Dietary and pharmacological alterations in endogenous angiotensin II: effect on noradrenaline pressor responsiveness in the rat.

Rats were placed on either a low sodium intake (low sodium diet 0.025% dry weight, tap water for drinking) or a high sodium intake (normal sodium diet 0.45% dry weight, 0.9% saline for drinking) for 10 days. The pressor-response curve to angiotensin II in rats previously on a high sodium intake was shifted to the left of that found in rats previously on a low sodium intake. Suppression of endogenous angiotensin II formation with captopril (0.3 mg kg-1) or acute volume repletion (3% body wt per 30 min) resulted in a significant parallel shift of the pressor-response curve for angiotensin II to the left in the low salt group. In the high salt group captopril produced a similar but smaller parallel shift of the dose-response curve to the left. Similar manipulation of endogenous angiotensin II concentrations with high and low salt intake plus captopril treatment or acute volume repletion, produced no alterations in the pressor response for noradrenaline. The attenuated in vivo response to angiotensin II in the low salt intake group may be explained in part by the suppressed vascular sensitivity to angiotensin II in this group, as measured in the isolated perfused kidney of the rat. In kidneys from rats previously on a low sodium intake, an enhanced maximal vasoconstrictor response to noradrenaline was observed as compared to kidneys from high sodium intake rats. These results indicate that, whereas alterations in endogenous angiotensin II concentrations within physiological limits affects the response to exogenous angiotensin, there is little if any effect on the pressor response to noradrenaline.     

Adrenal involvement in captopril-induced potentiation of morphine analgesia

The involvement of the angiotensin-adrenal system as a possible mechanism in the potentiation of morphine analgesia by the angiotensin-converting enzyme inhibitor, captopril (SQ 14225), was studied in rats. Captopril pretreatment sensitized the animals to the analgesic effects of morphine while angiotensin II exerted an attenuating influence. These effects, however, were not demonstrable in adrenalectomized animals. Although captopril could inhibit the plasma angiotensin-converting enzyme activity, it appeared to have no significant effect on the brain enzyme. It has been suggested that the effects of captopril and angiotensin II on morphine analgesia are mediated indirectly through their effects on adrenal function.     

Captopril given intracerebroventricularly, subcutaneously or by gavage inhibits angiotensin-converting enzyme activity in the rat brain

In rats with permanent brain cannulas intracerebroventricular (i.c.v.) injections of 2 microgram captopril nearly abolished drinking responses elicited by i.c.v. injections of 1 mUnit hog renin, 10 pmol synthetic renin substrate or 10 pmol angiotensin I but did not reduce drinking elicited by 10 pmol angiotensin II. Inhibition of the response to precursors of angiotensin II was long-lasting (at least 2 h) and dose-dependent (20 ng-2 microgram captopril). Captopril was 3-5 times more potent than SQ 20,881 i.c.v. Subcutaneous injections of captopril in doses 0.1 to 1.0 mg/kg reduced pressor responses to intravenous injections of angiotensin I without attenuating drinking elicited by i.c.v. injections of angiotensin precursors. Higher doses of captopril, however, given subcutaneously (5-50 mg/kg) or by gavage (10 mg/kg) did not reduce drinking to i.c.v. injections of renin or angiotensin I (but not angiotensin II). We conclude that captopril inhibits angiotensin-converting enzyme activity in the brain even when given subcutaneously or by gavage in doses commonly used in the rat.     

Roles of endogenous angiotensin II or kinin in the mechanism of altered renal vascular responsiveness to angiotensin II following acute blood volume expansion in the dog

To examine the role of endogenous angiotensin II or kinins in the mechanism of the increased renal vascular reactivity to exogenous angiotensin II following acute blood volume expansion, we examined whether captopril, a converting enzyme inhibitor, can prevent the increase in renal vascular response in anesthetized dogs. Pretreatment of dogs with captopril increased plasma renin activity, but it did not affect systemic blood pressure, renal blood flow and renal vascular resistance. Acute blood volume expansion with saline suppressed plasma renin activity in dogs with or without pretreatment with captopril. Basal level of renal vascular reactivity to angiotensin II was increased by pretreatment with captopril. In the control animals, acute blood volume expansion enhanced renal vascular reactivity to angiotensin II but not norepinephrine. The enhanced renal vascular reactivity to angiotensin II, however, was not prevented by the captopril treatment. The failure of captopril to prevent an increase in renal vascular reactivity to angiotensin II following acute blood volume expansion was associated with an increase in urinary excretion of bradykinin. These data suggest that endogenous angiotensin II level is not necessarily a determinant for vascular reactivity to exogenous angiotensin II, especially in the case of acute blood volume expansion.     

Angiotensin II facilitates tricyclic antidepressant-induced changes in QRS-duration in the rat.

Experimental evidence indicates that angiotensin II can modulate sodium channel and gap junction function. This raises the possibility that variations in angiotensin II could alter the effect of drugs that act on these mechanisms. In this study, the influence of changing salt status and angiotensin II activity has been investigated by evaluating the QRS prolonging effects of the sodium channel blocking drug, desmethylimipramine. In control rats with a normal salt intake, intravenous infusion of desmethylimipramine (0.8 mg/kg/min) over 60 min increased QRS duration over time to 150% of control by 60 min; mean arterial blood pressure and pulse rate were decreased. In salt-deplete rats, the response to desmethylimipramine was similar to controls for 30 min. Thereafter, QRS duration increased more rapidly than controls. In rats on a high salt diet, the same desmethylimipramine infusion produced no change in QRS duration for 30 min, despite equivalent reductions in mean arterial blood pressure. Thereafter, QRS duration increased, reaching values similar to control by 60 min. In rats on a normal salt diet pretreated with captopril, there was a similar blunting of the QRS response to desmethylimipramine to that observed in salt-loaded rats. The QRS response to desmethylimipramine and salt-loaded rats on normal salt diets receiving captopril returned to the control pattern after a subpressor infusion of angiotensin II (3 ng/min), while a higher rate of angiotensin II (10 ng/min) further enhanced the QRS prolonging effect of desmethylimipramine. These data demonstrate that endogenous angiotensin II contributes to the regulation of the cardiac electro-physiological response to DMI.     

The effect of chronic captopril therapy on platelet angiotensin II receptor density and vascular responsiveness to angiotensin II infusion

Summary The density of angiotensin II (Ang II) receptors on the platelet and the vascular responsiveness to infused angiotensin II before and after two weeks of captopril therapy were examined in ten healthy male volunteers. There was a significant increase in blood flow to the forearm, but no significant changes in either the density of angiotensin II receptors or the pressor response to infused angiotensin II following captopril therapy. The study demonstrates that long term reduction of angiotensin II formation by captopril in man does not increase the responsiveness of the receptors to infused angiotensin, nor results in an up regulation of the angiotensin receptors. It also provides further evidence that some of the long term vasodilator effects of captopril may be mediated by mechanisms other than inhibition of angiotensin I (Ang I) converting enzyme.     

Ultrafine carbon black attenuates the antihypertensive effect of captopril in spontaneously hypertensive rats

Abstract

Particulate matter (PM) has been associated with increased blood pressure (BP) by affecting renin-angiotensin system (RAS) on a systemic level in spontaneously hypertensive rats (SHR). RAS in SHR is also an important target for the angiotensin converting enzyme (ACE) inhibitors such as captopril. We aimed to determine if ultrafine carbon black (UCB) could affect antihypertensive effect of captopril in SHR. The rats were randomly divided into six groups. Group 1 did not receive intratracheal instillation; group 2 received saline instillation plus captopril administration; groups 3, 4 and 5 received 0.15?mg/kg, 0.45?mg/kg and 1.35?mg/kg UCB per instillation plus captopril administration, respectively; group 6 received 1.35?mg/kg UCB instillation only. Rats in the above groups were intratracheally instilled with saline or UCB once every two days for three times and captopril was administered to group 2–5 after the final UCB treatment, once a day for one week. The BP was measured 24?h after each intratracheal instillation. During captopril administration and 24?h after last captopril administration, we measured BP every two days for four times. Our results showed that UCB at the dose of 1.35?mg/kg induced pulmonary and systemic inflammation in SHR. Captopril reduced BP in rats exposed to 0, 0.15 and 0.45?mg/kg UCB seven and eleven days after the first UCB instillation, and had no effect on BP in rats exposed to 1.35?mg/kg UCB. Captopril also reduced angiotensin II (AngII) in rats exposed to saline. The reduction, however, was attenuated with increasing doses of UCB. We conclude that UCB attenuated the antihypertensive effect of captopril in SHR, and the effect was accompanied by a systemic increase in the concentration of AngII.     

Effect of sodium houttuyfonate on myocardial hypertrophy in mice and rats

Objectives The aim of the study was to determine the effect of sodium houttuyfonate on myocardial hypertrophy and its mechanism of action in mice and rats. Methods A mouse model of myocardial hypertrophy was established by subcutaneous injection with isoproterenol. Mice were randomly divided into five groups: normal control; isoproterenol control; isoproterenol plus metoprolol; isoproterenol plus low‐ and high‐dose sodium houttuyfonate. A rat model of myocardial hypertrophy was established by intraperitoneal injection with l ‐thyroxine. Rats were randomly divided into five groups: normal control; l ‐thyroxine control; l ‐thyroxine plus captopril; l ‐thyroxine plus low‐ and high‐dose sodium houttuyfonate. At the end of the experiments, the left ventricular weight index and heart weight index were determined in mice and rats, the size of cardiomyocytes was measured in rats and the concentrations of cAMP in plasma and angiotensin II in ventricular tissue of mice were detected by radioimmunoassay. The endothelin‐1 concentration was measured by radioimmunoassay and the hydroxyproline content was measured by a digestive method in ventricular tissue of rats. Key findings After 7–9 days of treatment, sodium houttuyfonate significantly reduced the left ventricular weight index and heart weight index in mice and rats with myocardial hypertrophy, decreased the size of cardiomyocytes in rats, and reduced the content of cAMP and angiotensin II in mice with myocardial hypertrophy. It also decreased the endothelin‐1 concentration and the hydroxyproline content in ventricular tissue in rats. Conclusions Sodium houttuyfonate can inhibit myocardial hypertrophy in mouse and rat models by restricting the activity of the sympathetic nervous system and decreasing the levels of angiotensin II and endothelin‐1 in ventricular tissue.     

Indomethacin and angiotensin II pressor responsiveness: importance of dietary sodium

Dietary sodium intake alters pressor responsiveness to angiotensin II (AII) as well as altering prostaglandin production. As a result, the effect of prostaglandin synthesis inhibition on the pressor responsiveness to AII was evaluated. Prostaglandin synthesis inhibition with meclofenamate (5 mg/kg) or indomethacin (5 mg/kg) significantly enhanced the pressor response for AII at infusion rates of 0.10, 0.30 and 1.0 microgram/kg per min (P less than 0.05) in rats previously on a low sodium intake but had no effect in rats previously on a high sodium intake. In low sodium intake rats, pretreatment with captopril (1 mg/kg) prevented the enhancing effect of indomethacin on angiotensin II pressor responsiveness. The pressor response for norepinephrine was unaltered by sodium intake or prostaglandin inhibition. These results suggest that prostaglandin synthetase inhibition may enhance the pressor response for angiotensin II in situations where endogenous angiotensin II levels are elevated (i.e. low sodium intake). In situations where angiotensin II levels are suppressed (i.e. captopril pretreatment or high salt intake), prostaglandin synthetase inhibitors have no effect on the pressor response to exogenous angiotensin II.     

A facilitatory effect of anti-angiotensin drugs on vagal bradycardia in the pithed rat and guinea-pig.

1. In pithed rats, preganglionic vagal nerve stimulation (at 5 Hz) elicited a bradycardia. This bradycardia was potentiated by the angiotensin converting enzyme inhibitor, captopril (1 mg kg-1, i.v.) by about 40%. Subsequent angiotensin II infusion (0.03 micrograms kg-1 min-1) reversed this effect. A similar facilitatory effect was also seen with the angiotensin receptor antagonist, losartan (10 mg kg-1, i.v.). These results suggest a tonic inhibitory effect of endogenous angiotensin II on vagal transmission. 2. The effect of captopril in potentiating vagal bradycardia appears to be at the level of vagal neurones, since the bradycardia elicited by the muscarinic agonist, methacholine was unaffected. 3. After the pithed rats were nephrectomized, captopril had no effect on vagally-induced bradycardia, suggesting that the formation of the endogenous angiotensin II responsible for the effect was dependent on renin release from the kidney. 4. When the sympathetic nerves of the pithed rat were electrically stimulated there was a tachycardia, and this was unaffected by captopril. However, when the sympathetic and vagus nerves were activated concurrently, the resulting tachycardia was inhibited by captopril. 5. In pithed guinea-pigs, captopril also potentiated the bradycardia caused by vagal nerve stimulation. This appears to be a tissue-selective effect since the bronchoconstriction due to the vagal stimulation was not affected by captopril. 6. These results suggest that endogenous angiotensin II can have a tonic inhibitory effect on cardiac vagal transmission. Disruption of this mechanism by anti-angiotensin drugs may attenuate the reflex tachycardia associated with the fall in blood pressure in anti-hypertensive therapy.     

Distribution and coregulation of three peptide receptors in adrenals

Receptors sites for angiotensin II and atrial natriuretic factor were concentrated in the zone glomerulosa of the adrenal cortex in the rat, mouse, hamster, rhesus monkey, guinea-pig and the cow. Angiotensin Ii receptor sites were also accumulated in adrenal medullary tissue of the rat, mouse and the hamster. With exception of the cow the zonae fasciculata and reticulata of the adrenal cortex were not labelled with the angiotensin II ligand, but showed a moderate density of atrial natriuretic factor receptor sites in all species except the rhesus monkey. In comparison, somatostatin receptors were even more heterogeneously distributed in all species mentioned above. In the rat, the increased growth of zona glomerulosa cells found after three weeks of sodium deprivation was accompanied by a similar increase in number of receptor sites for angiotensin II, atrial natriuretic factor and somatostatin. This shows that all three peptide receptors are regulated simultaneously by a single metabolic disturbance, suggesting that they might be localized on the same cell type in the adrenal cortex.     

Inhibitory effect of captopril on renal responses to frusemide in sodium-restricted rats

Indomethacin (10 mg kg-1 orally) caused a moderate inhibition of the renal responses to frusemide (30 mg kg-1 orally) only in Na+-deficient rats, suggesting that renal prostaglandins (PG) are necessary for optimal effects of frusemide during Na+ restriction. Captopril (1, 3 and 10 mg kg-1 orally) also inhibited frusemide-induced diuresis and natriuresis in Na+-deficient rats; the large effect of captopril at 10 mg kg-1 was accompanied by arterial hypotension. In normal rats, captopril did not disturb blood pressure or affect the renal effects of frusemide. By comparison, minoxidil (10 and 20 mg kg-1 orally) caused hypotension and reduced the natriuretic effects of frusemide in both normal and low-Na+ states. Since circulating angiotensin II (AII) is a stimulus for PG synthesis during Na+ restriction, it is suggested that captopril may impair the renal responses to frusemide through hormonal and haemodynamic changes resulting from inhibition of A II formation.     

Central angiotensin converting enzyme blockade and thirst

The role of endogenous brain angiotensin II (AII) in various thirst states was examined in the rat using the angiotensin converting enzyme inhibitor, captopril. Intracerebroventricular (ICV) captopril (7 micrograms) significantly attenuated the dipsogenic response to centrally administered angiotensin I (AI) (200 ng) for up to 2 hours. The same dose of captopril significantly potentiated the dipsogenic response to ICV AII (100 ng) but failed to alter the dipsogenic response to ICV carbachol (200 pmoles). Central pretreatment with captopril (7 micrograms), for 30 minutes, failed to alter markedly the cumulative water intake of 24 hour water deprived rats. However, a small, significant 8% decrease in water intake was noted in ICV captopril treated rats 60 minutes following the return of water. The same dose of captopril, administered intraperitoneally, significantly potentiated the cumulative water intake of 24 hour water deprived rats. Central pretreatment with captopril (7 micrograms), for 30 minutes, failed to alter the cumulative water intake of rats treated intraperitoneally with hypertonic saline (0.75 M given at a dose of 1% of the body weight). From these studies it would appear that central angiotensin converting enzyme plays only a minor role in thirst induced by water deprivation.     

Role of angiotensin and sodium intake in cardiac noradrenaline release

Summary The effects of exogenous and of endogenous angiotensin on noradrenaline overflow were investigated in saline perfused rat hearts with intact sympathetic nerves. The overflow of endogenous noradrenaline induced by electrical stimulation of the left stellate ganglion was determined in the coronary venous effluent by HPLC. The activity of the renin-angiotensin system was modulated by varying of the nutritional sodium load prior to the experiments. Endogenous angiotensin formation was blocked by angiotensin-converting enzyme inhibitors.Following high sodium intake, both angiotensin II (100 nmol/l) and angiotensin I (1 µmol/l) caused a marked increase of the electrically evoked noradrenaline overflow. After inhibition of the angiotensin-converting enzyme using captopril (350 nmol/l) or ramiprilat (50 nmol/l), angiotensin I (1 µmol/l) did not enhance noradrenaline overflow. This indicates an active cardiac angiotensin conversion, since the sole administration of captopril and ramiprilat did not affect noradrenaline overflow in rats with high sodium intake. Following low sodium intake, neither angiotensin II (100 nmol/l) nor angiotensin I (1 µmol/l) significantly affected noradrenaline overflow. Both captopril and ramiprilat, however, significantly reduced noradrenaline overflow induced by electrical stimulation, suggesting a facilitory action of endogenous angiotensin under these conditions.This concept was substantiated when evaluating the noradrenaline overflow during control stimulations. Following low sodium intake, stimulation evoked noradrenaline overflow was higher as compared to that after nutritional sodium load. The results are in keeping with a sodium-dependent intracardiac formation of angiotensin II which facilitates noradrenaline release from sympathetic nerve terminals. Following low sodium intake, cardiac angiotensin II formation is active, as indicated by the suppression of noradrenaline release by angiotensin-converting enzyme inhibitors and the ineffectiveness of exogenous application of angiotensin II. In contrast, suppression of endogenous angiotensin 11 formation in sodium loaded animals sensitizes the sympathetic nerves to exogenous angiotensin.This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 320 — Herzfunktion and ihre Regulation)Presented in part at the 63nd Scientific Sessions of the American Heart Association, Dallas/USA, November 1990 Send offprint requests to G. Richardt at the above address     

Dissociation of the effect of captopril on blood pressure and angiotensin converting enzyme in serum and lungs of spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) of the Okamoto-Aoki strain (n = 40) were treated with captopril (SQ 14,225; D-3-mercapto-2-methylpropanoyl-L-proline) orally, dose 0.2 mg/ml in drinking water. The treatment was initiated early and later during the course of developing hypertension. Continuously treated rats did not develop hypertension. Rats receiving captopril for 12 weeks remained normotensive, whereas withdrawal of the drug resulted in hypertension. Captopril treatment was effective in the rats with established hypertension and decreased the blood pressures to nearly normal values. Serum angiotensin converting enzyme (ACE) activity rose 3-fold in captopril treated rats. ACE in lung plasma membranes increased during captopril treatment, indicating that captopril induced biosynthesis of pulmonary ACE. No qualitative differences were found in the ACE from treated and not treated animals. The dissociation of the antihypertensive effect of captopril and of increased ACE activity in serum and lungs reduce the value of relating blood pressure effects of the drug to measured enzyme activity in the SHR.     

Blood pressure response to angiotensin II is enhanced in obese Zucker rats and is attributed to an aldosterone-dependent mechanism

BACKGROUND AND PURPOSE

Plasma aldosterone levels correlate positively with obesity, suggesting a link between the hypertension associated with obesity and increased mineralocorticoid levels. We tested the hypothesis that aldosterone is involved in the BP response to angiotensin II (AngII) in obese rats.

EXPERIMENTAL APPROACH

Lean (LZR) and obese (OZR) Zucker rats were treated with AngII (9 µg·h⁻¹; 4 weeks), and BP and plasma AngII and aldosterone were determined.

KEY RESULTS

Chronic AngII increased the BP in OZR markedly more so than in LZR. Plasma AngII levels in LZR and OZR were similar after AngII treatment. The AngII stimulated a rise in plasma aldosterone that was sixfold more in OZR than in LZR. The thickness of the zona glomerulosa of the adrenal glands was selectively increased by AngII in OZR. Adrenal mRNA levels of CYP11B2 aldosterone synthase and the AT_1B receptor were selectively increased in AngII-treated OZR. The BP response to chronic AngII stimulation was diminished in OZR after adrenalectomy when plasma aldosterone was absent. Acute bolus injections of AngII did not increase the BP response or aldosterone release in OZR.

CONCLUSIONS AND IMPLICATIONS

The AngII-induced BP response is enhanced in obesity and this is associated with a specific increase in circulating aldosterone. Due to the AngII-induced growth of the zona glomerulosa in OZR, the AT_1B receptors and aldosterone synthase may be selectively enhanced in obesity under concomitant AngII stimulation, increasing the adrenal synthesis of aldosterone. Our results confirm functionally that aldosterone plays a major role in obesity-related hypertension.     

Effects of acute administration of ethanol on the rat adrenal cortex

OBJECTIVE: The purpose of this study was to investigate the effect of a single dose of ethanol on rat adrenal cortex and to determine whether the estrous cycle can influence this effect of ethanol. METHOD: Adult female Wistar rats showing proestrus or diestrus Day 1 (n = 12) were treated intraperitoneally with ethanol (4 g/kg body weight). Untreated (n = 15) and saline-injected (n = 14) rats were used as controls. The animals were sacrificed by decapitation 0.5 hour after ethanol administration. Stereological analysis was performed on paraffin sections of adrenal glands stained with AZAN, and the following parameters were determined: absolute volume of the zona glomerulosa, the zona fasciculata and the zona reticularis, numerical density, volume and the mean diameter of adrenocortical cells and of their nuclei, and diameter and length of capillaries. RESULTS: The diameter and volume of adrenocortical cells in the zona fasciculata and the zona reticularis were significantly increased by acute ethanol treatment at proestrus. In the same group of animals, a single dose of ethanol induced significant decrease in numerical density of adrenocortical cells and of their nuclei in all three zones. Increased length of capillaries of the zona fasciculata as well as enhanced level of serum corticosterone was found in ethanol-treated rats at both phases of the estrous cycle, proestrus and diestrus Day 1. CONCLUSIONS: The obtained results indicate that a single dose of ethanol activates adrenal cortex in female rats and that the effect is more pronounced on morphometric parameters at proestrus.     

Effect of captopril on renal haemodynamics and the renin-angiotensin-aldosterone and osmoregulatory systems in essential hypertension

Summary The effect of captopril on renal plasma flow (RPF), glomerular filtration rate (GFR), plasma concentrations of renin, angiotensin II (Ang II), aldosterone (Aldo) and arginine vasopressin (AVP), serum osmolality (S_osm), free water clearance , fractional urinary excretion of electrolytes and blood pressure (BP), was examined in 10 patients with moderate essential hypertension. Placebo plus furosemide was given for 6 weeks, followed by a 6-week period on captopril and furosemide. The renin-angiotensin-aldosterone system was partly blocked by captopril, resulting in a 18% fall in BP. GFR was reduced by 8% during captopril treatment, whereas RPF remained unchanged. Water loading-induced suppression of Ang II and AVP was inhibited by captopril therapy. Without affecting BP in the placebo period, water loading almost abolished the captopril-induced reduction in BP. It is concluded that non-acute captopril treatment of moderate essential hypertension reduces GFR slightly, possibly by producing dilatation of efferent arterioles. The antipressor effect of captopril is lessened during volume expansion, which may be secondary to reduced activity of the renin-angiotensin-aldosterone and osmoregulatory systems.     

Chronic antihypertensive effects of captopril (SQ 14,225), an orally active angiotensin I-converting enzyme inhibitor, in conscious 2-kidney renal hypertensive rats.

Indirect systolic blood pressure (SBP) was monitored in 9 groups of 15 male conscious 2-kidney renal hypertensive rats (RHR) for over 6 months. Daily oral dosing with captopril (SQ 14,225, D-3-mercapto-2-methylpropanoyl-L-proline, 30 mg/kg), an orally active angiotensin I-converting enzyme inhibitor, lowered SBP 30--50 MM Hg during this period. Withdrawal of captopril for 5 days at 1, 3 and 6 months resulted in gradual return of SBP to control levels without overshoot. Resumption of dosage with captopril again decreased SBP. Daily oral dosing with hydrochlorothiazide (HCTZ, 6 mg/kg/day) alone for 6 months had little or no effect on SBP, but increased the antihypertensive effect of captopril. Daily oral dosing with hydralazine (6 mg/kg) caused an initial marked antihypertensive effect greater than that of captopril but almost complete tolerance developed within 4 weeks of dosing. Highest survival rates occurred in RHR treated with captopril plus HCTZ. In four other similarly treated groups of RHR and normotensive rats (NR), least cardiac hypertrophy and highest plasma renin activity occurred in captopril-treated animals compared with vehicle-treated controls. Plasma renin activity was about 2 to 4 fold higher in the rats dosed with captopril compared with vehicle-treated rats. Heart weight/body weight ratios, initially higher in the two RHR groups compared to NR, decreased only in the captopril treated group to or near those of the NR groups. These results indicate that chronic treatment with captopril decreased SBP and cardiac weights of RHR, and that HCTZ, or possibly other diuretics, can augment the antihypertensive effect of captopril while having little or no effect by themselves.     

Effect of captopril on changes in plasma noradrenaline induced by sodium nitroprusside.

There is much animal data to suggest that angiotensin II has a regulatory role in noradrenaline release. We sought evidence for such a mechanism in man by pretreating six normal volunteers with captopril (50 mg) or placebo and then infusing them with incremental doses of sodium nitroprusside. Pretreatment with captopril had no significant effect on the mean arterial pressure, heart rate or plasma noradrenaline response to sodium nitroprusside, despite increasing plasma renin activity. This suggests that in normotensive salt replete man, normal levels of angiotensin II do not exert any tonic effect on noradrenaline release.