The effects of altered sodium balance and adrenergic blockade on renin release induced in rats by angiotensin antagonism.

Circulating angiotensin II is said to inhibit renin release by a direct, intrarenal action. This effect of angiotensin was studied indirectly using the selective angiotensin II antagonist saralasin (1Sar-8-Ala-angiotensin II) in conscious normal, sodium-depleted, and sodium-loaded rats. Saralasin caused a dose-related increase in plasma renin concentration (PRC) in normal and sodium-depleted rats, but had no effect on PRC in sodium-loaded animals. However, saralasin was 300 times more active in sodium-depleted rats than in normal rats. Saralasin caused hypotension and tachycardia in sodium-depleted rats, but not in normals. Propranolol inhibited saralasin-induced renin release by 99% in normal rats and by 75% in sodium-depleted rats but not alter the hypotensive effect of saralasin in the latter. Saralasin potentiated phentolamine-induced renin release, hypotension, and tachycardia in normal rats, and this potentiated renin release was blocked by propranolol. We conclude that a portion of saralasin-elicited renin release in sodium-depleted rats is mediated by hypotensive activation of the carotid baroreceptor reflex which increases sympathetic nervous activity in the kidney. However, in sodium-depleted rats saralasin induced a 42-fold increase in PRC, whereas an equipotent hypotensive dose of the vasodilator hydralazine caused only a 3.5-fold increase in PRC. Thus, we find that saralasin appears to have a selective effect on renin release over and above its hypotensive effect, which suggests an angiotensin-mediated, feedback mechanism inhibitory to renin release. Thus, we have come to the conclusion that for part of saralasin-induced renin release appears to be caused by disinhibition of angiotensin suppression of renin secretion. This "short-loop" feed-back mechanism is closely associated with intrarenal beta-adrenergic receptors, since propranolol impaired saralasin-induced renin release under all circumstances in our experiments.     

Evidence for a renal alpha-adrenergic receptor inhibiting renin release.

The mechanism by which clonidine suppresses renin release was investigated in conscious rats. This suppression was studied by means of selected autonomic interventions in conjunction with changes in sodium balance. Serum renin activity and direct arterial pressure were monitored. Clonidine administration suppressed basal (by 68-85%), diuretic-induced (by 89%), and sympathetic nervous system-mediated (by 75-100%) renin release. Cholinergic, ganglionic, and peripheral sympathetic neuronal blockade did not prevent this inhibitory effect of clonidine. These results indicate a peripheral site of action for suppression of renin release by clonidine. The alpha-adrenergic blocking drug phentolamine prevented clonidine suppression of renin release in sodium-depleted rats and was partially effective in normal rats. Phentolamine blocked the decrease in renin caused by clonidine in ganglion-blocked rats. Clozapine, a new neuroleptic agent with alpha-adrenergic blocking activity, or phenoxybenzamine blocked the effect of clonidine on renin release in both sodium-depleted and normal rats. After ganglionic blockade in sodium-depleted rats, clonidine caused a significantly greater suppression of renin release than did an equipressor dose of methoxamine. These data, combined with hemodynamic correlates, suggest that clonidine inhibits renin release by activation of an intrarenal alpha-adrenergic receptor.     

An orally active inhibitor of renin

A potent renin inhibitor, U-71038 (Boc-Pro-Phe-N-MeHis-Leu psi[CHOHCH2]Val-Ile-Amp), was tested for oral effectiveness. Enzyme kinetic studies indicated that U-71038 was a competitive inhibitor of hog renin with an inhibitor constant (Ki) value of 12 nM. Intravenous as well as oral administration of U-71038 to anesthetized, ganglion-blocked rats infused with hog renin elicited dose-related hypotensive responses. Intravenous administration of U-71038 to conscious, sodium-depleted monkeys caused dose-related decreases of blood pressure and plasma renin activity without affecting heart rate. Similarly, the oral administration of U-71038 at 50 mg/kg to conscious, sodium-depleted monkeys elicited a pronounced hypotension and decrease in plasma renin activity that persisted for 5 hours. The hypotensive responses elicited by intravenous and oral administration of U-71038 to hog renin-infused rats and sodium-depleted monkeys were shown to be due entirely to inhibition of the renin-angiotensin system. A comparison of the results obtained after the intravenous administration of U-71038 with the results obtained after the oral administration of U-71038 implied that at least 10% of the orally administered U-71038 must have been absorbed to cause the observed effects in hog renin-infused rats and sodium-depleted monkeys. The studies demonstrated that an inhibitor of renin with a long duration of action and with oral effectiveness is a feasible entity.     

Des-1-Asp-angiotensin II. Possible intrarenal role in homeostasis in the dog.

The relative effects of des-a-Asp-angiotensin 3I and angiotensin II on renal function, including renin secretion, were investigated in normal and sodium-depleted dogs. Intrarenal arterial infusion of the heptapeptide fragment into normal dogs at a rate which was calculated to increase blood levels by only 7 ng/100 ml decreased renal blood flow from 254 +/- 9 ml/min to 220 +/- 12 and 219 +/- 12 ml/min (P less than 0.01 for both values) after 10 and 30 minutes of infusion, respectively; renin secretion decreased from 502 +/- 214 ng/min to 253 +/- 109 and 180 +/- 53 ng/min (P less than 0.05 for both values). Infusion of angiotensin II at the same rate decreased renal blood flow from 251 +/- 26 ml/min to 224 +/- 22 and 220 +/- 16 ml/min (P less than 0.01 and 0.025, respectively) and decreased renin secretion from 374 +/- 25 ng/min to 166 +/- 76 and 131 +/- 37 ng/min (P less than 0.025 for both values). Neither peptide significantly changed mean arterial blood pressure, creatinine clearance, or excreted sodium in these dogs. Infusion of des-1-Asp-angiotensin II into sodium-depleted dogs decreased renin secretion from 1094 +/- 211 ng/min to 768 +/- 132 and 499 +/- 31 ng/min (P less than 0.025 for both values) after 10 and 30 minutes of infusion. Angiotensin II infusion decreased renin secretion from 1102 +/- 134 to 495 +/- 235 and 502 +/- 129 ng/min in these dogs (P less than 0.05 and 0.025, respectively). Neither peptide significantly altered renal blood flow, arterial blood pressure, creatinine clearance, or excreted sodium in the sodium-depleted dogs. The data demonstrated that these two peptides have similar effects on the renin secretory mechanism and the vascular receptor at the level of the renal arterioles.     

Changes of Plasma Renin Activity by Intracerebroventricular Administration of Biological Active Peptides in Conscious Rats

We studied the effects of intracerebroventricular administration of angiotensin II (ANG II), bradykinin (BK), leucine-enkephalin (Leu-ENK) and neurotensin (NT) on plasma renin activity (PRA), blood pressure and heart rate in conscious and unrestrained rats. Five μ1 of each peptide solution was injected into the lateral cerebral ventricle.

These four peptides all produced pressor effects after intracerebroventricular injection. ANG II and NT significantly suppressed PRA, BK did not affect PRA, and Leu-ENK significantly increased PRA. The central peptidergic stimulation caused by these four peptides increased blood pressures in conscious rats but showed different effects on PRA.     

Influence of angiotensin converting enzyme inhibition with captopril on blood pressure and adrenergic function in normal and sodium restricted rats

Observations with both captopril and teprotide suggest interplay of the renin angiotensin and sympathetic nervous systems during sodium depletion. We therefore examined adrenergic responses in normal or sodium restricted (8 days low sodium chow; trichlormethiazide 3 mg/kg, p.o., days 5-7) normotensive rats orally pretreated with placebo and captopril (3 or 10 mg/kg; twice on day 7, once on day 8) and pithed 2 hrs after the last dose. Consistent hypotension in conscious intact animals was observed only in sodium-depleted groups receiving captopril. Pressor responses to low frequency (2.5 Hz--5 sec) sympathetic stimulation and phenylephrine were reduced in normal sodium, pithed normotensive Sprague-Dawley rats receiving 10, but not 3 mg/kg captopril and low sodium animals receiving both doses. Suppression of phenylephrine by captopril was accentuated in sodium-depleted groups. Pressor responses to angiotensin II were less in all salt-depleted animals receiving either placebo or captopril. Captopril failed to reduce tachycardia to either sympathetic nerve stimulation or isoproterenol. These effects of captopril suggest that angiotensin plays a role in maintenance of vascular, but not cardiac adrenergic function. This role is manifested at a post-junctional site and becomes critical in the sodium deficient state.     

Control of arterial pressure and renal function during chronic renin inhibition

The aim of this study was to determine whether the renin inhibitor CP-71362 (Pfizer Central Research, Groton, Connecticut, USA) is capable of inducing sustained reductions in arterial pressure in sodium-depleted dogs and to examine the changes in renal function associated with chronic renin inhibition. In addition, we also examined the chronic effects on renal function and blood pressure of the angiotensin converting enzyme (ACE) inhibitor enalaprilat. Infusion of CP-71362 (1.1 micrograms/kg per min, intravenously) for 7 days decreased mean arterial pressure from 87 +/- 3 to 75 +/- 2 mmHg, while causing no significant changes in sodium excretion, the glomerular filtration rate, or effective renal plasma flow. Plasma renin activity was suppressed to undetectable levels throughout the 7 days of CP-71362 infusion. Infusion of enalaprilat (4 mg/kg per day) for 7 days in sodium-depleted dogs decreased mean arterial pressure (from 85 +/- 2 to 64 +/- 3 mmHg) and renal vascular resistance, and increased effective renal plasma flow and sodium excretion, but caused no significant changes in the glomerular filtration rate. Thus CP-71362 is a potent inhibitor of dog plasma renin, and we observed no waning of this inhibitory effect of CP-71362's hypotensive actions over 7 days. The mechanisms responsible for the differences in the blood pressure and renal responses to CP-71362 and ACE inhibition are not clear, but may be dose-related or due to differences in the distribution of these compounds to various tissues, including the kidney.     

Role of the renin-angiotensin system in the control of vasopressin secretion in conscious dogs

The present studies were designed to evaluate the physiological significance of angiotensin II in the control of vasopressin secretion in conscious dogs. They demonstrated that exogenous angiotensin II (10 ng/kg per min) increased vasopressin secretion more when the pressor effect of angiotensin II was abolished. The fact that endogenous angiotensin II levels are normally increased without an increase in arterial pressure suggests that angiotensin II may play a greater role in the control of vasopressin secretion than was previously thought. The present study also evaluated the role of endogenous angiotensin II in the control of vasopressin secretion during sodium depletion, a state in which angiotensin II levels are elevated. Intracarotid infusion of a low dose of the angiotensin II antagonist, saralasin, decreased plasma vasopressin concentration, suggesting that endogenous angiotensin II acts in an area of the brain perfused by the carotid arteries to stimulate vasopressin secretion in sodium-deprived dogs. Finally, the present experiments evaluated the role of angiotensin II in baroreceptor reflex control of vasopressin secretion. Baroreflex function was assessed by examining the relationship between the change in blood pressure and the log of the change in vasopressin secretion over a range of blood pressure levels. Exogenous angiotensin II (10 ng/kg per min) altered baroreflex function by causing a shift of this relationship to a higher pressure level in sodium-replete dogs. In sodium-depleted dogs, inhibition of the renin-angiotensin system with saralasin or captopril produced an opposite shift. These results suggest that endogenous angiotensin II may be necessary for the maintenance of normal baroreflex control of vasopressin secretion during sodium depletion. Collectively, these results support the hypothesis that endogenous angiotensin II plays a role in the control of vasopressin secretion.     

Mechanism of the blood pressure and renal hemodynamic effects of captopril

This study was designed to investigate the mechanisms of captopril's chronic effect on arterial pressure and renal function. In dogs maintained on high sodium intake (250 mEq/day), 6 days of captopril infusion caused no change in arterial pressure, renal hemodynamics, sodium excretion or plasma aldosterone concentration. Infusion of captopril for 7 days also caused no significant changes in arterial pressure or renal function in dogs made hypertensive by chronic infusion of angiotensin II and high sodium intake, a model of hypertension in which plasma renin activity is undetectable and prostaglandin and bradykinin formation may be elevated. In dogs maintained on low sodium intake, chronic infusion of captopril decreased arterial pressure and plasma aldosterone concentration markedly while increasing effective renal plasma flow. Infusion of aldosterone (200 μg/day) for 8 days during captopril infusion restored plasma aldosterone concentration but did not significantly change arterial pressure or renal function, indicating that decreased plasma aldosterone concentration did not play a major role in the hypotensive and renal effects of captopril. However, angiotensin II infusion (10 ng/kg/min) for 8 days during captopril infusion restored arterial pressure, plasma aldosterone concentration and renal function toward control levels. These data suggest that the effects of captopril on arterial pressure, renal hemodynamics and electrolyte excretion are mediated primarily by decreased angiotensin II formation.     

Effect of infused captopril on blood pressure and the renin-angiotensin-aldosterone system in normal dogs subjected to varying sodium balance

Infusion of captopril at 20, 200, 2,000 and 6,000 μg/kg/hour into sodium-depleted conscious dogs produced a rapid, dose-dependent decrease in blood pressure and plasma angiotensin II and III, maximal suppression being achieved at 200 μg/kg/hour (97 ± 14 to 65 ± 8 [standard deviation]mm Hg, 38 ± 10.6 to 3.2 ± 1.5 pmol/liter and 7.0 ± 4.8 to 1 ± 0.5 pmol/liter, respectively). Angiotensin I concentration increased with each infusion rate to a maximal 16-fold increase at 6,000 μg/kg/hour (26 to 416 pmol/liter). For all infusion rates the percentage decrease in blood pressure correlated with the percentage decrease in plasma angiotensin II (r = 0.65, p < 0.001). Infusion of captopril at 6,000 μg/kg/hour into sodium-loaded dogs also produced a decrease in both blood pressure (117 ± 9 to 96.6 ± 11 mm Hg) and plasma angiotension II (11.0 ± 3 to 1.6 ± 1.3 pmol/liter). Plasma aldosterone concentrations decreased whereas both blood angiotensin I and renin concentration increased. In another experiment angiotensin II was infused at 2, 6, 18 and 54 ng/kg/min into sodium-depleted dogs firstly without modification and secondly combined with captopril (6,000 μg/kg/hour) given for 1 hour before the angiotensin dose-response study and continued throughout. Angiotensin II infusion raised mean arterial pressure and plasma angiotensin II in each animal. However, the angiotensin II blood pressure dose-response curve was shifted downwards and to the right in the captopril-treated animals.These results suggest that arterial pressure and aldosterone secretion in normal dogs are partly dependent on the renin-angiotensin system but that not all of the acute decrease in blood pressure produced by captopril can be explained by the suppression of the acute vasoconstrictor effect of circulating angiotensin II.     

Effects of captopril on the renin angiotensin system, oxidative stress, and endothelin in normal and hypertensive rats

There is substantial evidence suggesting that angiotensin II plays an important role in elevating blood pressure of spontaneously hypertensive rats, despite normal plasma renin activity, and that converting enzyme inhibitors (captopril) can effectively normalize blood pressure in the spontaneously hypertensive rats. One mechanism by which angiotensin II induces hypertension is via oxidative stress and endothelin, as seen in subpressor angiotensin II-induced hypertension. In fact, it has been shown that antioxidants lower mean arterial pressure in spontaneously hypertensive rats. However, the relationship between angiotensin II, oxidative stress, and endothelin in the spontaneously hypertensive rats is still relatively undefined. This study examines the relationship between mean arterial pressure, plasma renin activity, angiotensin II, oxidative stress, and endothelin in spontaneously hypertensive rats compared with normotensive Wistar Kyoto rats, and the effects of captopril on this association. Untreated spontaneously hypertensive rats had increased plasma angiotensin II levels despite normal plasma renin activity, oxidative stress, and endothelin. Captopril treatment in spontaneously hypertensive rats lowered mean arterial pressure, angiotensin II, oxidative stress, and endothelin, and increased plasma renin activity. In contrast, captopril increased plasma renin activity (suggesting effective captopril treatment) but did not significantly alter mean arterial pressure, angiotensin II, oxidative stress, or endothelin of Wistar Kyoto rats. These results suggest that in spontaneously hypertensive rats, angiotensin II is a primary instigator of hypertension, and that captopril selectively lowers angiotensin II, oxidant stress, and endothelin, which in turn may contribute to the blood pressure-lowering efficacy of captopril in spontaneously hypertensive rats.     

The Effects of Saralasin, an Angiotensin II Antagonist on Blood Pressure and the Renin-Angiotensin-Aldosterone System in Normal and Hypertensive Subjects

Summary: The effects of saralasin, an angiotensin II antagonist, on blood pressure and the renin-angiotensin-aldosterone system in recumbent normal and hypertensive subjects.
Blood pressure reduction with saralasin infusion was seen only in hypertensive patients with abnormally elevated basal plasma renin and angiotensin II levels, and after sodium depletion the reduction in blood pressure was more marked. In normal subjects, and in hypertensives with plasma renin and angiotensin II levels within the normal range, there was no marked fall in blood pressure across saralasin infusion regardless of the sodium status of the individual.
Plasma aldosterone concentration fell during saralasin infusion in those subjects with high baseline renin and angiotensin II levels. This fall occurred in the sodium replete and deplete states. In the normal subjects, and those hypertensives with normal plasma renin levels, there was no fall in aldosterone in the sodium replete state. However, after sodium depletion the expected rise in aldosterone was abolished during saralasin infusion, the plasma aldosterone falling to within the normal sodium replete range, rising again after the saralasin infusion was stopped.
This study supports the concept of a direct role for renin and angiotensin II in the maintenance of hypertension in those subjects with elevated basal plasma renin. Plasma aldosterone would appear to be controlled, at least in part, by the prevailing plasma angiotensin II level in those subjects with elevated basal levels of angiotensin II; that is in high renin hypertensives, and in normal subjects and normal renin hypertensives who are sodium deplete.     

Endogenous angiotensin-aldosterone-pressure relationships during sodium restriction

The effects of moderate restriction of dietary sodium and potassium supplementation on plasma levels of renin, angiotensin II, aldosterone, and cortisol and on arterial pressure were studied in 12 patients with mild essential hypertension. To define hormone-blood pressure relationships, venous hormone levels were measured hourly and intra-arterial pressure continuously for 24 hours after 4 to 6 weeks of sodium restriction, 4 to 6 weeks of potassium supplementation, and a similar period of control diet. Our results show that compared with the control diet, moderate sodium restriction was associated with increased levels of aldosterone but no overall change in renin, angiotensin II, or cortisol levels. Further, slopes of regression lines relating log renin and log angiotensin II to aldosterone were increased, as were log cortisol/aldosterone regression lines. On the contrary, regression lines of log renin and log angiotensin II versus arterial pressure were unaltered by sodium restriction. Hormone and blood pressure relationships were not changed by the potassium supplemented diet. Although confirmatory data are needed, our findings suggest that moderate sodium restriction enhances aldosterone responsiveness to endogenous angiotensin II and adrenocorticotropic hormone without diminishing the pressor activity of endogenous angiotensin II. These results may explain in part the disappointingly small hypotensive effect of modest sodium restriction in mild essential hypertension.     

The effect of angiotensin I converting enzyme inhibitor (SQ 14225) on plasma 18-hydroxycorticosterone and aldosterone in sodium depleted conscious rats

Altered sodium intake is known to cause a greater change in plasma 18-hydroxycorticosterone (18-OHB) level than in plasma aldosterone level, resulting in an increase of plasma 18-OHB/aldosterone ratio in sodium-depleted man and rats. To evaluate the role of endogenous angiotensin II in the high plasma 18-OHB/aldosterone ratio in sodium-depleted rats, we examined the effect of the angiotensin I converting enzyme inhibitor SQ 14225 on plasma 18-OHB and aldosterone in sodium-depleted (SD) and sodium-repleted (SR) conscious rats. Plasma renin activity (PRA) and plasma angiotensin II were higher in the SD rats than in the SR rats. The ingestion of SQ 14225 caused an increase in PRA and a decrease in plasma angiotensin II, whereas these changes were more prominent in the SD rats than in the SR rats. Plasma 18-OHB and aldosterone levels were higher in the SD rats than in the SR rats. The plasma 18-OHB/aldosterone ratio was also higher in the SD rats than in the SR rats. The ingestion of SQ 14225 caused decreases in plasma 18-OHB and aldosterone levels in both the SR and SD rats, whereas the SQ 14225-induced decreases in plasma 18-OHB and aldosterone levels were more prominent in the SD rats than in the SR rats. Thus, the ingestion of SQ 14225 induced a decrease in the plasma 18-OHB/aldosterone ratio in both the SR and SD rats. The decrease in plasma 18-OHB/aldosterone ratio was more prominent in the SD rats than in the SR rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renin-angiotensin system in dogs following chronic bile-duct ligation. Relation to vascular reactivity

The pressor response to angiotensin II, blood volume, angiotensin II in arterial blood, renin substrate, renin concentration, renin activity and aldosterone in venous blood, liver function tests, kidney function tests, glucose, sodium, potassium, plasma osmolality and complete blood count were examined before and 1, 2, 3 and 5 weeks after ligation of bile ducts in nine conscious trained dogs. The pressor response to angiotensin II was markedly suppressed after bile-duct ligation, especially at 1-3 weeks postoperation. A maximal decrease in plasma renin substrate, and maximal increases in plasma renin concentration, plasma renin activity and aldosterone were noted at 1 week postoperatively. Plasma angiotensin II levels were elevated at 1 and 5 weeks postoperatively but were near normal 2 weeks postoperatively despite suppression of the angiotensin II pressor response. Endogenous levels did not correlate with suppression of the pressor response to exogenous angiotensin II.     

Hormonal and Cardiovascular Effects of Losulazine Hydrochloride in Relation to Sodium Balance in Nonhuman Primates

Losulazine hydrochlonde, a peripheral norepinephrine-depleting agent, was studied in conscious sodium-replete and sodium depleted cynomolgus monkeys. Blood pressure, heart rate, plasma renin activity, and plasma catecholamines were monitored before and after the oral administration of losulazine at a dose which caused a submaximal hypotension in sodium-replete monkeys.The hypotension observed in both sodium depleted monkeys was not significantly different from that observed in sodium-replete monkeys. The hypotension observed in both sodium states was accompanied by quantitatively similar decreases in plasma norepinephrine concentrations in the absence of significant alterations of heart rate and plasma renin activity. These results were consistent with the conclusion that losulazine reduced arterial blood pressure in nonhuman primates via peripheral norepinephrine depletion. These data also indicated that the hypotensive effect of losulazine in conscious monkeys was not dependent on alterations in renin angiotensin system activity or on the state of sodium balance.     

Role of the Renin-Angiotensin-Aldosterone and Kallikrein-Kinin Systems in the Control of Fluid and Electrolyte Metabolism,Renal Function,and Arterial Blood Pressure

The long-term effects of angiotensin I converting enzyme (kininase II) inhibition with Captopril on fluid and electrolyte metabolism, aldosterone secretion, renal function, and arterial pressure were evaluated in conscious sodium deficient dogs. Plasma aldosterone concentration (PAC), plasma renin activity (PRA), urinary sodium excretion (U_NaV), arterial pressure (AP), renal blood flow (RBF), glomerular filtration rate (GFR), blood kinin concentration (BK), urinary kinin excretion (UK), and urinary kallikrein activity (UKA) were determined during long-term inhibition of angiotensin I converting enzyme (kininase II). In response to Captopril administration (20 mg/kg/day) PAC decreased from 38.9 ± 6.7 to 14.3 ± 2.3 ng/dl, PRA increased from 3.58 ± 0.53 to 13.7 ± 1.6 ng/ml/hr, U_NaV increased from 0.65 ± 0.27 to 6.4 ± 1.2 mEq/day, AP decreased from 102 ± 3 to 65 ± 2mmHg, RBF increased from 136 ± 7 to 156 ± 8 ml/min, GFR decreased from 65 ± 8 to 36 ± 7 ml/min, BK increased from 0.17 ± 0.02 to 0.41 ± 0.04 ng/ml, UK increased from 7.2 ± 1.5 to 31.4 ± 3.2 ug/day, and UKA decreased from 23.6 ± 3.1 to 5.3 ± 1.2 E.U./day. Aldosterone infusion in sodium deficient dogs maintained on Captopril failed to alter urinary sodium excretion, renal function, or arterial blood pressure. However, angiotensin II infusion (3 ng/kg/min) restored aldosterone secretion, renal function, and arterial blood pressure within three days to levels observed in untreated sodium deficient dogs. The marked alterations in renal function and urinary sodium excretion during angiotensin II infusion indicate that angiotensin II is several times more potent than aldosterone in the long-term control of sodium excretion. Also, our studies demonstrated that the long-term hypotensive and natriuretic actions of inhibitors of angiotensin I converting enzyme (kininase II) are mediated by inhibition of angiotensin II formation.     

Characterization of the antihypertensive effect of a thiazide diuretic in angiotensin II-induced hypertension

OBJECTIVES : The antihypertensive effect of thiazide diuretics in angiotensin II induced hypertension has never been characterized. In the current study, we sought to determine the effect of a thiazide diuretic on arterial pressure and renal fluid excretion in rats receiving a chronic intravenous infusion of angiotensin II while on fixed normal or high sodium intakes. DESIGN AND METHODS : Male rats were chronically instrumented with arterial and venous catheters for drug injection and direct daily measurements of blood pressure and heart rate. Rats were maintained on high salt intake (HS), 6 mEq/day, or on normal salt intake (NS), 2 mEq/day. Rats were randomly assigned to four groups: HS and NS with 15 day angiotensin II infusion (5 ng/min) and HS and NS without angiotensin II infusion. Trichlormethiazide (TCM), a thiazide diuretic, was orally administered, approximately 10 mg/kg per day, for the middle 5 days of angiotensin II infusion. RESULTS : Only HS rats receiving angiotensin II infusion became hypertensive. Angiotensin II infusion did not produce changes in heart rate, sodium balance or water balance. Chronic administration of TCM significantly reduced mean arterial pressure (MAP) within 24 h in HS rats receiving angiotensin II, but did not affect MAP in any other group. TCM produced a similar loss of Na+ and water in all rats. Blood volumes and plasma electrolytes did not change during the study. CONCLUSIONS : The antihypertensive effects of thiazide diuretics are not due exclusively to volume depletion. We propose that salt and water loss caused by TCM may lower MAP by impairment of salt-sensitive pressor mechanisms activated by angiotensin II.     

Effect of angiotensin II on baroreceptor reflex control of heart rate in conscious baboons

Studies of the baroreceptor-heart rate reflex were performed in four conscious, unrestrained male baboons to determine whether changes in circulating angiotensin II within the physiological range are associated with alterations in baroreceptor reflex sensitivity. With the animals on a high sodium intake, studies were performed before and during graded angiotensin II infusion (10 and 20 ng/kg/min). To separate effects on baroreceptor reflex function mediated by angiotensin II-induced increases in arterial pressure, these studies were repeated on a different day with simultaneous glyceryl trinitrate infusion to prevent increases in pressure during angiotensin II infusion. With the animals on a low sodium intake, studies were performed before and after angiotensin converting enzyme inhibition with captopril (1 and 5 mg/kg). These studies were also repeated on a separate day during simultaneous phenylephrine infusion to prevent a decrease in pressure with captopril. Reduction in sodium intake had no significant effect on arterial pressure, heart rate, or plasma volume, although arterial plasma angiotensin II concentration and renin activity were significantly increased (p less than 0.01). Infusion of angiotensin II produced a significant reduction in baroreceptor reflex sensitivity (p less than 0.01), and converting enzyme inhibition produced a significant increase (p less than 0.05). These effects accompanied significant increases and decreases in arterial angiotensin II concentration, respectively (p less than 0.01), but were independent of angiotensin II-related changes in arterial pressure. The data indicate that physiological variations in circulating angiotensin II have a direct effect on sensitivity of the baroreceptor-heart rate reflex.     

Effects of chronic infusion of renin inhibitor A-64662 in sodium-depleted monkeys

The potent and primate-selective renin inhibitor A-64662 (n = 8) or vehicle (n = 6) was administered intravenously for 7 days to sodium-depleted cynomolgus monkeys to investigate the chronic effects on arterial pressure, sodium excretion, and the renin-angiotensin-aldosterone system. A 0.1-mg/kg i.v. bolus followed by a continuous 0.01-mg/kg/min infusion of A-64662 lowered mean arterial pressure from 89 +/- 3 (average of 4 control days) to 75 +/- 4 mm Hg (p less than 0.05) after 1 day of administration. This decrement was associated with marked inhibition of plasma renin activity (PRA) from 57.7 +/- 11.1 to 1.3 +/- 0.6 ng angiotensin I (Ang I)/ml/hr (p less than 0.05). Similar hypotensive levels (range 73 +/- 4 to 77 +/- 4 mm Hg) were observed on days 2-7 of A-64662 infusion and PRA remained suppressed, ranging from 0.6 +/- 0.4 to 1.9 +/- 1.0 ng Ang I/ml/hr. Plasma angiotensin II (Ang II) levels were reduced (p less than 0.05) from the control value of 66.7 +/- 20.2 to 12.4 +/- 3.3 and 26.4 +/- 6.5 pg/ml on the second and seventh days, respectively, of A-64662 infusion. In contrast, infusion of vehicle alone had no discernible effect on mean arterial pressure, PRA, or plasma Ang II concentrations. Plasma aldosterone decreased (p less than 0.05) from control on the second and third days of A-64662 infusion, although differences between the treatment groups were not detected throughout the study. Urinary sodium excretion remained at control levels throughout the infusion of A-64662. Cessation of A-64662 administration resulted in a recovery of mean arterial pressure to preinfusion levels within 1 day. This study indicates that continuous infusion of A-64662 results in a sustained hypotension in sodium-depleted monkeys. This effect appears to be related, at least partially, to inhibition of PRA and lower plasma Ang II levels.