renal adaptation to sodium deprivation: effect of captopril in the rat

SESSION I

Renal Adaptation to Sodium Deprivation

Effect of Captopril in the Rat

ALBERT MIMRAN. M.D.

BERNARD JOVER, B.S.

DANIEL CASELLAS, Ph.D.

Montepellier, France

Dietary sodium restriction is associated with a rapid decrease in urinary sodium excretion and achievement of a new sodium balance within three to five days. In addition, renal vasoconstriction and progressive activation of intrarenal systems with vasoconstrictor (renin-angiotensin) or vasodilating (kallikrein-kinin and prostaglandins) properties are observed. The relationship between sodium homeostasis and the renin-angiotensin system was assessed through the use of captopril in the rat. Treatment with captopril, before and during a six-day period after suppression of dietary sodium, was associated with sodium wasting (urinary sodium always exceeded sodium intake during the observation period); in addition, the normal increase in urinary aldosterone was blunted by about 80 percent. When captopril treatment was given for six days to rats maintained on long-term sodium restriction (at least four weeks) urinary sodium increased, although transiently; at the end of the study, renal vasodilatation together with a redistribution of glomerular blood flow to nonsuperficial glomeruli was observed. These studies indicate that captopril administration markedly blunts the renal and systemic adaptations to a reduced sodium intake in the rat. They suggest that the renin-angiotensin system is probably indispensable in preventing sodium loss when dietary sodium is suppressed.

The kidney plays a pivotal role in adapting to changes in sodium intake. Restriction of dietary sodium is associated with a rapid and marked decrease in the renal excretion of sodium to achieve a new steady state compatible with the maintenance of circulatory homeostasis. Almost a century ago Carl Ludwig observed that about three days were required to reach a new steady state when man was shifted from a normal sodium intake to a lower level of dietary sodium intake. Strauss et al [l] later demonstrated that the decrease in urinary sodium excretion in response to restriction of dietary sodium was exponential with a half-life of about 24 hours in adults.

From the Department of Medicine, Centre Hos- pitalier Universitaire, Montpellier, France. Re- quests for reprints should be addressed to Dr. Albert Mimran, Department of Medicine, Centre Hosoitalier Universitaire. 34059 Montoellier. Cedex, France. filtration rate and single nephron glomerular filtration of superficial

Despite the negative sodium balance, and thus the decrease in extracellular fluid volume, arterial pressure is maintained within values observed in animals fed a normal or high sodium diet, and cardiac output is unchanged or slightly decreased in sodium-deprived animals [2,3]. In addition, in most studies, restriction of sodium intake is associated with either a decrease [2,4,5] or no change [6-81 in glomerular filtration rate and a disorooortionate decrease in renal blood flow [2,5,8ithis resulting in an increase in the filtration fraction and probably in the efferent colloid osmotic pressure. Recent studies conducted in Munich-Wistar rats showed that whole kidney glomerular

14 May 31, 1964 The American Journal of Medicine

REGIONAL HEMODYNAMICS FOLLOWING CAPTOPRIL THERAPY-MIMRAN ET AL

glomeruii are either unaltered [7] or decreased [4] during two weeks’ sodium deprivation. Steiner et al [4] and Schor et al [ 71 both found that chronic sodium restriction was associated with a marked fall in glomerular ultrafiltration coefficient. The former group thought that this was sufficient to explain the decrease in glomerular filtration rate, whereas the latter group concluded that the maintenance of glomerular filtration rate at levels found in sodium repleted rats could be explained only through higher values of glomerular capillary pressure, which counterbalanced the lower glomerular blood flow values found in rats with low sodium intake. The dif- ferences between the findings of the two groups may, however, be due to the fact that a more marked degree of sodium depletion was achieved in the animals studied by Steiner et al [4], who used a low sodium diet and furosemide treatment.

In addition to changes in glomerular filtration rate, sodium deprivation is associated with intrarenal vasoconstriction, as suggested by the common finding of decreased total renal blood flow [2,3,5,8,9] and blood flow to superficial glomeruli [7]. Several groups have pointed out that renal adaptation to sodium deprivation may be sustained by changes in intrarenal distribution of blood flow consisting of a reduction in the perfusion of the outer cortical glomeruli that is larger than that in the juxtamedullary glomeruli as found in man with the xenon washout method [lo] and in rabbits with the radioactive microsphere technique [2]. However, in the rat, both methods failed to show a redistribution of intrarenal blood flow in response to chronic sodium deprivation [3,9,11]. In fact, when we combine our results (SEM) on total renal blood flow estimated with microspheres in anesthetized rats with high (n = 14) and low (n = 15) sodium intake (6.33 [f0.3] and 4.5 [f0.3] ml/min/g of kidney weight, respectively [3]) with the values of plasma flow to superficial glomeruli obtained in Munich-Wistar rats with similar dietary manipulation (113 [Jo 111 in rats with low sodium intake and 140 [& 121 nl/min in rats with high sodium intake [7]) it appears that both the flow to superficial glomeruli and whole renal blood flow are reduced to the same extent in response to sodium deprivation.

In addition to changes in renal hemodynamics, sodium restriction is associated with activation of the renin-angiotensin-aldosterone system together with an increase in the activity of endogenous and intrarenal systems with vasodilator and natriuretic properties (kallikrein-kinin system and prostaglandins). When dietary sodium is suppressed, plasma concentrations of renin, angiotensin II, and aldosterone increase signi- cantly within 24 to 36 hours [ 121 and reach a maximum within two to three weeks [ 13,141. Moreover, the renin content of renal tissue increases by approximately 50 percent within one week and more than doubles within

four weeks of sodium deprivation [ 131; in the rat, the intrarenal distribution of renin is unaltered when the ratio of renin content of superficial to juxtamedullary glomeruli is considered [ IS].

In several species, including man and rat, urinary kallikrein, an index of the activity of the renal kallikrein-kinin system, increases by 70 percent within one week and by approximately 200 percent after four weeks of dietary sodium restriction [ 16,171. Prosta- glandins are present in the cortical and medullary renal tissue, and prostaglandin-forming cycle-oxygenase activity was detected by an immunohistofluorescence technique in the renal cortex, predominantly in the en- dothelial cells lining the arterioles and in cortical col- lecting tubules in several species [ 181. In addition, predominant synthesis of prostacyclin and prostaglandin EP by glomerular epithelial and mesangial cells, respectively, was demonstrated [ 191. Stahl and co- workers [ 201 recently showed that renal biosynthesis as well as urinary excretion of prostaglandin E2 are markedly stimulated by chronic sodium restriction, primarily in the outer medulla and to a lesser extent in papilla and cortical tissue in the rabbit. These observations suggest that stimulation of prostaglandin and kallikrein release may counterbalance or modulate the intrarenal vasoconstrictor action of angiotensin II, thus minimizing the extent of renal ischemia that would occur in response to the reduction in intravascular volume associated with chronic sodium deprivation. This as- sumption is reinforced by the finding of a reduction in renal blood flow in rats on a low sodium intake given the prostaglandin synthesis inhibitor indomethacin [7,21] or treated for several days with aprotinin, a nonspecific inhibitor of rat renal kallikrein [22]. As already men- tioned, changes in the activity of endogenous vasoconstrictor as well as vasodilating substances are progressive and reach a maximum within several days or weeks, whereas maximum reduction in extracellular fluid volume occurs within three to five days after dietary sodium restriction. This suggests that the role of mechanisms that permit adaptation to manipulations of sodium intake might change when subjects are studied in the early (first week) or long-term (several weeks) phase of the process.

Whether changes in renal function and hemodynamics mediate the renal adaptation to sodium restriction or occur as a consequence of volume depletion remain to be elucidated. Since the renin-angiotensin system is rapidly activated by sodium depletion, the availability of agents that inhibit angiotensin II generation (converting enzyme inhibitors) or the vasoconstrictor action of angiotensin II at the receptor level (saralasin) has made it possible to assess the role of this endogenous system in the adaptation of the kidney to abrupt suppression of dietary sodium and when a new sodium

May 31, 1994 The American Journal of Medicine 15


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Tgure 1. Effecf of captopril (SO 14225) administration on water and sodium balances in rats on a high sodium intake. Note that natriuresis increased only when sodium intake was allowed to change.

balance has already been achieved after sodium deprivation.

EFFECT OF CAPTOPRIL TREATMENT IN THE SODIUM REPLETED STATE

As shown by Bengis et al [ 141, long-term oral administration (seven days) of captopril to rats on an ad libitum sodium intake is associated with a substantial and sustained increase in urinary water and sodium excretion; however, the amount of sodium ingested as well as changes in body weight were not reported. Analysis of their results shows that if sodium intake had been maintained at a constant level a markedly negative sodium balance of approximately 5 mmol (corre- sponding to 40 percent of total exchangeable sodium) would have developed.

We assessed the effect of a three-day period of captopril administration in rats maintained on a high sodium diet. When the daily intake of sodium was kept constant, no change in natriuresis occurred although a parallel but slight increase in water intake and urine volume was observed in response to captopril; how-

ever, when rats were given isotonic saline solution to drink, captopril administration was associated with an increase in urinary sodium that closely paralleled the increase in the intake of isotonic saline solution, thus resulting in no change in sodium balance (see Figure 1). These observations demonstrate that long-term treatment with captopril resulted primarily in an increase in fluid intake; however, this increase was more marked when isotonic saline solution rather than water was the drinking fluid, thus resulting in an increase in urinary sodium excretion. Similar observations on increased drinking during captopril treatment have been reported by others [ 14,231. These studies suggest that captopril may not possess a natriuretic efficacy in rats on a high sodium intake.

To explain the increased thirst induced by captopril while the generation of dipsogen angiotensin II was being inhibited by the agent, Schiffrin and Genest [23] performed studies suggesting an important role for captopril-induced accumulation of angiotensin I, con- verted into angiotensin II in sites of the brain inac- cessible to systemic captopril. With respect to the effect of captopril on renal hemodynamics and function in sodium-repleted animals, it was shown that intrarenal or systemic administration of the agent has a variable effect on renal vascular resistance. In conscious dogs, intrarenal administration of captopril at doses that se- lectively inhibited the renal vasoconstrictor action of angiotensin I (0.4 to 1.5 pug/kg per minute) had no effect on renal vascular resistance [24], whereas systemic administration of the agent at a markedly higher dose of 10 mg/kg plus 10 pg/kg per minute produced a slight decrease in arterial pressure and a 25 percent increase in renal plasma flow associated with an increase in glomerular filtration rate and natriuresis [25]. In anesthetized rats with a high sodium intake, renal blood flow slightly increased in response to a bolus injection of 0.25 mg of captopril [26].

Similar observations were made in sodium-repleted animals using the nonapeptide converting enzyme inhibitor, teprotide, which did not affect renal resistance when injected into the renal artery at a dose of 2 pg/kg per minute in the conscious dog [27]. In anesthetized dogs, intravenous administration of teprotide (I mg/kg) resulted in a decrease in arterial pressure and renal vasodilation associated with a redistribution of blood flow to the juxtamedullary cortex [ 281. In the anesthetized rabbit [2] and rat [30], teprotide had no effect on systemic and renal hemodynamics [2]. When sodium repleted dogs [27,29] or rats [26,30] were infused with the angiotensin-antagonist saralasin, no effect on renal function was observed; however, dose-related renal vasoconstriction related to the partial agonistic activity of saralasin was shown in rabbits with a high sodium intake [ 21.



From these studies, it appears that captopril has no detectable renal effect when administered at the min- imal dose required for consistent blockade of intrarenal conversion of angiotensin I. Therefore, under basal conditions the intrarenal renin-angiotensin system may have a limited role in the regulation of renal vascular tone and function. The finding that intravenous administration of captopril at high doses was associated with renal vasodilatation, an increase in glomerular filtration, and a natriuretic response [25] suggests that captopril may exert its action through a direct action on vascular smooth muscle cells, a decrease in adrenergic tone resulting from the disappearance of the potentiating action of angiotensin II on the response to norepi- nephrine, and, finally, an accumulation of kinins or prostaglandins. The last hypothesis is, however, unlikely since indomethacin did not alter the renal vasodilating effect of captopril in the sodium-repleted dog [24,25]. Although the influence of the dose of captopril on the effect of the agent on systemic and renal resistance in the salt-repleted state may be important, the lack of renovasodilator action of captopril in saralasin-infused animals [24] is an argument against a direct action of captopril on the renal vasculature and favors a con- tinuing role of intrarenal angiotensin even when the renin system is not activated.

EFFECT OF CAPTOPRIL PRETREATMENT ON THE RENAL RESPONSE TO ABRUPT SUPPRESSION OF DIETARY SODIUM

The mechanisms underlying the early renal response to abrupt suppression of dietary sodium have seldom been investigated. We recently assessed the influence of oral captopril treatment on the systemic and renal responses to sodium deprivation. Rats maintained for at least four weeks on a high sodium diet (low sodium chow plus 0.9 percent saline solution as drinking fluid) were housed in metabolic cages. After three daily urine collections, 12 rats (mean body weight 378 f 8 g) were given captopril dissolved in the drinking fluid (isotonic saline solution) at a concentration of 0.5 mg/ml, and urine collections were obtained for a further three days. Animals were then given the low sodium diet and dis- tilled water containing captopril as their drinking fluid for six days. In a group of 13 rats (control group, mean body weight 366 f 9 g), captopril was omitted. At the end of the studies, six animals of each group were anesthetized for the determination of arterial pressure and systemic and renal hemodynamics using the radioactive microsphere technique [2,31]. In the control group a new sodium balance was achieved within three to five days of sodium deprivation (urinary sodium 0.03 [ fO.0 11 mmol on day 5). As shown in Figure 2, in rats treated with captopril before and during sodium depri-

0 CONTROL Group In=13 I

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vation sodium balance was not achieved within the observation period, and sodium loss permanently exceeded intake in this group (natriuresis 0.12 [f0.04] mmol on day 5). The total amount of sodium excreted in the urine during the six-day period of sodium deprivation in these rats was 1.86 (f0.14) mmol, a value higher (p X0.001) than that of the control group (1.04 [f0.07] mmol). Moreover, the decrease in water intake and urine volume that occurred immediately after withdrawal of dietary sodium (-32 [f8] and -32 [f9] percent, respectively) in the control group was blunted but not suppressed in the captopril-treated group. In addition, the decrease in urinary potassium excretion associated with sodium restriction was not affected by treatment with the converting enzyme inhibitor whereas the increase in urinary excretion of aldosterone above the high salt level (-415 [f 1231 percent in the control



TABLE I Systemic and Renal Hemodynamics (mean f SEM) in Control and Captopril Pretreated Rats Submitted to Sodium Restriction for Six Days

Control Group Captopril-Treated

Group

Number 6 6 Mean arterial pressure 109 f 5 65f5’

(mm Hg) Cardiac output 194 f 16 220 f 13

(ml/min/kg body weight) Renal blood flow 5.5 f 0.5 8.6 f 1”

(ml/min/g kidney weight)

l p <0.05 compared with the control group

group) was blunted but not abolished by captopril (i-81 [k 161 percent). At the end of the studies, urinary ex-

cretion of creatinine, a good index of glomerular filtra-

tion, was similar in both groups. As summarized in Table I, arterial pressure was strikingly lower and renal blood flow consistently higher (i-56 percent) in rats treated with the converting enzyme inhibitor.

These studies show that renal adaptation to suppression of dietary sodium is markedly modified in captopril-treated rats. Preliminary experiments show that the sodium loss persists during the second week

UK V y mole/ day

UKallikreinV

7gure 3. Effect of long-term (six days) administration of captopril in chronically (at least four weeks) sodium-deprived rats.

of low sodium diet in rats treated with the converting enzyme inhibitor: however, discontinuation of the agent is immediately associated with a decrease in natriuresis to undetectable values. The finding of a low arterial pressure level in treated rats suggests that a decrease in extracellular fluid volume amounting to approximately 20 percent (if we assume an extracellular fluid volume of 160 ml/kg body weight in rats) may have striking consequences on arterial pressure regulation in the absence of a normally functioning renin-angiotensin system. In our laboratory, long-term treatment with captopril was associated with a moderate and less marked decrease in arterial pressure in rats that had been fed a sodium-free diet for at least four weeks [3 I]. Tucker and Blantz [32] recently made similar observations. This suggests that some mechanisms active in the long-term adjustment to a low sodium diet may tend to reduce the effectiverole of angiotensin in blood pressure regulation during long-term sodium deprivation.

The finding of a sodium-wasting state in captopril- treated rats despite low systemic pressure indicates that blockade of angiotensin II generation is associated with a shift to the left of the relationship between perfusion pressure and natriuresis and that the renin-angiotensin system is indispensable for the necessary reduction of sodium output in response to a decrease in arterial pressure. Among the mechanisms underlying the dis- turbances in renal adaptation to sodium restriction in rats treated by the converting enzyme inhibitor are (1) the marked blunting by captopril of the increase in aldosterone release associated with sodium deprivation; (2) accumulation of kinins resulting from blockade by captopril of kininase II, the main but not sole degradation enzyme of kinins; (3) activation of the intrarenal release of vasodilating prostaglandins either through a direct effect of captopril [33] or the increase in kinins; (4) renal vasodilatation per se or via a decrease in filtration fraction and thus peritubular oncotic pressure antici- pated in our experiments from the finding of higher renal blood flow and unchanged urinary excretion of creatinine in captopril-treated rats; and finally, (5) the removal by captopril of the direct tubular effect of angiotensin II.

In our studies, the increase in aldosterone release associated with sqdium restriction was blunted but not abolished by captopril (angiotensin blockade probably unmasked the effect on the adrenals of the slight re- tention of potassium associated with sodium deprivation); this could have contributed to the impairment in sodium conservation. It has, however, been reported that constant infusion of aldosterone does not modify the natriuretic effect of captopril in dogs on a low sodium diet [34] and that prevention of changes in aldosterone levels (by adrenalectomy and maintenance of constant aldosterone and cortisol levels similar to those


REGIONAL HEMODYNAMICS FOLLOWING CAPTOPRIL THERAP”.--MIMRAN ET AL

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I Outer Imr Fanth of Cortex , I F&we 4. Renal blood flow (RBF), blood pressure (MAP), and glomerular blood flow in control rats and after short- and long-term inhibition of the renin-angiotension system in rats on a low sodium intake. Asterisks denote p < 0.05 compared with values obtained in the control group.

found in the sodium-repleted state) did not affect the renal response to the abrupt suppression of dietary sodium in dogs with an intact renin-angiotensin system [8]. Although the dose of captopril used in our studies may have induced an increase in circulating kinins [35], it remains to be shown that such a change in kinins has a renal vasodilating and natriuretic potency. In fact, renal vasodilation together with the captopril-induced defi- ciency in the response of aldosterone and the absence of direct tubular action of angiotensin II probably contributed to the impairment in the renal capacity to conserve sodium when the intake was strikingly reduced.

EFFECT OF CAPTOPRIL IN LONG-TERM SODIUM DEPRIVATION

The role of the renin-angiotensin system in the regulation of arterial pressure and renal function in chronically sodium-deprived animals has been widely investigated through acute blockade of angiotensin II or converting enzyme [2,4,29,30,31]. These studies showed that angiotensin II participates in the regulation of arterial pressure and mediates the decrease in renal blood flow associated with long-term sodium restriction [ 2,3,27,29,30,31]. In addition, blockade of angiotensin failed in most studies to induce an increase in natriuresis [ 2,3 11; however, when renal perfusion pressure was kept constant, blockade of converting enzyme was associated with an increase in renal blood flow, a less marked increase in glomerular filtration rate, and a natriuretic response [27,36].

In recent studies we have compared the effects of short-term blockade of the renin-angiotensin system by saralasin or captopril with those of long-term administration of captopril in rats given a low sodium diet for at least four weeks [31]. The decrease in arterial pressure induced by short- or long-term blockade of angiotensin was similar and the final arterial pressure achieved in chronically sodium-deprived rats was clearly higher than the arterial pressure found in captopril-treated rats submitted to abrupt sodium restriction for six days (see Table I and Figure 4). These observations suggest that the influence of angiotensin on blood pressure regulation is progressively reduced during long-term reduction of dietary sodium. Whereas short-term administration of saralasin or captopril failed to induce changes in natriuresis and glomerular filtration, long-term treatment with captopril (Figure 3) elicited a natriuretic response similar to that observed by others [ 14,341 and was associated with a decrease in urinary aldosterone excretion. The contribution of such a change in aldosterone secretion to the natriuretic response to long-term captopril treatment remains uncertain since chronic superimposition of aldosterone in amounts sufficient to increase plasma aldosterone to precaptopril sodium-depleted levels did not alter the natriuretic effect of captopril [34]. As shown in Figure 4, renal blood flow was significantly higher in all treated groups than in rats on low sodium diets, and the esti- mation of the distribution of glomerular blood flow using the microsphere technique showed that a selective increase in blood flow to nonsuperficial glomeruli occurred in response to short- or long-term blockade of



angiotensin [31]. Although the use of microspheres for determining the intrarenal distribution of blood flow has been controversial, our studies suggest that redistribution of renal blood flow to inner cortical glomeruli may have occurred in response to the decrease in arterial pressure within the autoregulatory range, renal vasodilatation per se, and the intrarenal inhibition of the renin-angiotensin system.

The finding that captopril and saralasin had a similar effect does not favor a nonangiotensinogenic mechanism of action for captopril, at least in the rat. In addition, since redistribution of blood flow to the inner cortex occurred in experiments associated with either no natriuretic (saralasin and short-term captopril) or a natriuretic (long-term captopril) response to treatment, it is suggested that the relationship between renal blood flow distribution and sodium excretion is poor. The advent of more accurate methods for estimating glo-

merular blood flow distribution may help our under- standing of the precise relationship between changes in blood flow to the heterogeneous glomerular popu- lation and sodium balance.

The renal effects of captopril or other converting enzyme inhibitors are probably largely the consequence of inhibition of systemic and intrarenal generation of angiotensin II; however, participation of kinin accumulation or activation of intrarenal prostaglandin synthesis [33] and blunting of adrenergic mechanisms by captopril [37] may interfere. The present studies, mainly those on the effect of converting enzyme inhibition on the renal response to an abrupt suppression of dietary sodium, strongly suggest that one major function of the systemic and intrarenal renin-angiotensin system is to prevent a decrease in arterial pressure and sodium loss in response to sodium restriction.

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renal adaptation to sodium deprivation: effect of captopril in the rat

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