION

powerful c o m p o n e n t of the sodium conserving influ­ ence of A N G II. There are several m e a n s by w h i c h effective A N G II concentrations can be delivered to the responsive cells. Clearly, A N G II that is formed systemically, primarily by the angiotensin converting e n z y m e (ACE) localized on the endothelial cells of the lung, can h a v e a s u b ­ stantial effect on the kidney. In addition, renin may be secreted directly into the interstitium of the kid­ ney a n d there is apparently ample substrate present to allow the local intrarenal generation of angiotensin I (ANG I). It also seems clear that there are a d e q u a t e amounts of ACE so that A N G II can be formed as a consequence of intrarenally generated A N G I d u e to increased renin formation. It should also be recognized that the concentrations of A N G I in the circulation are approximately the same as A N G II a n d thus, A N G I delivered to the kidney can be converted to A N G II a n d exert a local effect. Data obtained by Rosivall et a l indicate that at least 2 0 % of systemically delivered A N G I can be converted to A N G II in a single pass t h r o u g h the kidney. Because the metabolic clearance rate by the kid­ ney of A N G II is very high (80 to 90%), it h a s b e e n pointed out that the A N G II that is delivered to the kidney is degraded very rapidly; therefore, the A N G II that is formed within the kidney is also probably d e ­ graded equally rapidly. Data related to the actual local tissue A N G II concentrations h a v e b e e n difficult to in­ terpret b u t the available m e a s u r e m e n t s suggest that these levels are higher t h a n can be accounted for on the basis of delivery rate. These data provide further s u p ­ port to the contention that a substantial a m o u n t of the locally active A N G II is formed within the kidney. Fi­ nally, it should be e m p h a s i z e d that the m o r e recent data on the molecular biology of the renin - angiotensin sys­ tem h a v e indicated that all of the c o m p o n e n t s , including the m R N A for angiotensinogen, h a v e b e e n found within the k i d n e y . ' The effects of A N G II on sodium excretion h a v e b e e n studied for m a n y years a n d were quite controversial initially. Some earlier papers reported that administra­ tion of renal extracts, renin, or angiotensin could cause m a r k e d diuresis a n d natriuresis in spite of the decrease in renal blood flow (RBF). As the experiments were re­ fined, it b e c a m e a p p a r e n t that smaller doses were pri­ marily antinatriuretic while larger doses could cause n a ­ triuresis either by a direct effect or as a consequence of the associated elevations in arterial pressure. The anti­ natriuretic effect of the lower doses w a s often associated with concomitant reductions in RBF a n d glomer­ ular filtration rate (GFR). As s h o w n by Barraclough et a l a n d Johnson a n d Mal v i n , however, it w a s possible to demonstrate antinatriuretic effects even in the absence of changes in GFR. This p h e n o m e n o n is illustrated in the data s h o w n from a recent series of experiments where efforts were m a d e to infuse the lowest doses that exerted the antinatriuretic effect (Figure 1). In these ex-

91

130 Arterial Pressure mmHg

Renal Blood Flow ml/min-g

120 110 5.0 4.0 1.1

GFR

1.0

ml/min-g .9

4

2

Urine Flow

6

8

3

9

10

1.0

ml/min 0.5

5

4

7

1.5

0 200 Sodium Excretion Rate uEq/min

150 100 50

Control

-L

Angiotensin II 2-3ng/min-kg

FIGURE 1. Effects of intrarenal arterial infusion of low doses (2-3 ng/kg/min) of ANG II in anesthetized dogs (n — 5). Dogs were treated for several days with a long-acting ACE inhibitor (lisinopril) and were also given a high salt diet to inhibit the renin-angiotensin system. On the day of the experiment, the dogs were given an acute infusion of another ACE inhibitor (enalaprilat; 1 mg/kg).

periments, dogs were maintained on a high s o d i u m chlo­ ride intake a n d the long lasting angiotensin converting e n z y m e (ACE) inhibitor, lisinopril, w a s administered for four to eight days prior to the experiment. Also, they were given an additional ACE inhibitor (enalaprilat; 1 m g / k g ) on the m o r n i n g of the experiment in order to avoid activation of t h e renin - angiotensin system during the acute experimental procedures. As is s h o w n in Figure 1, A N G II infusions at very low subpressor doses (2 to 3 n g / k g / m i n ) elicited substantial decreases in urine flow a n d s o d i u m excretion that w e r e not d e p e n d e n t on reductions in GFR. In this series of exper­ iments, GFR w a s not significantly altered a n d RBF w a s reduced only slightly. Thus, these effects o n s o d i u m excretion were the consequence of A N G II m e d i a t e d increases in fractional s o d i u m reabsorption rates. Fur­ thermore, the responses occurred rapidly within a few

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Ν Α V A R ET AL

m i n u t e s indicating that it w a s not necessary to activate aldosterone release in order for the responses to occur. Several m o r e direct studies h a v e b e e n conducted in order to unravel the m e c h a n i s m s responsible for angio­ tensin's action on the tubules. A l t h o u g h the early stud­ ies failed to s h o w a n y effect on proximal reabsorption or actually s u p p o r t e d a n inhibitory effect of A N G I I at b o t h proximal a n d distal tubular sites, Harris a n d Y o u n g reported that A N G II could exert b o t h stimulatory a n d inhibitory actions on t h e proximal tubule. Low concen­ trations in t h e range of 1 0 ~ m o l / L to 1 0 ~ m o l / L e n h a n c e d proximal reabsorption rate w h e r e a s high concentrations ( > 1 0 ~ m o l / L ) inhibited reabsorption rate. Similar data were obtained by Shuster et a l in isolated perfused proximal tubules. These data, coupled w i t h those s h o w i n g the presence of A N G II receptors on proximal cells, lent further support to the existence of a direct action of A N G II on the proximal tubule. While it is also possible that A N G II m a y directly influence distal tubule reabsorptive function as well, this h a s not b e e n clearly demonstrated. In all likelihood, the distal n e p h r o n s o d i u m conserving effect of the r e n i n angiotensin system is m e d i a t e d primarily by the actions of aldosterone. Using a n o t h e r a p p r o a c h to evaluate the possible ac­ tions of A N G II on tubule reabsorptive function, several studies h a v e assessed t h e effects of angiotensin block­ a d e o n proximal tubule reabsorption rate. In studies by Steiner et a l it w a s d e m o n s t r a t e d that s o d i u m depleted rats r e s p o n d e d to blockade of the angiotensin system with a receptor blocker, saralasin, with reductions in b o t h fractional a n d absolute proximal reabsorption rates. Since these were associated with modest increases in single n e p h r o n glomerular filtration rate (SNGFR), t h e obvious interpretation w a s that there w a s direct inhi­ bition of proximal reabsorption rate following receptor blockade. In a n o t h e r series of experiments performed by H u a n g et a l t h e responses of the nonclipped kidney of the Goldblatt hypertensive rat to a n ACE inhibitor, teprotide, were assessed. In this preparation, there are high circulating levels of A N G II d u e to the increased renin production by the stenotic kidney. H u a n g et a l s h o w e d that t h e nonclipped kidney of the Goldblatt hypertensive rat r e s p o n d e d to administration of a n ACE inhibitor with an increase in GFR. Again, b o t h fractional as well as absolute proximal reabsorption rates d e ­ creased. In b o t h of these studies absolute proximal reabsorption w a s decreased in t h e presence of increases in SNGFR suggesting that angiotensin blockade directly interfered with reabsorptive processes. These a n d sev­ eral other studies using inhibitors a n d blockers further support the view that angiotensin blockade interferes with the stimulatory influence of A N G II on proximal reabsorption rate. 11

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ated the effects of systemic infusions of A N G II on trans­ port of several constituents in early a n d late proximal tubule s e g m e n t s . They s h o w e d that in the early seg­ m e n t of the proximal tubule, there w a s a stimulation of net bicarbonate reabsorption rate along with v o l u m e reabsorption rate. They suggested that A N G II exerts its stimulatory effect on proximal transport t h r o u g h a m e c h a n i s m linked to the s o d i u m / h y d r o g e n exchanger. This pivotal issue of t h e ability of A N G II to increase proximal tubular reabsorptive function by stimulating luminal s o d i u m / h y d r o g e n exchange h a s b e e n tested di­ rectly in recent studies using intact proximal tubule cells isolated from r a b b i t s . ' Two specific types of re­ sponses h a v e b e e n evaluated. In one series of experi­ ments, isolated proximal cells were treated with ouabain a n d maintained in a sodium free m e d i u m . The rate of u p t a k e of N a w a s evaluated in either control cells or cells treated with A N G II. W h e n s o d i u m is a d d e d to the m e d i u m , the rate of influx of sodium into t h e cell is u s e d as a m e a s u r e of the activity of the transport m e c h a n i s m s w h i c h allow influx of sodium into the cell. As s h o w n in Figure 2, A N G II w a s able to e n h a n c e sodium u p t a k e by these cells. These stimulatory effects were exerted at concentrations of 1 0 ~ m o l / L , 1 0 ~ m o l / L , a n d 1 0 " 16

17

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More recent studies h a v e addressed specific aspects of t h e proximal actions of A N G II. Liu a n d Cogan evalu­

H

Ang II

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Amil

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FIGURE 2. Effects of ANG II, amiloride (Amil) and ANG II + Amil on the Na uptake and intracellular pH (pH) recov­ ery rates of isolated intact rabbit proximal tubule cells. The rate of Na uptake by sodium-depleted, ouabain-treated cells and the rate of pH recovery of sodium-depleted, acid-loaded cells were determined over the initial 10 sec following expo­ sure of the cells to 1 mmol/L Na and 100 mmol/L Na CI, respectively. Values shown represent the percent changes (mean ± SEM) in Na uptake and pH recovery rates caused by ANG II (10~ and 20~ mmol/L in the Na uptake and pH recovery experiments, respectively), Amil (0.5 and 1.0 mmol/L in the Na uptake and pH recovery experiments, respectively) and ANG II + Amil. Data are taken from Ref. 17 and 18. 22

22

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AJH-JANUARY

1991-VOL

4, NO. 1, PART 1

ANGIOTENSIN O N TUBULAR REABSORPTION

m o l / L . The A N G II-mediated e n h a n c e m e n t in sodium uptake w a s blocked by amiloride, indicating that A N G II increased s o d i u m u p t a k e by stimulating s o d i u m / h y drogen exchange. This w a s further evaluated in addi­ tional experiments in w h i c h w e used the p H sensitive fluorescent dye, BCECF [2',7'-bis(carboxyethyl)-5(6)carboxyfluorescein], to measure changes in intracellular pH in response to A N G II. First, the cells were acidified in a sodium free m e d i u m . Once sodium is a d d e d to the medium, the intracellular p H increases a n d the rate of increase appears to be primarily a function of the amiloride sensitive s o d i u m / h y d r o g e n exchanger. In the presence of A N G II, there w a s an augmentation of the rate of alkalinization t h u s indicating that A N G II w a s stimulating the s o d i u m / h y d r o g e n exchanger (Figure 2). Indeed, the differences in the rate of alkalinization b e ­ tween control a n d A N G II treated cells were abolished by amiloride. These data provide direct evidence s u p ­ porting the hypothesis that A N G II can directly stimu­ late the s o d i u m / h y d r o g e n exchanger and, in this m a n ­ ner, e n h a n c e net sodium a n d fluid reabsorption by the proximal tubule. While the studies in isolated proximal cells provide a means of examining cellular m e c h a n i s m s more directly, it should be recognized that neither these studies nor those involving systemic infusions of A N G II can allow discrimination regarding w h e t h e r the peptide is acting from the basolateral side, or from the tubule lumen. Studies h a v e clearly s h o w n that angiotensin receptors are present on b o t h sides of the cells a n d t h u s it is not clear w h a t w o u l d be the effects of increases in local interstitial concentrations of A N G II above the endoge­ nous levels. Based on data from Harris a n d Y o u n g a n d from Shuster et a l , it w o u l d seem that if the local con­ centrations were elevated b e y o n d some critical level of about 1 0 ~ m o l / L , t h e n further increases in interstitial ANG II concentrations w o u l d paradoxically inhibit proximal tubular reabsorption. This specific issue h a s been addressed recently using in vivo micropuncture methodology a n d the peritubular capillary infusion technique. By adding A N G I or A N G II directly into surrounding peritubular capillaries, the effects of baso­ lateral application on transport rate a n d n e p h r o n func­ tion can be determined. With this approach, t w o issues were considered. In one series of experiments, w e deter­ mined if addition of A N G II, above the normal e n d o g e ­ nous levels, w o u l d either a u g m e n t reabsorption rate or perhaps diminish it, if the concentrations were above those s h o w n to inhibit reabsorption rate in isolated per­ fused tubules. The other issue w a s w h e t h e r or not suffi­ cient conversion of A N G I to A N G II could occur locally within the interstitium at sites b e y o n d the glomerular circulation to elicit similar responses. This w a s a p ­ proached by infusing A N G I into the peritubular circu­ lation. Interestingly, these studies demonstrated that both A N G I a n d A N G II a d d e d to the peritubular capil­ 13

11

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93

lary system could diffuse out into the interstitium a n d e n h a n c e reabsorption rate. In o n e set of experiments, w e kept the doses in a range such that the filtration rate w a s not greatly altered in order to evaluate the action of the peptides on proximal reabsorption rate. It w a s d e m o n ­ strated that at these doses, there w e r e significant in­ creases in fractional reabsorption rate. As s h o w n in Fig­ ure 3, peritubular infusion of either A N G I or A N G II caused small decreases in SNGFR, b u t proportionally greater decreases in fluid flow out of the proximal tu­ bule. These effects w e r e d u e to the effects of A N G I a n d A N G II to increase fractional reabsorption rate. Indeed, with A N G II, proximal fractional reabsorption rate in­ creased from 45 ± 2 % to 53 ± 3 % a n d during A N G I infusions, proximal fractional reabsorption rate in­ creased to 59 ± 3 % . With further increases in the infu­ sion rates of either A N G I or II, w e observed substantial decreases in SNGFR, w h i c h t h e n precluded accurate assessment of reabsorption rate. With this experimental approach, n o inhibitory effects of angiotensin could be delineated because of concomitant reductions in SNGFR at higher infusion rates. These data indicate that increased interstitial concentrations of A N G II, above the e n d o g e n o u s levels, will cause a reduction in fluid flow out of the proximal tubule a n d into the distal n e p h r o n . The effects observed with A N G I w e r e of par­ ticular interest because they provided further s u p p o r t to the concept that increases in interstitial concentrations of A N G I, w h i c h could normally occur in response to a n increase in renin secretion, could i n d e e d b e converted to A N G II a n d exert local effects to alter proximal r e a b sorption rate. These effects of A N G I to increase reabsorption rate a n d decrease distal volume delivery were not observed if a n ACE inhibitor w a s infused along with A N G I (Figure 3). It should be recognized that effects of agents on prox­ imal reabsorption rate a n d v o l u m e delivery out of the proximal tubule w o u l d alter steady-state sodium deliv­ ery into the distal n e p h r o n segment only if they w e r e not counteracted by other regulatory m e c h a n i s m s w h i c h normally operate to maintain distal flow constant. H o w ­ ever, it is well recognized that the tubuloglomerular feedback (TGF) m e c h a n i s m serves such a function a n d w o u l d be expected to r e s p o n d to changes in distal flow a n d solute concentration a n d alter signals to the afferent arterioles. Presently, it is t h o u g h t that in­ creases in tubular fluid solute concentration at the level of the macula densa cells elicit alterations in macula densa cytosolic calcium concentration w h i c h t h e n leads to release of a vasoconstrictor mediator into the intersti­ tium surrounding the extraglomerular mesangial cells a n d afferent arterioles. Because the early distal N a C l concentration is directly related to the flow t h r o u g h the loop of Henle, A N G II mediated reductions in volume delivery could b e manifested as reduced N a C l concen­ trations at the macula densa. This w o u l d lead to feed20

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N A V A R ET AL

SUDAN BLACK STAINED CASTOR OIL

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peptide to alter the operating range a n d / o r sensitivity of the TGF mechanism. Fortuitously, t h e available data indicate that A N G II also serves as a very powerful regulator of the sensitivity of t h e TGF mechanism. Indeed, several studies h a v e s h o w n that t h e sensitivity of t h e TGF m e c h a n i s m is reduced b y angiotensin receptor blockers, such as saralasin, a n d b y ACE i n h i b i t o r s . ' In addition, it h a s b e e n s h o w n that systemic A N G II infusions given either to n o r m a l r a t s or Goldblatt hypertensive rats treated with ACE i n h i b i t o r s will increase t h e m a g n i t u d e a n d sensitivity of t h e TGF responses to alterations in distal volume delivery. In more recent studies, w e further a d ­ dressed t h e ability of interstitially generated A N G II to alter TGF sensitivity. Using t h e peritubular infusion technique previously described, experiments w e r e con­ ducted to determine if A N G II, w h e n increased in t h e interstitium of t h e kidney, will amplify t h e TGF re­ sponse to alterations in e n d proximal tubule perfusion. Both A N G I a n d A N G II were infused into t h e intersti­ tium, a n d stop flow pressure feedback responses were determined. As s h o w n in Figure 4, u n d e r n o r m a l condi­ tions, increasing t h e distal perfusion rate led to typical decreases in stop flow pressure reflecting decreases in glomerular pressure a n d afferent arteriolar vasoconstric­ tion mediated b y t h e tubuloglomerular feedback m e c h a ­ nism. Following t h e control determinations, peritubular capillary infusion of A N G I or A N G II w a s initiated at 20 n L / m i n ; however, for each experiment, t h e infusion rate w a s adjusted so that t h e resting stop flow pressure in t h e absence of distal n e p h r o n perfusion w a s n o t s u b ­ stantially decreased from t h e control value. In spite of the fact that t h e angiotensin infusion w a s n o t directly reducing glomerular pressure, there w a s a substantial augmentation of t h e TGF response to equivalent in­ creases in late proximal perfusion rate. W e observed this effect during peritubular capillary infusions of either A N G I or A N G II. Thus, e n h a n c e d interstitial A N G II generation, can clearly amplify t h e TGF m e c h a n i s m and, b y this mechanism, allow a n A N G II mediated reduction in distal flow to b e sustained. It s h o u l d also be e m p h a s i z e d that increasing t h e interstitial levels of A N G II further caused m a r k e d a n d consistent decreases in glomerular pressure a n d in SNGFR. W e h a v e not observed increases in glomerular pressure in response to increases in interstitial concentrations of A N G I a n d A N G II as w o u l d be expected if t h e p r e d o m i n a n t vascu­ lar effect of increased interstitial A N G II were o n the efferent arterioles. 21

35

1991-VOL

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FIGURE 3. Summary of the effects on single nephron GFR and late proximal fluid flow of peritubular capillary infusion, at a rate of 20nL/min, of ANG II (10~ mol/L), ANG I (10~ mol/L) and ANG 1 together with the ACE inhibitor, enalaprilat (MK422,10~ mol/L). The schematic figure (top) shows the positions of the pi­ pettes used to evaluate the single nephron GFR and late proximal fluid flow responses to peritubular capillary infusion of either ANG II, ANG I or ANG I + MK422. *P < .05; **P < .01 com­ pared with corresponding control (Con) value. Data are taken from Ref. 19. 7

5

3

back mediated afferent arteriolar vasodilation w h i c h w o u l d t h e n allow SNGFR to increase in a n effort to return distal delivery back to n o r m a l . Such effects w o u l d counteract t h e actions of A N G II o n proximal reabsorption rate a n d w o u l d help to restore distal n e p h r o n v o l u m e a n d s o d i u m delivery rate a n d t h u s nullify t h e actions of angiotensin on proximal reabsorp­ tion rate. T h e only w a y that this m e c h a n i s m w o u l d n o t nullify t h e actions of A N G II o n t h e proximal tubule w o u l d b e if there w e r e also a concomitant effect of t h e

In s u m m a r y , recent d e v e l o p m e n t s provide strong evi­ dence to support a n important intrarenal role of A N G II as a stimulator of proximal tubule reabsorption rate. At concentrations in t h e "physiological r a n g e " ( 1 0 ~ to 1 0 ~ m o l / L ) , angiotensin e n h a n c e s proximal reabsorp­ tion rate t h r o u g h a m e c h a n i s m mediated b y a n amilor­ ide inhibitable s o d i u m / h y d r o g e n exchanger. However, 9

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1991-VOL.

4, NO. 1, PART 1

wax blocking pipette ,,

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ANGIOTENSIN O N TUBULAR REABSORPTION

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20 10

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15 2 0

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LATE PROXIMAL PERFUSION RATE (nl/min)

FIGURE 4. Effects of peritubular infusions of ANG I and ANG II on stop-flow (SFP) pressure feedback responses to step increases in late proximal perfusion rate. These data are derived from Ref. 24. Control SFP tubuloglomerular feedback re­ sponses were obtained by varying the rate of distal nephron perfusion from a late proximal site. Then, per­ itubular infusion of either ANG II (1(Y mol/L) or ANG Ι(10~ mol/L) was initiated by infusing the solu­ tion at a low rate into the efferent arteriolar blood stream. The infu­ sion was varied slightly to minimize direct effects on SFP at zero distal perfusion rate. *P < .05; **P < .01 compared with corresponding con­ trol value. 7

30

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5

5 10 15 2 0 2 5 3 0 35 4 0 45 LATE PROXIMAL PERFUSION RATE (nl/min)

this effect m u s t be coupled with the ability of A N G II to increase the sensitivity of the TGF mechanism. This ac­ tion of A N G II is an integral part of the response w h i c h allows the proximal reabsorption effect to be reflected as a sustained change in distal tubular flow a n d sodium delivery. In essence, high A N G II levels sensitize the afferent arteriole to signals from macula densa cells; conversely, w h e n A N G II levels are reduced or the an­ giotensin receptors are blocked pharmacologically, the TGF m e c h a n i s m exhibits a m a r k e d reduction in sensitiv­ ity. This coupled action is probably the most physiologi­ cally relevant function of intrarenal A N G II at n o r m a l concentrations. These synergistic actions of A N G II act in concert to allow sustained changes in distal delivery. In turn, the consequences of the direct effects of A N G II on the kidney are c o m p o u n d e d by the indirect actions mediated by aldosterone on the distal n e p h r o n w h i ch further contribute to the efficacy of the renin angiotensin system as a homeostatic m e c h a n i s m for so­ dium conservation. Finally, it should be recognized that at higher concentrations or u n d e r conditions w h e r e the r e n i n - a n g i o t e n s i n system is being activated even further, A N G II directly vasoconstricts preglomerular as well as postglomerular resistance elements. Because A N G II at higher doses can reduce glomerular pressure a n d glomerular filtration rate, it seems unlikely that the inhibitory actions of higher concentrations of A N G II on proximal reabsorption rate are manifested in an in vivo setting because such concentrations, that may directly inhibit proximal reabsorption rate, w o u l d have concomitant effects to reduce the filtered load. The

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