Volume expansion enhances the recovery of renal function and prolongs the diuresis and natriuresis after release of bilateral ureteral obstruction: a possible role for atrial natriuretic peptide.

Plasma atrial natriuretic peptide (ANP) levels are elevated in patients with bilateral ureteral obstruction (BUO). To further evaluate the role of ANP in postobstructive diuresis, natriuresis and recovery of renal function, 3 groups of dogs were studied: Group 1, 6 dogs that underwent 48 hours of unilateral ureteral obstruction (UUO); Group 2, 6 dogs that underwent 48 hours of BUO; and Group 3, 6 dogs volume replete with normal saline during 48 hours of BUO. All 3 groups underwent hourly hemodynamic and clearance studies for 15 hours after the release of obstruction. Group 1 experienced no increase in either urine output or sodium excretion from the ipsilateral or contralateral kidney after release of obstruction. Groups 2 and 3 both experienced an initial diuresis and natriuresis after BUO (p < 0.01). However, in Group 2 diuresis and natriuresis after BUO ceased at 5 and 2 hours, respectively, while in Group 3 both persisted for 10 and 9 hours, respectively. Before obstruction the GFR was similar in all three groups. In Group 1 the GFR decreased significantly in the ipsilateral kidney (34.5 +/- 1.4 to 14.48 +/- 1.5 ml. per minute, (p < 0.01)) and increased significantly in the contralateral kidney (32.4 +/- 2.8 to 44.4 +/- 2.0 ml. per minute, (p < 0.05)) and remained so throughout the postobstruction period. The GFR in Groups 2 and 3 decreased to a similar level 1 hour after release (13.3 +/- 1.7 and 17.5 +/- 3.4 ml. per minute, respectively); however, Group 2 remained decreased during the period after release while group 3 increased to 23.4 +/- 3.4 ml. per minute (p < 0.01) at 11 hours after release of obstruction. In Group 2 the control plasma ANP level was 17.9 +/- 3.7 pg./ml. and was not altered by BUO, whereas ANP increased significantly after 48 hour BUO in Group 3, from 30.6 +/- 6.7 to 63.7 +/- 11.7 pg./ml. (p < 0.01). Before and after 48 hours of BUO, the pulmonary capillary wedge pressure was 5.0 +/- 2.0 mm. Hg and 7.0 +/- 1.0 mm. Hg (NS) in Group 2, while it increased from 7.18 +/- 1.5 mm. Hg to 11.6 +/- 1.9 mm. Hg (p < 0.01) in Group 3. We conclude that volume expansion during BUO enhances postobstructive diuresis and natriuresis and allows a greater recovery of GFR after release of the obstruction. This effect may be mediated through elevated plasma levels of ANP as measured in this study.

Angiotensinogen depletion by high renin levels in hypertensive rats: no evidence for tonic stimulation of angiotensinogen by angiotensin II.

OBJECTIVE: Data concerning the effect of angiotensin II (Ang II) on plasma angiotensinogen levels are conflicting. Although Ang II is reported to stimulate the biosynthesis of angiotensinogen, plasma angiotensinogen is often depleted by renin when the level of renin, and therefore Ang II, increases. In the present study we used the Ang II subtype 1 (AT1) receptor antagonist losartan to investigate whether rising plasma Ang II levels stimulate angiotensinogen production to counteract the falling plasma angiotensinogen levels caused by increasing renin activity in plasma. METHOD: Angiotensinogen was measured in plasma from two previously reported studies in which 6-week-old stroke-prone spontaneously hypertensive rats (SHRSP) or Dahl salt-sensitive (Dahl-S) rats were fed high-salt diets (4 and 8% sodium chloride, respectively) for 10-12 weeks with or without losartan. RESULTS: As reported previously, plasma renin was suppressed during the first 4 weeks of the high-salt diet but then paradoxically increased in both strains. When plasma renin increased, plasma angiotensinogen levels fell to 45 and 62% of the baseline value. The plasma renin concentration was negatively correlated with plasma angiotensinogen both in SHRSP and in Dahl-S rats (r = -0.76, P < 0.001 and r = -0.60, P < 0.001, respectively). In Dahl-S rats losartan treatment was associated with lower levels of plasma angiotensinogen but caused greater increases in plasma renin. When differences in renin were taken into account, plasma angiotensinogen levels were not different in losartan-treated and untreated Dahl-S rats. Similarly to Dahl-S rats, plasma angiotensinogen fell in SHRSP when renin increased, but SHRSP had higher plasma angiotensinogen levels during losartan treatment because plasma renin concentration was lower. CONCLUSION: The present study shows, in two strains of hypertensive rat, that an increase in plasma renin levels is associated with a fall in plasma angiotensinogen levels. Concurrent treatment with an Ang II AT1 receptor antagonist does not augment this fall, except to the extent that renin rises further. The results provide no evidence for a significant tonic stimulatory effect of Ang II on plasma angiotensinogen levels.

Angiotensinogen dependency of blood pressure in two high-renin hypertensive rat models.

In this analysis we investigated whether angiotensinogen (Aogn) levels were related to blood pressure (BP) in two hypertensive rat models when renin secretion was either under physiologic regulation or out of control. These relationships were investigated using BP data from previous reports in which SHRsp and Dahl S rats were studied for 10 to 12 weeks while ingesting a high-salt diet with and without the angiotensin II (AngII) antagonist losartan. During the first 4 weeks of high-salt diet, plasma renin concentration (PRC) was appropriately suppressed but it subsequently increased paradoxically in both strains. During the first 4 weeks, when renin secretion was under normal control, as indicated by its suppression by the high-salt diet and by an inverse relationship between PRC and BP (r = -0.69, P < .001 and r = -0.53, P < .01 in Dahl S and SHRsp, respectively), there was no relationship between BP and plasma Aogn. In contrast, when renin secretion increased paradoxically, the inverse relationship between BP and PRC was lost and a positive relationship was found between BP and plasma Aogn in both Dahl S rats (r = 0.70, P < .01) and SHRsp (r = 0.57, P < .01). There was no relationship between BP and Aogn in either strain during treatment with losartan either before or after 4 to 6 weeks of salt feeding. These results show Aogn dependency of BP, but only under conditions in which renin cannot feed back normally. The Aogn relationship to BP was most likely dependent on the vasoconstrictor effect of AngII since it was lost during AngII AT1 receptor antagonism.

Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidence.

A comprehensive review of physiological and molecular biological evidence refutes claims for synthesis of renin by cardiac and vascular tissues. Cardiovascular tissue renin completely disappears after binephrectomy. Residual putative reninlike activity, where investigated, has had the characteristics of lysosomal acid proteases. Occasional reports of renin or renin mRNA in vascular and cardiac tissues can be ascribed to failure to remove the kidneys 24 hours beforehand, overloading of detection systems, problems with stringency in identification, and illegitimate transcripts after more than 25 cycles of polymerase chain reaction. Others, using more stringent criteria, have failed to detect cardiac and vascular renin mRNA. Accordingly, a growing number of investigators have concluded that the kidneys are the only source of cardiovascular tissue renin. Although prorenin is secreted from extrarenal tissues as well as from the kidneys, there is no evidence that it is ever converted to renin in the circulation. The kidney is the only tissue with known capacity to convert prorenin to renin and to secrete active renin into the circulation. Accordingly, renin of renal origin determines plasma and hence, extracellular fluid renin levels. In these loci, angiotensin (Ang) I, formed by renin cleavage of circulating and interstitial fluid angiotensinogen, is in turn cleaved by angiotensin converting enzyme, located in plasma and extracellular fluids and on the luminal surface of pulmonary and systemic vascular endothelial cells, to Ang II, which perfuses and bathes the heart and vasculature. Consistent with this model, plasma renin and angiotensin and the antihypertensive action of renin inhibitors, converting enzyme inhibitor, or Ang II antagonists all disappear after binephrectomy. Thus, the plasma renin level, via Ang II formation, determines renin system vasoconstrictor activity, the antihypertensive potential of anti-renin system drugs, and the risk of heart attack in hypertensive patients. This analysis redirects renin research to renal mechanisms that create the plasma renin level, to renal prorenin biosynthesis and its processing to renin, and to their regulated secretion, extracellular distribution, and possible binding to by target tissues. In this context, it is still possible that changes in circulating and interstitial renin substrate or available converting enzyme might exert subtle modulating influences on Ang II formation. However, this analysis redefines the importance of plasma renin measurements to assess clinical situations, because plasma renin is the only known initiator driving the cardiovascular renin-angiotensin system, and its strength can be measured.

Control of blood pressure and end-organ damage in maturing salt-loaded stroke-prone spontaneously hypertensive rats by oral angiotensin II receptor blockade.

OBJECTIVE: To study the effects of renin-angiotensin system blockade by a novel non-peptide angiotensin II receptor antagonist, losartan, on development of hypertension and acceleration of end-organ damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). DESIGN AND METHODS: One hundred and eighty-one male SHRSP were fed a 4% sodium diet from 6 to 18 weeks of age. Seventy-eight SHRSP were treated orally with losartan, 30 mg/kg per day. One hundred and three rats constituted untreated controls. Blood pressure, plasma renin activity (PRA), renal function and end-organ damage were monitored during the transition to malignant hypertension. RESULTS: Losartan prevented a blood pressure rise during the first 4 weeks of salt loading. Thereafter, blood pressure rose slowly in losartan-treated rats; however, at each time-point studied blood pressure was significantly lower in losartan-treated rats than in control rats. Losartan treatment increased PRA during the first 4 weeks, but this effect was not sustained. Thereafter, PRA decreased to control (week 0) levels. In contrast, 2 weeks after high-sodium feeding started, untreated SHRSP failed to suppress PRA appropriately; thereafter, PRA rose significantly. Losartan affected renal pathophysiology by blunting the decline in glomerular filtration rate, controlling proteinuria and preventing or delaying the appearance of malignant nephrosclerosis. Losartan treatment significantly increased survival and completely prevented cerebrovascular infarcts. CONCLUSIONS: The results indicate that angiotensin II blockade markedly reduces both hypertension and end-organ damage in chronically salt-loaded SHRSP and that the renin-angiotensin system may play an important role in the development of hypertensive cardiovascular disease in SHRSP.

Angiotensin II receptor antagonist delays renal damage and stroke in salt-loaded Dahl salt-sensitive rats.

OBJECTIVE: To study the effects of blockade of the renin-angiotensin system upon the development of hypertension, end-organ damage and mortality in Dahl salt-sensitive (DSS) rats using an angiotensin II receptor antagonist, losartan. DESIGN AND METHODS: DSS rats (n = 186) were fed 8% NaCl from 6 to 16 weeks of age. One group received losartan whilst the control group was untreated. Changes in blood pressure and plasma renin activity (PRA), as well as renal and cerebrovascular damage and survival were assessed during the study. RESULTS: Losartan blunted the blood pressure rise only transiently. Salt loading suppressed PRA in both groups until week 4 and thereafter it rose more markedly in the treated group. With no treatment renal lesions were first detected at 2 weeks, and strokes at 6 weeks. However, losartan transiently decreased the incidence and delayed the progression of renal damage and cerebrovascular lesions (strokes) and increased survival. PRA correlated with renal damage and the incidence of strokes in both groups. Blood pressure only partially affected survival, but did not correlate with stroke incidence. CONCLUSIONS: These results indicate that whereas the rise in blood pressure is dependent upon sodium loading, morbidity and mortality in salt-loaded DSS rats are associated with activation of the renin-angiotensin system and are only partially related to blood pressure.

The greater renin system. Its prorenin-directed vasodilator limb. Relevance to diabetes mellitus, pregnancy, and hypertension.

A greater renin system is proposed. Evidence is presented that a greater renin system exists that has both vasodilator and vasoconstrictor properties. Vasodilator activity is induced by prorenin, vasoconstrictor activity by renin. Our model is based on evidence that both prorenin and renin have the capacity to generate angiotensin and that angiotensin causes vasodilation at high concentrations and vasoconstriction at low concentrations. In our model, prorenin acts only at particular target sites while renin of renal origin acts via the general circulation. Prorenin's designation as a biosynthetic precursor implies lack of intrinsic catalytic activity whereas in fact it can become reversibly active. Activation may occur in vivo at binding sites without cleavage of the prosequence. In this framework, prorenin should be more aptly called renin I and circulating active renin, renin II. In our model, the role of renin I (prorenin) is to generate localized high concentrations of angiotensin II, eg, in the afferent arteriole of the kidney and in other vital organs, causing regional dilation by rendering tissues insensitive (tachyphylactic) to the vasoconstrictor effect of circulating angiotensin II or by releasing vasodilator substances. The role of renin II (active renin) is to constrict resistance vessels and the efferent arteriole of the kidney, thereby raising blood pressure, maintaining glomerular filtration rate, and enabling more blood flow to those organs that selectively bind prorenin. This twin control system is ideally designed to maintain blood flow to vital organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased plasma prorenin but not renin after bilateral ureteral ligation in dogs.

Plasma prorenin is normally higher than renin and usually changes in response to the same stimuli. In dogs, plasma prorenin and renin disappear after bilateral nephrectomy, indicating that both are of renal origin. It has been proposed that prorenin may mediate tissue renin systems via its reversible intrinsic renin-like activity. The renin-angiotensin system has been implicated in the changes in renal function that occur with bilateral ureteral obstruction, but plasma prorenin has not been investigated. We therefore studied the effect of 48-hour bilateral obstruction on plasma prorenin in two groups of dogs: one was volume expanded (N = 5), while the other group (N = 6) was euvolemic. Plasma prorenin concentration increased fourfold in both groups, angiotensinogen increased twofold, while plasma renin activity was unchanged. Following release of obstruction, plasma renin fell slightly while prorenin and angiotensinogen remained elevated. There was a positive relationship between plasma prorenin and renin before (r = 0.63, P less than 0.05) and after (r = 0.76, P less than 0.01) obstruction. Post-obstruction, ERPF and GFR were subnormal but filtration fraction was maintained; the higher the ERPF and GFR the higher the plasma prorenin post-obstruction (r = 0.83, P less than 0.01 and r = 0.77, P less respectively; N = 11). These results show that impairment of renal function during bilateral obstruction is associated with an increase in plasma prorenin but not renin. Nonetheless, there is a positive relationship between plasma prorenin and renin both pre- and post-obstruction. Thus, preferential impairment of clearance of prorenin relative to renin may occur during bilateral obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

DuP 753 increases survival in spontaneously hypertensive stroke-prone rats fed a high sodium diet.

We studied the effects of the nonpeptide angiotensin II receptor antagonist, DuP 753, on blood pressure, body weight, plasma renin activity, sodium excretion, and mortality in male stroke-prone spontaneously hypertensive rats (SHRsp) fed a 4% NaCl diet for 12 weeks. The rise in blood pressure, due to high sodium intake, was blunted in the first 8 weeks of the study in the DuP 753-treated group; however, it started slowly to rise in the following weeks. In the untreated group, blood pressure rose steadily and it was significantly higher than that of the treated group during the whole experimental period. DuP 753-treated rats gained weight continuously during the study in contrast to the untreated group, where weight gain was arrested after 4 weeks. Plasma renin activity rose significantly after 4 weeks of treatment with DuP 753; by week 6 its values returned to baseline values and remained at these lower values until week 12. In the untreated group, plasma renin activity was not suppressed by high sodium intake after 4 weeks; it continued to rise and it was significantly elevated by 8 and 12 weeks. Survival at 12 weeks was 84% in DuP 753-treated group and 26% in the untreated group. The data demonstrate that DuP 753 decreased mortality and dramatically blunted the blood pressure rise in SHRsp fed a high sodium diet.

Angiotensin II receptor antagonist markedly reduces mortality in salt-loaded Dahl S rats.

We investigated the effect of blockade of the renin-angiotensin system (RAS) on morbidity and hypertension in salt-loaded Dahl salt-sensitive (Dahl S) rats. Six-week-old male Dahl S rats (n = 198) were fed a high sodium diet (8% NaCl) for 10 weeks. One group of rats (n = 91) was treated with 30 mg/kg/day of the nonpeptide angiotensin II receptor antagonist, DuP 753, whereas the control group (n = 107) was left untreated. Blood pressure rose steeply in both groups, reaching levels above 200 mm Hg by week 6. DuP 753-treated animals were less hypertensive than controls between weeks 3 and 5 of the study, but had similar blood pressure before and after that time. Although the angiotensin II antagonist had only a transient effect on blood pressure it markedly prolonged survival. After 10 weeks, 68.3% of rats receiving DuP 753, but only 30.1% of controls, were still alive (P less than .0001). Higher morbidity in controls than in DuP 753-treated rats was also suggested by body weights. Following 6 weeks of high salt diet, untreated rats progressively lost weight while DuP 753-treated animals maintained a steady body weight. These results show that the angiotensin II receptor antagonist DuP 753 greatly enhanced survival in salt-loaded Dahl S rats although it reduced blood pressure only transiently. Our data are consistent with a contribution of the RAS to morbidity in this model of hypertension.

Effect of zinc depletion on angiotensin I-converting enzyme in arterial walls and plasma of the rat.

The effect of zinc depletion and of additional angiotensin I-converting enzyme (ACE) inhibitor treatment was studied on ACE in aortic and other tissues, in plasma and on systolic blood pressure of the rat. Zinc deprivation significantly reduced plasma zinc concentration, plasma and testicular ACE activities and blood pressure, but stimulated aortic ACE while lung values remained constant. Zinc deficiency combined with ACE inhibition further suppressed plasma ACE and stimulated the aortic enzyme earlier. Zinc repletion experiments (in vitro) suggest the existence of a feedback mechanism controlling ACE synthesis depending on plasma ACE activity.

Suppression of renin-angiotensin system in the heart of spontaneously hypertensive rats.

Renin-like enzyme and angiotensin converting enzyme (ACE) were identified and their specific activities measured in cardiac tissues of spontaneously hypertensive rats (SHR) and their Wistar-Kyoto (WKY) normotensive controls. In addition, the enzyme activities were determined following administration of hypotensive drugs. The pH optima of cardiac renin-like enzymes were identical with those in vascular walls, the specific activity being higher in the heart. Cardiac ACE revealed similarities with the venous wall enzyme. The highest specific cardiac renin-like activity was found in the septum and that of ACE in atria/auricles. Both enzyme values were lower in the hearts of SHR than in those of normotensive controls. Following nifedipine treatment, specific renin-like activities increased in all cardiac structures studied (P less than 0.01); with nitrendipine and muzolimine less pronounced elevations were obtained. Administration of these three hypotensive drugs resulted in a stimulation of ACE in all the cardiac structures except in atria/auricles, where their activities were lowered.

Effect of hypotensive agents on the renin-angiotensin system in vascular walls of spontaneously hypertensive rats.

Previous investigations have shown that the renin-angiotensin system (RAS) is activated in vascular walls of spontaneously hypertensive rats (SHR). The present study was undertaken to determine whether antihypertensive drugs attenuate this activation. Two calcium channel blockers, nifedipine and nitrendipine, and the diuretic muzolimine were applied to SHR for 2-4 weeks, and angiotensin (ANG) I-forming angiotensinogenase (AIFA) and ANG I converting enzyme (ACE) activities were determined. The values for both enzymes were elevated in arterial tissues of SHR (P less than 0.01), whereas in venous walls AIFA activity was decreased (P less than 0.01). All hypotensive drugs reduced arterial ACE activities in SHR (nifedipine and muzolimine: P less than 0.01; nitrendipine: P less than 0.05). Angiotensin I-forming angiotensinogenase activity was increased following treatment with nifedipine (P less than 0.01) but reduced by nitrendipine (P less than 0.05); with muzolimine, no significant alterations were observed. The results obtained indicate that in SHR, stimulation of vascular wall ACE is abolished following treatment with hypotensive agents, and the effect is independent of their mode of action. It is assumed that the activation of vascular ACE is not caused by, but rather a reaction to, elevated blood pressure.

The effect of zinc in vivo and in vitro on the activities of angiotensin converting enzyme and kininase-I in the plasma of rats.

Two groups of rats were pair fed, for 18 days, diets containing either 2.6 (Zn deficient) or 100 mg Zn/kg (control diet). Plasma was assayed spectrophotometrically for the activity of kininase-I and angiotensin converting enzyme (ACE) in the presence of varying concentrations of added Zn2+. Zinc deficient rats had only 76% of the activity of both kininase-I and ACE compared with zinc supplemented control rats. There was a significant linear relationship between enzyme activity and concentration of zinc in plasma for both enzymes. When zinc was added to the enzyme incubation mixture for zinc deficient rats, the activity of ACE increased by 73% and that of kininase-I by 33%. This Zn2+-stimulated increase in enzyme activity was negatively correlated with the in vivo concentration of zinc in plasma, and a plateau in enzyme activity was seen at concentrations of plasma zinc that were commensurate with normal zinc status (over 14 mumol/1). The results demonstrate that the activities of both kininase-I and ACE are dependent on the concentration of zinc in vivo and in vitro, and suggest that information concerning the concentration of zinc in plasma and assay solutions be a prerequisite solutions be a prerequisite for the use of these enzymes in the clinical diagnosis of disease states. The results also showed that the activity of ACE and kininase-I in plasma could be used for the biochemical diagnosis of a suboptimal zinc status.

Evidence for a potent angiotensin I degrading enzyme different from angiotensin I converting enzyme in rat vascular tissues.

There are indications for the existence of an intrinsic renin angiotensin system in vascular walls, which is assumed to participate in blood pressure regulation and in pathogenesis of arterial hypertension. It was evaluated if and to what extent the decapeptide angiotensin (A) I, one of the natural substrates of A I converting enzyme (ACE), is degraded by other peptidases than ACE in rat vascular tissues. A I and A II degradation was studied in arterial and venous vascular wall extracts. The activities ranged between 0.068 +/- 0.025 U and 0.044 +/- 0.025 U. The enzymes involved were biochemically characterized by determination of isoelectric points (pI), pH optima, molecular weights and by investigation of their inhibition behavior in vitro. One potent A I degrading enzyme (AIDE) was identified with pI between 3.6 and 3.9, and pH optimum at 7.75. In vitro studies revealed that AIDE activity was not blocked by the specific ACE inhibitors MK 421 or MK 422 (both 11 nMol/ml). The molecular weight of AIDE ranged between 440,000 and 457,000. The results indicate that AIDE is not identical to ACE (pI 4.2-5.0; pH optimum 8.3). AIDE was also observed in aortic smooth muscle cells cultured in vitro. AIDE decreased following bilateral nephrectomy or administration of aldosterone combined with sodium chloride loading, whereas it was elevated in spontaneously hypertensive rats (Okamoto strain). Since AIDE metabolizes A I, one of the substrates of ACE, it may indirectly affect A II formation and bradykinin inactivation as well.