Angiotensin II restoration of reflex adrenal medullary secretion to anephric dogs is physiologically dose dependent

Acute nephrectomy seriously impairs hypovolemic adrenal epinephrine (E) release in the anesthetized dog. That systemically delivered angiotensin II totally restores E release to acutely anephric dogs is equally clear, but the dose-response relationship of this angiotensin II effect is not known. Adrenal secretion rates and arterial plasma E, norepinephrine (NE), and dopamine levels were studied in nine groups of mongrel dogs (n = 5 in each group) under pentobarbital anesthesia: 1) resting animals; 2) hemorrhage (25 ml/kg); 3) hemorrhage after acute nephrectomy; 4-7) hemorrhage, acute nephrectomy, plus iv angiotensin II at a) 0.01 ng/kg X min, b) 0.10 ng/kg X min, c) 1.00 ng/kg X min, or d) 10.00 ng/kg X min; 8) no hemorrhage, acute nephrectomy, angiotensin II (10.00 ng/kg X min); and 9) hemorrhage, kidneys intact, iv angiotensin II (10.00 ng/kg X min). Arterial and adrenal blood were sampled during a baseline prehemorrhage period and 15, 30, 60, and 90 min after hemorrhage. We confirm blunting of reflex E release by acute nephrectomy in the anesthetized dog and show that angiotensin II restores E (P less than 0.01), NE (P less than 0.01), and dopamine (P less than 0.01) release in acutely anephric dogs. Aortic plasma E and NE were also restored to normal by angiotensin II (P less than 0.01 for each). Dogs with intact kidneys show a blunted hemorrhage response of arterial plasma E (P less than 0.01), NE (P less than 0.01), and DM (P less than 0.05) to our largest angiotensin II infusion rate (10 ng/kg X min). The study demonstrates that in acutely anephric conditions, angiotensin II support of reflex catecholamine release is sensitively dose dependent to physiological infusion rates of systemic angiotensin II and suggests further that this angiotensin II effect is restrained by the kidneys.     

Adrenal responses to pharmacological interruption of the renin-angiotensin system in sodium-restricted normal man.

We assessed the role of the renin-angiotensin system in the control of aldosterone secretion in response to sodium restriction in 62 normal subjects. Both saralasin, an angiotensin II antagonist, and SQ 20881, a converting enzyme inhibitor, induced a dose-related decrease in plasma aldosterone levels when the renin-angiotensin system was activated by restriction of sodium intake. Two types of experiments were performed with saralasin. In the first set, a dose-response relationship was established 20 min after beginning infusions ranging from 0.03-1.0 microgram/kg/min. The optimal dose was 0.1 microgram/kg/min, with a reduction in aldosterone levels of -10.1 +/- 3.8 ng/dl (P less than 0.025). Higher doses induced smaller reductions in aldosterone levels. In the second set, a 3-h infusion was given. The results were qualitatively similar but the magnitude was greater (-15 +/- 4 ng/dl; P less than 0.01). The aldosterone response 20 min after administration of SQ 20881 paralleled the angiotensin II response, with the first significant decrement (-6.5 +/- 1.5 ng/dl; P less than 0.01) occurring at 0.1 mg/kg and maximum (-10 +/- 3 ng/dl) occurring at 0.3 mg/kg. Thus, both agents produced qualitatively similar changes in aldosterone secretion in sodium-restricted normal subjects. However, neither reduced sodium restricted aldosterone levels to that measured in sodium-loaded subjects because of the intrinsic limitation of each agent. Saralasin is a partial agonist. SQ 20881 induces an increase in plasma renin activity via interruption of the short feedback loop, which probably limits its action. Yet, these data do support the hypothesis that angiotensin mediates the adrenal's response to sodium restriction in normal man.     

Estimating renin participation in hypertension: superiority of converting enzyme inhibitor over saralasin.

This study was designed to examine more closely the differences in blood pressure responses in hypertensive patients to two agents which block the renin-angiotensin system. Accordingly, 39 seated patients received under the same conditions both saralasin, an octapeptide competitive antagonist of angiotensin II, and the nonapeptide converting enzyme inhibitor, SQ20881, which blocks the generation of angiotensin II from angiotensin I. A second component of the study involved administration of these agents in 10 addtional studies in anephric subjects. Although both agents produced maximal responses in blood pressure that correlated well with each other (p less than 0.001) and with the pretreatment plasma renin levels (p less than 0.001), analysis of the results by renin subgroups revealed significant differences. Thus, both drugs lowered the diastolic pressures of patients with high renin levels, but but converting enzyme inhibitor produced changes of greater amplitude (p less than 0.05). In contrast, saralasin was consistently pressor in both patients with low renin levels and anephric patients in whom converting enzyme blockade preduced no significant changes in blood pressure. Another impressive disparity in the responses to the two agents occurred in the group with normal renin levels in whom saralasin produced either neutral or pressor responses (mean change was +2.0 +/- 1.5 standard error of the mean (SEM) per cent control diastolic pressure) whereas the converting enzyme inhibitor consistently induced depressor responses (mean change was -10.2 +/- 1.2 per cent, p less than 0.001). Altogether, the results suggest that converting enzyme inhibitor tests for angiotensin II-dependent blood pressure with more sensitivity than the partial agonist saralasin. Moreover, it is unlikely that the differences between the responses to the two agents were due to bradykinin accumulation, since depressor responses to converting enzyme inhibitor were not observed in the patients with low renin levels and the anephric patients.     

Effect of intrarenal angiotensin II blockade on renal function in conscious dogs.

The effects of intrarenal infusion of 1-sar-8-ala angiotension II (P 113) and a converting enzyme inhibitor, SQ 20881, at doses that did not affect systemic blood pressure (2.0 mug/kg per min) were studied in conscious, uninephrectomized dogs. In dogs receiving approximately equal to 5 mEq/day of sodium, intrarenal infusion of P 113 increased renal blood flow (RBF) from 219.8 +/- 32.3 to 282.7 +/- 20.0 ml/min (P less than 0.004), and with intrarenal SQ 20881 infusion from 215.3 +/- 14.2 to 278.0 +/- 22.2 ml/min (p less than 0.005). In sodium-restricted dogs (approximately equal to 5 mEq/day), glomerular filtration rate (GFR) also increased with intrarenal P 113 infusion from 57.9 +/- 5.7 to 66.3 +/- 6.6 ml/min (P less than 0.05), and with SQ 20881 infusion from 43.1 +/- 2.1 to 55.7 +/- 4.5 ml/min (P less than 0.01). Dogs on approximately equal to 5 mEq/day of sodium showed significant increases in plasma renin activity (PRA) with intrarenal infusion of the peptides, unmasking a negative feedback inhibition of renin release by angiotensin II. No increases in RBF, GFR, or PRA were seen with infusion without inhibitors, or in dogs give P 113 or SQ 20881 while on approximately equal to 80 mEq/day of sodium. In addition, angiotensin II inhibition increased sodium excretion during sodium restriction. These findings suggest that intrarenal angiotensin II is intimately involved in renal responses to sodium restriction which result in conservation of sodium and water.     

Interaction of angiotensin-converting enzyme inhibitors with the function of the sympathetic nervous system

The effects of the converting enzyme inhibitors captopril and SQ 20881 and the angiotensin II antagonist saralasin were studied on neurogenic vasoconstriction in the rat using both in vivo and in vitro techniques. In the pithed rat the presser response to nerve stimulation at 1 to 30 Hz was reduced by captopril (0.1 and 1 mg/kg), saralasin (4 gmg/kg/min) and SQ 20881 (10 mg/kg). The pressor responses to noradrenaline (10 to 500 ng total dose) were also antagonized by captopril (1 mg/kg only), SQ 20881 and saralasin. In animals bilaterally nephrectomized 18 to 24 hours previously, captopril and saralasin were without effect on responses to nerve stimulation, but captopril still had a small residual effect on responses to noradrenaline.In isolated mesenteric vessels perfused with Krebs solution exogenous angiotensin I and II potentiated vasoconstrictor responses to nerve stimulation in doses that themselves did not have a direct vasoconstrictor effect. This potentiating effect of angiotensin I was antagonized by captopril (6.7 × 10^?8 to 2 × 10^?6mol) and by saralasin (10^?8 mol). The potentiating action of angiotensin II was blocked only by saralasin. These concentrations of the antagonists themselves had no effect on vasoconstrictor responses to nerve stimulation in the absence of angiotensin although higher concentrations of captopril (10^?4 to 3 × 10^?4mol/liter) did antagonize vasoconstrictor responses to both nerve stimulation and noradrenaline.These results indicate that inhibitors of the renin-angiotensin system may impair neurogenic vasoconstriction by interfering with both a preand postjunctional action of angiotensin. In addition, very high concentrations of captopril antagonize neurogenic vasoconstriction by a nonangiotensin-dependent mechanism. This important interaction of angiotensin with the sympathetic nervous system may help to explain the effectiveness of converting enzyme inhibitors as antihypertensive agents.     

Renin and aldosterone secretion under converting enzyme inhibition

The converting enzyme inhibitor (CEI) is known to inhibit the conversion of angiotensin I to angiotensin II. In order to analyse the regulatory mechanisms involved in aldosterone secretion independent of renin-angiotensin system, one of the CEIs, SQ 14,225 was infused to the dogs in association with several pharmacological agents. To the mongrel dogs under pentobarbital anesthesia, SQ 14,225 was administered intravenously as a bolus injection (0.5 mg/kg), followed by two hour infusion (0.5 mg/kg/hr). The effects of several pharmacological agents on plasma renin activity (PRA) and aldosterone concentration (PA) were examined in the condition in which endogenous angiotensin II production was blocked by CEI. PRA was increased significantly from the basal level (6.4 +/- 1.2; mean +/- SEM) to 14.1 +/- 2.6 ng/ml/hr 60 min after the administration of SQ 14,225. PA, on the other hand, was decreased from 12.2 +/- 3.6 to 7.6 +/- 2.2 ng/dl. The CEI-induced increase in PRA was completely blocked by infusion of angiotensin II (40 ng/kg/min), physiological saline (0.25 approximately 0.44 ml/kg/min), pretreatment of propranolol (0.5 mg/kg) or norepinephrine (200 ng/kg/min). Both pindolol and indomethacin had no significant effect on the CEI-induced increase in PRA. Increase in PRA was also observed by the infusion of furosemide, prostaglandin 1 or E1. PA was increased by KCl infusion (1.0 mEq/kg/hr), but was not affected significantly by the administration of furosemide, pindolol, prostaglandin A1 or E1, during the SQ 14,225 infusion. An elevation of PRA observed under the converting enzyme inhibition, was considered to be due to decreased feedback inhibition as a result of reduction of angiotensin II formation. It was suggested from the present results, that the CEI-induced increase in PRA might be mediated by beta-receptor and baroreceptor in addition to the direct negative feedback by angiotensin II. The present data also suggested that both furosemide and prostaglandins stimulated aldosterone secretion via the renin-angiotensin system, rather than by acting directly on the adrenal cortex.     

Reactive hyperreninemia in renovascular hypertension after angiotensin blockage with saralasin or converting enzyme inhibitor.

Baseline plasma renin activity and responses to saralasin and converting enzyme inhibitor SQ 20881 (teprotide) in 47 untreated patients with surgically correctable renovascular hypertension were compared to those in 100 patients with high- and normal-renin essential hypertension. All 32 renovascular patients on normal sodium intake had high renin-sodium profiles and renin values greater than or equal to 5 ng angiotensin I/mL.h, as compared to 20 of 64 with essential hypertension. Diagnostic discrimination was greatly enhanced by infusion of saralasin or SQ 20881, which elicited marked reactive hyperreninemia in 31 of 32 renovascular patients but in only two of 64 with essential hypertension. Reactive hyperreninemia appeared to be more a specific test for renovascular hypertension than depressor responses. Prior dietary sodium depletion abolished this specificity. The results suggest that after initial screening with renin measurements, testing with angiotensin blocking agents may be a useful secondary screening procedure for more invasive and definitive procedures.     

6-Hydroxydopamine treatment diminishes noradrenergic and pressor responses to angiotensin II in adrenalectomized ducks

The extent to which the vasopressor action of angiotensin II (AII) in birds depends upon the sympathetic nervous system in not known. Therefore, we have tested whether the sympathetic neurotransmitter norepinephrine (NE) mediates the residual vasopressor response to AII in adrenalectomized ducks (Anas platyrhynchos). Treatment with 6-hydroxydopamine (6-OHDA) inhibited by up to 100% the pressor effect of exogenous AII in anesthetized adrenalectomized ducks. After high doses of AII, a transient drop in blood pressure (BP) often preceded or supplanted the pressor response. Systolic BP responses to injections of tyramine also were decreased by 6-OHDA, but responses to NE were increased (diastolic BP) or not affected significantly (systolic BP). Inhibition with SQ20881 of converting enzyme, to decrease endogenous production of AII, reduced pressor responses to AI, but did not affect either baseline BP or responses to AII. Thus, the diminished responsiveness to AII in these catecholamine-depleted ducks was not due to competition from endogeneous AII. Furthermore, the increases in plasma NE and E concentrations that normally follow AII injection were abolished by adrenalectomy and 6-OHDA treatment. The coincident extinction of both cathecholamine and vasopressor responses comprises new evidence that AII raises BP in the Pekin duck by stimulating the sympathetic nervous system. The vasopressor response is mediated by extraadrenal as well as adrenal sources of NE.     

Changes in plasma norepinephrine after intravertebral artery infusion of saralasin in sodium depleted dogs

This study was designed to investigate the central action of circulating angiotensin II on the regulation of blood pressure in sodium depleted states. The effects of intravertebral arterial infusion of angiotensin II and [Sar-1, Ala-8] angiotensin II (saralasin) on plasma norepinephrine (NE) were studied in alpha-chloralose anesthetized dogs. Intravertebral arterial infusion of angiotensin II (10 ng/kg/min) increased mean arterial pressure (MAP), heart rate (HR) and plasma NE. Plasma NE was decreased by intravertebral arterial infusion of saralasin (0.40 +/- 0.05 to 0.28 +/- 0.04 ng/ml, p less than 0.05) in normal dogs. The administration of furosemide produced significant increases in plasma NE (142.4 +/- 23.7%, p less than 0.01), plasma renin activity (PRA) (158.6 +/- 26.3%, p less than 0.01) and HR (32.3 +/- 6.0 beats/min, p less than 0.01). A slight rise in mean blood pressure (3.9 +/- 1.2 mmHg, p less than 0.05) was observed during the furosemide administration. Saralasin infused into the vertebral artery significantly suppressed the furosemide-induced increases in plasma NE, HR and PRA, and lowered mean arterial blood pressure. Intravenous infusion of the same dose of saralasin produced no changes in arterial blood pressure, HR and plasma NE. These results suggest that the central sympathetic potentiation induced by circulating angiotensin II may contribute to the regulation of blood pressure in sodium and volume depleted states produced by furosemide.     

Converting enzyme inhibition in hypertensive emergencies.

The diagnostic and therapeutic value of the angiotensin converting enzyme inhibitor teprotide (SQ 20881) was assessed in 18 patients with hypertensive emergencies. Mean blood pressure fell 31 +/- 18 mm Hg in the 10 subjects who responded to 1 mg/kg body weight administered intravenously, whereas it fell 5 +/- 3 mm Hg in the eight nonresponders. In patients who had received no previous drug treatment, log baseline plasma renin activity and change in mean blood pressure after SQ 20881 correlated significantly (r = 0.651, P less than 0.05). After acute therapy with SQ 20881, the patients who had a satisfactory response to the drug were treated with propranolol and a relatively normal sodium intake (88 meq/day). Nonresponders were treated with diuretics and sodium restriction (10 meq/day), and intermediate responders were given combination therapy. Mean blood pressure responded favorably within 24 h to the chosen regimen for each group from 152 +/- 47 to 102 +/- 31 mm Hg. SQ 20881 allows prompt evaluation of the role of renin in hypertensive emergencies and permits early choice of appropriate therapy based on the prevailing mechanism.     

Effect of tetradecapeptide renin substrate on blood pressure, plasma renin activity, and vasopressin and adrenocorticotropin concentrations.

The effects of third ventricular injection of tetradecapeptide renin substrate (TDP) and natural renin substrate prepared from dog cerebrospinal fluid were compared in anesthetized dogs. Central injection of 350 pmol TDP caused a long lasting increase in arterial blood pressure, a reduction in PRA, and increases in plasma levels of vasopressin, and ACTH. In marked contrast, central administration of equimolar doses of natural renin substrate had no effect on these variables. Intracranial administration of the converting enzyme inhibitor SQ 20881 prevented the effects of central injection of TDP. Thus, TDP exerts its effects via conversion to angiotensin II and does not necessitate the postulation of the action of an enzyme with renin-like activity in the brain.     

Haemodynamic effects of angiotensin converting enzyme inhibition after cardiopulmonary bypass in dogs

Recent studies have suggested a possible causative relationship between elevated plasma levels of Angiotensin II (AII) and the vasoconstriction associated with conventional cardiopulmonary bypass. The haemodynamic effects of SQ14225, a specific angiotensin converting enzyme inhibitor, have been studied in a group of five dogs submitted to a 60 min period of cardiopulmonary bypass (CPB). A 20 min infusion of SQ14225 in a dose of 2 microgram .kg-1 .h-1 was administered to each dog 2 h after the end of the period of CPB. Measurements of peripheral vascular resistance index (PVRI), cardiac index (CI) and plasma levels of Angiotensin II were obtained at the start and end of the infusion period. The results in the five blocked dogs were compared with a control series of ten unblocked dogs submitted to an identical cardiopulmonary bypass regine. In the blocked dogs, PVRI fell significantly during infusion of SQ14225 from 38.27 units to 21.70 units (P <0.01). There was a simultaneous significant increase in cardiac index from 3.00 to 3.98 litre.m2 .min-1 (P <0.01). Plasma Angiotensin 11 levels fell in the blocked dogs from 57 to 11.5 pg.cm-2 during the infusion period (normal levels <15 pg.cm-3). In the control unblocked dogs, there was no corresponding fall in PVRI, no rise in cardiac index, and no fall in elevated plasma AII levels. The difference between the groups were statistically highly significant (P <0.005). These results indicate that reduction in elevated plasma AII levels after CPB using converting enzyme inhibitor SQ14225 is associated with a significant fall in peripheral vascular resistance and a significant rise in cardiac index. In addition, the study confirms the causative relationship between elevated plasma levels of Angiotensin II and the increased vasoconstriction associated with non-pulsatile CPB.     

Relative contribution of vasopressin and angiotensin II to the altered renal microcirculatory dynamics in two-kidney Goldblatt hypertension

The renal microcirculation was assessed in non-clipped kidneys of 23 Munich-Wistar rats with two-kidney one-clip Goldblatt hypertension. Four weeks after placement of a renal arterial clip, mean systemic arterial pressure averaged 163 +/- 5 mm Hg in hypertensive rats as compared to 108 +/- 2 in sham-operated controls (n = 6 rats). Non-clipped kidneys in hypertensive rats were characterized by higher glomerular capillary hydraulic pressures, single nephron glomerular filtration rate, and afferent arteriolar resistance. The glomerular capillary ultrafiltration coefficient was significantly reduced in hypertensive rats. In 10 of these rats, intravenous infusion of the angiotensin antagonist, saralasin, or the converting enzyme inhibitor, SQ20881, led to significant reductions in systemic arterial pressure and in afferent and efferent arteriolar resistance, on average by 8 +/- 3%, 15 +/- 4%, 28 +/- 5%, respectively. These changes were associated with significant increase in glomerular plasma flow, while ultrafiltration coefficient remained unaffected. In the presence of saralasin or SQ20881, infusion of a specific antagonist of the vascular action of arginine vasopressin led to significant systemic but not renal vasodilation. Thus, whereas systemic arterial pressure fell further, on average by 23 +/- 2%, renal arteriolar resistance remained constant, resulting in marked reduction in glomerular capillary hydraulic pressures (by 18 +/- 2%) and glomerular plasma flow rate (by 28 +/- 10%). Because of these pronounced reductions in glomerular pressures and flows induced by vasopressin antagonist, single nephron glomerular filtration rate fell markedly in hypertensive rats (by 34 +/- 6%) despite normalization of ultrafiltration coefficient. When hypertensive rats (n = 7) were treated with vasopressin antagonist alone, a modest fall in systemic arterial pressure was again observed in the absence of changes in renal arteriolar resistance. Due to this selective extrarenal vasodilatory action of vasopressin antagonist, glomerular capillary hydraulic pressure, plasma flow rate, and single nephron glomerular filtration rate again fell markedly. When these vasopressin antagonist pre-treated hypertensive rats were given saralasin or SQ20881, marked reductions in renal arteriolar resistance were observed in association with a significant increase in glomerular plasma flow rate. These observations made during acute inhibition of angiotensin II and vasopressin indicate that both of these vasopressin hormones may play important roles in maintaining systemic hypertension in hypertensive rat. By virtue of its preferential constrictor effects on extrarenal rather than renal vasculature vasopressin serves to maintain high glomerular pressures and flows in the non-clipped kidney of Goldblatt hypertensive rats.     

Effects of dopamine and synthetic atrial natriuretic polypeptide on the release of norepinephrine and epinephrine from the adrenal medulla of rats

We evaluated the effects of dopamine (DA) and synthetic atrial natriuretic polypeptide (ANP) on the release of catecholamines (CA) from the adrenal medulla. Adrenal glands of male Wistar rats were superfused with Ringer's solution saturated with 95%, O2, 5% CO2 by the use of a continuous flow incubation system, and norepinephrine (NE) and epinephrine (E) concentrations in the perfusate were continuously measured by high pressure liquid chromatography with fluorescent reaction. And the effects of DA and ANP on the CA release were evaluated. Next the effects of metoclopramide (MC), dopamine (D2) antagonist, and glucagon were added in the Ringer's solution, and the changes of NE and E in the perfusate were determined. Basal secretion of NE and E were 0.02-0.04 ng/mg.wet weight/min and 0.05-0.1 ng/mg.wet weight/min, respectively. DA remarkably decreased both NE and E release, and the suppressive effect was dependent on DA concentration in the perfusate. MC clearly raised NE and E release as well as glucagon. The increasing effect of MC was perfectly suppressed by 10(-4) M of DA. But the effect of glucagon was not blocked by the same dose of DA. Alpha rANP (10(-5)M) slightly decreased the releases of NE and E from adrenal medulla, and the magnitude of the effect of rANP was smaller than that of DA. MC significantly increased NE and E release even when the adrenal gland was superfused with Ringer's solution containing 10(-5)M of rANP. These data suggest that the release of CA from adrenal medulla may be regulated by DA, and that the receptors specifically binding to DA may exist in adrenal medulla as well as sympathetic presynaps. We concluded that DA (but not ANP) may play an important role in controlling (suppressing) the activity of sympathoadrenomedullary system.     

The biochemistry of the renin-angiotensin system and its role in hypertension.

The renin-angiotensin system has an important role in maintaining elevated blood pressure levels in certain forms of experimental and human hypertension. Renin, an enzyme produced by the juxtaglomerular cells of the kidney, acts on a protein substrate found in the alpha 2-globulin fraction of the plasma to produce a decapeptide, angiotensin I. This decapeptide is not directly pressor, but on passage through the pulmonary circulation is converted to an octapeptide, angiotensin II, a very potent pressor substance which acts by causing constriction of arteriolar smooth muscle. In addition to its direct action which increases blood pressure, angiotensin II acts on the adrenal cortex to cause the release of the sodium-retaining hormone aldosterone. Recent evidence suggests that this action may be mediated by the heptapeptide, angiotensin III. Both renin and its protein substrate exist in multiple forms and renin may also exist as a high molecular-weight "pro-hormone," although the physiologic significance of these forms is not clear. The elucidation of the biochemistry of the renin-angiotensin system has provided us with inhibitors which allow the system to be blocked effectively in vivo. Thus, angiotensin antagonists such as Sar 1, IIe 8-angiotensin II and converting enzyme inhibitors such as BPP 9a (SQ 20881) have proved useful in the study of experimental and human hypertension.     

Cholesterol potentiates the coronary artery response to norepinephrine in anesthetized and conscious dogs

We investigated the effect of hypercholesterolemia on coronary and cardiac hemodynamic responses to intracoronary norepinephrine (NE) (0.01 to 10.0 micrograms/min as the bitartrate) in a Gregg cannula autoperfusion system. Coronary blood flow was measured by the radioactive microsphere technique in two groups of open-chest dogs anesthetized with pentobarbital: 10 controls and 8 that were fed a cholesterol-rich diet (CD) which doubled the serum cholesterol level. In the control dogs, NE in doses of 0.01 to 1.0 micrograms/min had no effect on coronary vascular resistance (CVR) but 10 micrograms/min caused a significant decrease to 0.58 +/- 0.12 of control. In the CD dogs, NE at doses of 1.0 and 10.0 micrograms/min significantly reduced CVR, to 0.72 +/- 0.06 and 0.52 +/- 0.11 of control, respectively. There was no consistent effect of NE, at these doses, on myocardial oxygen uptake, left ventricular stroke work index, or maximal positive dP/dt. In a second series of experiments we measured coronary flow with electromagnetic flowmeters in 11 chronically instrumented conscious dogs, 5 controls, and 6 CD. In the control dogs, intravenously administered NE hydrochloride, 0.01 microgram/min, reduced CVR to 0.74 +/- 0.07 of control, and 1.0 microgram/min increased CVR to 1.26 +/- 0.09 of control. In the CD animals, these effects were seen at a 10-fold lower NE dose, 0.001 microgram/min (0.83 +/- 0.11 of control) and 0.1 microgram/min (1.32 +/- 0.06 of control). The vasodilation was blocked by propranolol, and vasoconstriction by phentolamine. We conclude that NE at low doses activates beta-adrenoreceptors to reduce CVR and at higher doses activates alpha-adrenoreceptors to increase CVR; the vasoconstrictor response is inhibited in pentobarbital anesthetized dogs, and hypercholesterolemia sensitizes coronary vessels to both the dilator and constrictor effects of NE.     

Failure of renin suppression by angiotensin II in hypertension

Angiotensin II was infused at rates varying from 0.1 to 10 ng/kg per minute into 49 subjects with hypertension and 26 normotensive subjects and changes in blood pressure, plasma angiotensin II, and plasma renin activity (PRA) were determined after 20 and 30 minutes at each dose. Similar dose-related increases in angiotensin II and blood pressure occurred with a threshold of 1 ng/kg per minute in the normotensive and hypertensive subjects. Whereas angiotensin II induced a significant, dose-related decrement in renin activity in the normotensive subjects, with a threshold of 1.0 ng/kg per minute, no significant change in renin activity occurred in either the normal-renin or high-renin hypertensive subjects. In a separate study, nine normotensive and six hypertensive sodium-restricted subjects were given a converting enzyme inhibitor, SQ 20881, 30 microgram/kg. Despite a significantly greater fall in blood pressure (P less than 0.006) and angiotensin II concentration (P less than 0.045) in the hypertensive subjects, they did not have a greater rise in plasma renin activity. We conclude that angiotensin II reduces renin release in normal man at infusion rates that yield plasma angiotensin II levels within the physiological range but has a strikingly reduced influence on renin release in hypertension. In high-renin hypertension due to renal artery stenosis or nephrosclerosis, renin release is presumed to be relatively autonomous because of a dominant, intrarenal mechanism. The mechanism in normal-renin essential hypertension is not clear, but the abnormality could well be related to the pathogenesis of the hypertension.     

Prior receptor occupancy as a determinant of the pressor activity of infused angiotensin II in the rat.

The pressor responsiveness to angiotensin II and norepinephrine was examined in rats before and during blockade of coverting enzyme activity with the nonapeptide SQ 20881. Responses to angiotensin II were impaired by sodium deprivation but enhanced by sodium loading or bilateral nephrectomy. During the period of converting enzyme blockade, a twofold increase in the angiotensin II pressor response was observed in the salt-restricted rats, whereas only a small change occurred in the salt-loaded rats. Infusion of the inhibitor produced a profound fall in the blood pressure of the salt-depleted rats with a relatively minor fall in the sodium-loaded rats. Norepinephrine pressor responses were slightly potentiated in the salt-restricted rats after administration of SQ 20881, but no change occurred in the salt-loaded or the nephrectomized rats. These observations support the view that the decreased angiotensin II pressor activity during salt deprivation is the result of a prior occupancy of receptor sites by endogenous hormone. Therefore, a change in the number or the affinity of receptors consequent to changes in sodium balance need not be postulated to explain the phenomenon.     

Effects of converting enzyme inhibitor (SQ 20881) on changes in blood pressure and plasma aldosterone induced by angiotensin I or acute hemorrhage in rabbits

The effects of angiotensin converting enzyme inhibitor (CEI) upon blood pressure and plasma aldosterone (PA) were studied in rabbits with a simultaneous infusion of angiotensin I (ANG I) or with hemorrhagic hypotension. Pretreatment with CEI (SQ 20881), 1.0 mg/Kg, inhibited the effects of infused ANG I, 30 ng/Kg/min, upon PA and blood pressure at 30 min of the infusion, but the inhibition on PA was not significant at 60 min of the infusion. The same dose of CEI was ineffective in blocking the effect of 100 ng/Kg/min of ANG I on PA and blood pressure even at 30 min of the infusion. In rabbits with hemorrhagic hypotension, injection of CEI resulted in the decrement in blood pressure, whereas no decrement in blood pressure was observed in normal control rabbits. This study suggests that CEI exerts it's effect in part by inhibiting conversion of ANG I to angiotensin II (ANG II), but this can't exclude other mechanisms.     

Mechanism of the dipsogenic action of tetradecapeptide renin substrate in dogs.

Dogs with chronically implanted third ventricular cannulae showed significant drinking responses to central injections of angiotensin II and tetradecapeptide renin substrate (TDP). The threshold dose for angiotensin II was 1 pmol and for TDP was 70 pmol. Although central injections of TDP led to drinking and appearance of angiotensin II in cerebrospinal fluid, renin substrate prepared from dog cerebrospinal fluid had no effect. The dipsogenic action of TDP was blocked by prior administration of converting enzyme inhibitor SQ20881 (P less than 0.01) but was not affected by either pepstatin or N-acetyl-pepstatin. Thus, converting enzyme acts directly on TDP to produce angiotensin I and then angiotensin II. The results of the present study do not provide evidence for the presence of an enzyme in the brain with renin-like activity.