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PubMed1987

Effect of inhibition of central angiotensin pressor mechanisms on blood pressure in spontaneously hypertensive rats.

The present experiments were designed to elucidate the role of central angiotensin II (AII) mechanisms in maintenance of established hypertension in adult spontaneously hypertensive rats (SHR) by determining the blood pressure response to chronic intraventricular (i.v.t.) infusion of the converting enzyme inhibitor teprotide or the AII receptor antagonist 1sar,8Thr-AII (sarthran). Male SHR (240-300 g) were given chronic indwelling arterial and venous catheters and bilateral lateral cerebral ventricular cannulae. The acute pressor responses to successive intravenous infusions of AII (sarthran experiments) or angiotensin I (AI; teprotide experiments) and to an intraventricular bolus injection of AII or AI were determined in the conscious rats. A 5-day intraventricular infusion of sarthran (1 or 6 micrograms/h) or teprotide (10 micrograms/h) in isotonic saline was maintained by subcutaneously implanted osmotic minipumps, and pressor responses were retested on the 5th day of intraventricular infusion. Five-day intraventricular sarthran infusion at 1 and 6 micrograms/h reduced the pressor response to intraventricular AII by 48 and 74%, respectively, while intraventricular teprotide (10 micrograms/h) inhibited the pressor response to intraventricular AI by 25%. None of the intraventricular infusions significantly decreased pressor responsiveness to intravenous AII or AI. In separate groups of SHR, tail-cuff blood pressure was monitored before, during, and after a 1-week intraventricular teprotide infusion (10 micrograms/h) or successive intraventricular infusions of sarthran at 1 microgram/h for 2 weeks followed by 6 micrograms/h for 1 week. Neither chronic intraventricular sarthran or teprotide caused a significant lowering of blood pressure in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1988

Interactions between angiotensin II and alpha-adrenoceptor agonists mediating pressor responses in the pithed rat.

1. The aim of the study was to investigate the interactions between angiotensin II (AII) and adrenoceptor-mediated pressor responses in the pithed rat. Emphasis was placed on the effects of AII on blood pressure per se and the possibility of differential effects on alpha 1- and alpha 2-adrenoceptor-mediated pressor responses. 2. A low concentration of the angiotensin converting enzyme (ACE) inhibitor, teprotide (1 mg kg-1) lowered the resting diastolic blood pressure (BP) and attenuated only the second phase components of pressor responses to both alpha 1- and alpha 2-adrenoceptor agonists. Infusion of AII (50 ng kg-1 min-1) did not reverse the attenuating effect of teprotide and did not reliably restore the basal diastolic BP. 3. Although teprotide (10 mg kg-1) did not produce a greater fall in diastolic BP than did the low dose (1 mg kg-1), it attenuated the peak and second phase pressor responses to alpha 1- and alpha 2-adrenoceptor agonists but had no effect on pressor responses to AII or 5-hydroxytryptamine (5-HT). Infusion of AII reversed the effects of teprotide (10 mg kg-1) provided that rats were pretreated with flurbiprofen (5 mg kg-1), confirming that the depressor effects of the higher dose of teprotide are AII-dependent but that demonstration of this was complicated by products of cyclo-oxygenase. 4. The AII-receptor antagonist, saralasin (4 micrograms kg-1 min-1) attenuated alpha 1- and alpha 2-adrenoceptor-mediated pressor responses in a manner similar to that of teprotide (10 mg kg-1), suggesting that in this pithed rat model the alpha-adrenoceptor-mediated responses were selectively facilitated by endogenous AII. 5. Infusion of AII (50 ng kg-1 min-1) over a 60 min period did not produce a pressor response in the absence of other drugs but did facilitate pressor responses to alpha-adrenoceptor agonists. This confirms that AII can modulate alpha-adrenoceptor-mediated responses independently of basal blood pressure. 6. Overall the results indicate a facilitatory role for endogenous AII on alpha-adrenoceptor-mediated pressor responses. This is discussed in relation to the failure to demonstrate this convincingly under similar conditions on sympathetic nerve-mediated pressor responses.

Adrenergic alpha-Agonists↗
PubMed1981

Mechanisms involved in the renal responses to intravenous and renal artery infusions of noradrenaline in conscious dogs.

1. The renal haemodynamic and glomerular filtration rate (G.F.R.) responses to intravenous and intrarenal infusions of noradrenaline were studied in conscious dogs, either with or without prior blockade of angiotensin II formation with teprotide. 2. Infusion noradrenaline by either route resulted in dose-related rises in plasma renin activity. 3. Pretreatment with teprotide reduced the rise in mean arterial pressure and abolished the rise in G.F.R. seen during intravenous infusions of noradrenaline (0.1, 0.2 and 0.4 microgram/kg . min). Noradrenaline also reduced filtration fraction more after teprotide pretreatment. 4. Renal blood flow rose and renal vascular resistance fell in response to I.V. noradrenaline infusions. This renal vasodilatation was unaffected by pretreatment of the dogs with teprotide, indomethacin or DL-propranolol. However after pentolinium pretreatment, I.V. noradrenaline infusion caused a dose-related renal vasoconstriction. 5. Infusion of noradrenaline into the renal artery (0.02, 0.05 and 0.1 microgram/kg . min) resulted in rises in mean arterial pressure and G.F.R. which were abolished by teprotide pretreatment. Filtration fraction rose when noradrenaline was administered alone but fell when it was infused after teprotide treatment. 6. Thus angiotensin II formed as the result of increased renin release acted to maintain G.F.R. and filtration fraction during noradrenaline infusion. In addition, I.V. noradrenaline infusions in conscious dogs caused reflex vasodilatation of the renal vasculature.

Animals↗
PubMed1988

Interactions between angiotensin II, sympathetic nerve-mediated pressor response and cyclo-oxygenase products in the pithed rat.

1. The influence of angiotensin II (AII) on resting blood pressure and on sympathetic nerve-mediated pressor responses in the pithed rat was investigated either by inhibiting the renin-angiotensin system or by infusing AII. 2. Plasma AII levels in the pithed rat were approximately 20 fold higher than in normotensive rats. 3. Infusion of a subpressor dose of AII (50 ng kg-1 min-1) had no effect on sympathetic nerve mediated pressor responses but a pressor dose of AII, (200 ng kg-1 min-1) facilitated nerve-mediated pressor responses. 4. The angiotensin converting enzyme inhibitor, teprotide, and the AII-receptor antagonist, saralasin, lowered the diastolic blood pressure and attenuated sympathetic nerve-mediated pressor responses. There was no difference in the effects of teprotide at 1 mg kg-1 and 10 mg kg-1. Infusion of sodium nitroprusside at concentrations producing a fall in diastolic blood pressure of similar magnitude to that produced by teprotide and saralasin significantly attenuated nerve-mediated pressor responses. 5. After teprotide, AII 50 mg kg-1 min-1 increased diastolic blood pressure. The inhibitory effect of teprotide on nerve-mediated pressor responses was antagonized by this infusion of AII only if the rats were pretreated with the cyclo-oxygenase inhibitor, flurbiprofen. 6. It is concluded that AII is a major determinant of vascular tone in the pithed rat and that inhibition of the renin-angiotensin system attenuates sympathetic nerve-mediated pressor responses at least in part through the fall in blood pressure per se. The demonstration of this is complicated by an excessive release of vasodilator prostaglandins possibly due to the infused AII. Since plasma All levels are high, the effects of blockade of the renin-angiotensin system will be exaggerated and so the importance of All as a modulator of sympathetic responses will be overestimated in this model.

Angiotensin II↗
PubMedDate not supplied

Role of endothelium in conversion of angiotensin I to angiotensin II in rabbit aorta.

Rabbit aortic rings with either an intact endothelium or a disrupted endothelium were used to generate dose response curves to angiotensin I (AI) in the presence (ED50 = 3 X 10(-7) M) and absence (ED50 = 1.7 X 10(-8) M) of 10 micrograms/ml teprotide, a converting-enzyme inhibitor. Treatment with teprotide did not alter responses to angiotensin II (AII). Comparable dose-dependent responses were obtained with AII regardless of endothelial integrity. Contraction velocities in response to angiotensin I (10(-7) M) and AII (10(-7) M) were also measured. Angiotensin II produced a significantly greater contraction velocity (p less than 0.001) than that produced by AI. The amount of conversion to AII by both intact rabbit aortic rings and rings following removal of the endothelium was determined using 125I-AI and 125I-AII. Waters C18 SEP-PAK columns were used to separate AI and AII. During the first 3 to 4 minutes after the addition of AI, contraction velocity measurements and conversion were greater in intact rings than rings without endothelium. Conversion of AI to AII in endothelial-disrupted rings was the same as in intact rings by 5 minutes after the addition of AI. Conversion of AI to AII was inhibited by 30 micrograms/ml teprotide at all times measured, and there was no evidence of an alternate route of metabolism. Angiotensin I contraction velocity measurements after 10 micrograms/ml teprotide also demonstrated impaired efficiency of conversion of AI to AII. Thus, it was established that a lack of endothelium attenuated the rate of conversion of AI to AII initially, and formation of AII with or without endothelium was blocked by teprotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗
PubMed1983

Redundant nature of the vasopressin and renin--angiotensin systems in the control of mesenteric resistance vessels of the conscious fasted cat.

[1-deaminopenicillamine, 4-valine, 8-D-arginine]Vasopressin (DPVDAVP), a specific antagonist of the pressor activity of vasopressin, and teprotide, a converting enzyme inhibitor, were infused intravenously in conscious, fasted (24-30 h) but not water-deprived cats which had been implanted previously with flow probes on their superior mesenteric arteries and with arterial and venous cannulae. Infusion of DPVDAVP (20 micrograms/min) alone or teprotide (1 mg over 5 min) alone caused only small and statistically nonsignificant changes in mesenteric conductance and arterial pressure. However, infusion of DPVDAVP during the plateau phase of the response to teprotide or, conversely, administration of teprotide during the plateau phase of the response to DPVDAVP caused large increases in mesenteric conductance and small but significant decreases in arterial pressure. The results are consistent with the hypothesis that vasopressin and angiotensin are redundant overlapping mechanisms that play a significant role in the control of the mesenteric resistance vessels of the conscious fasted cat; when one system is inhibited, the other compensates to maintain resistance.

Animals↗
PubMed1982

No effect of intrarenal converting enzyme inhibition on canine renal blood flow.

Captopril and teprotide were administered intra-arterially to the kidney and intravenously to inhibit intrarenal and extrarenal converting enzyme (CE), respectively. Captopril was infused at 0.4, 0.8, and 1.6 micrograms . kg-1 . min-1 intra-arterially, and teprotide was given at 0.4 and 0.8 micrograms . kg-1 . min-1 intra-arterially in salt-replete dogs (group 1). Both agents were also given intravenously in the dose of 0.2 mg/kg, known to cause maximal extrarenal CE inhibition. The intra-arterial infusions of the inhibitors had no effect on renal hemodynamics but caused a graded degree of intrarenal CE inhibition. A lesser degree of extrarenal CE inhibition was seen after captopril in these doses. Intravenous administration of captopril and teprotide inhibited extrarenal CE, but only captopril increased renal blood flow (13%). When teprotide was given in a higher dose (group 3, 1.02 mg/kg), it too increased renal blood flow. In salt-deplete dogs (group 2), captopril infused intra-arterially caused a degree of intrarenal CE inhibition comparable with that in the salt-replete dogs but again produced little or no renal hemodynamic changes. When given intravenously in this group, captopril inhibited extrarenal EE and elicited a greater increase in renal blood flow (36%) than in the group 1 dogs. These results indicate that in conscious dogs renal vasodilatation is associated with extrarenal, but not intrarenal, CE inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1978

Renin-angiotensin system inhibition in conscious sodium-depleted dogs. Effects on systemic and coronary hemodynamics.

The role of the renin-angiotensin system in the regulation of the systemic and coronary circulations during sodium depletion was studied in conscious normotensive dogs by i.v. administration of teprotide (0.5 mg/kg), an angiotensin-converting enzyme inhibitor, and saralasin (0.05-5 mug/kg per min), an angiotensin-receptor antagonist. Sodium depletion was produced by administering a low sodium diet and furosemide for 5 days. Administration of both teprotide and saralasin lowered systemic arterial blood pressure and total peripheral vascular resistance. Simultaneously, cardiac output increased, but left ventricular end-diastolic pressure, dP/dt, and dP/dt/P did not change significantly. Furthermore, both agents reduced diastolic coronary vascular resistance and increased coronary blood flow, but did not affect myocardial oxygen consumption, left ventricular work, or myocardial efficiency. These systemic and coronary vasodilator effects of teprotide and saralasin, however, were not observed in normal dogs on a regular sodium diet; in this group, the only effect noted was a slight increase in arterial pressure during saralasin infusion. Arterial plasma concentration of norepinephrine did not differ between normal and sodiumdepleted dogs, nor did it change significantly after teprotide administration. These results suggest that, during salt depletion, angiotensin II exerts an active vasoconstrictor action on the systemic and coronary vessels, but has no significant effects on myocardial contractility or energetics. It also appears likely that the increase in cardiac output observed in sodiumdepleted dogs after angiotensin inhibition was caused, at least in part, by the decrease in systemic arterial pressure.

Angiotensins↗
PubMed1982

Plasma catecholamines and cardiovascular responses during converting enzyme inhibition in normotensive and hypertensive man.

The hemodynamic and plasma catecholamine responses to isometric exercise and head up tilt were investigated in normotensive and hypertensive subjects during normal and low sodium intake and before and during the administration of the converting enzyme inhibitors teprotide or captopril. Although teprotide and captopril decreased significantly the mean arterial pressure during both sodium intakes the normal pattern of hemodynamic response to hand grip and head up tilt was preserved. Moreover changes of plasma catecholamines during hand grip and head up tilt were not affected either by teprotide or captopril. When following the administration of teprotide or captopril fainting occurred either in the seated position or during head up tilt it was associated not only with a decrease in arterial pressure but also with a concurrent reduction in cardiac output and/or hypovolemia. It is concluded that converting enzyme inhibition does not impair significantly the cardiovascular responses which are mediated via the sympathetic nervous system either in normotensive or in hypertensive subjects.

Adult↗
PubMed1983

Inhibition of renin in the primate Callithrix jacchus (common marmoset).

The effects of an antiserum against human kidney renin and of H-142, a peptide inhibitor of human renin, were studied in the primate Callithrix jacchus (common marmoset). In severely volume-depleted (low-salt diet and repetitive injections of furosemide), conscious marmosets, the antiserum reduced blood pressure to the same extent as the converting enzyme inhibitor teprotide (-31 +/- 7 SEM mmHg and -30 +/- 5 mmHg). In mildly volume-depleted (normal salt diet and single injection of furosemide), conscious marmosets, H-142 and teprotide induced a similar fall in blood pressure (-14 +/- 4 mmHg and -15 +/- 2 mmHg). When H-142 was infused after the injection of teprotide, it had no further effect on blood pressure. Conversely, teprotide was ineffective when injected during the infusion of H-142. These results show that in marmosets blood pressure can be lowered by specific inhibitors of human renin. A converting-enzyme inhibitor has similar effects. Hence the renin-angiotensin system appears to contribute significantly to the maintenance of blood pressure in conscious, volume-depleted marmosets.

Angiotensinogen↗
PubMed1993

Angiotensin-converting enzyme inhibitors have no effect on ovulation and ovarian steroidogenesis in the perfused rat ovary.

The null hypothesis of this study was that the angiotensin-converting enzyme inhibitors, captopril and teprotide, would not reduce the number of ovulations in vivo and in vitro in the rat. Captopril (in three regimens) was administered continuously beginning prior to pregnant mare's serum gonadotropin and hCG to trigger ovulation. The number of in vivo ovulations were counted. Ovaries similarly primed with pregnant mare's serum gonadotropin were dissected and perfused in media with hCG and captopril (two regimens) or teprotide (one regimen). The number of in vitro ovulations and steroid production in the perfusions were evaluated. The results were evaluated by the Student's t test. Power calculations gave only a 20% chance of missing a 16% difference in ovulations or steroidogenesis. There was no inhibition of ovulation or change in steroid production in angiotensin-converting enzyme treated rats in vivo or in vitro. While angiotensin II has been shown to be an important mediator in the mechanism of ovulation, angiotensin-converting enzyme inhibition via captopril or teprotide does not result in angiotensin II antagonistic effects. Hypothetical mechanisms to explain this paradox are presented.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Combined intrarenal renin-angiotensin blockade alters renal function and this is reversed by angiotensin II.

All the components of the renin-angiotensin system are present within the kidney and intrarenal effects have been demonstrated. We have previously shown that intrarenally confined doses of angiotensin II (Ang II) decreased renal excretory and haemodynamic function. In the present study we investigated an increase in renal excretory and haemodynamic function in response to intrarenally confined doses of the renin inhibitor ACRIP to inhibit renin, teprotide to inhibit the angiotensin converting enzyme (ACE) and saralasin to block Ang II receptors. We studied the effects of combined intrarenal blockade of the renin-angiotensin system in five female uninephrectomized conscious dogs on a sodium metabolic balance of 5 mmol/day. We infused ACRIP, teprotide and saralasin combined over 30 min in doses confined to the kidney, and again with an intrarenally confined dose of Ang II. There were no changes in renal function during the control study. During the combined infusion (ACRIP + teprotide + saralasin), the urine flow rate increased from 0.4 +/- 0.1 to 0.9 +/- 0.1 ml/min (P less than 0.001), urinary sodium excretion increased from 6.4 +/- 0.4 to 30.2 +/- 2.5 mumol/min (P less than 0.0001), the glomerular filtration rate increased from 29.3 +/- 0.7 to 42.0 +/- 1.2 ml/min (P less than 0.0001), renal plasma flow increased from 60.3 +/- 0.8 to 139.6 +/- 1.8 ml/min (P less than 0.001) and the fractional sodium excretion increased from 0.1 +/- 0.01 to 0.5 +/- 0.04% (P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1982

Effect of converting enzyme inhibition on the renal haemodynamic responses to noradrenaline infusion in the rat.

1 The renal haemodynamic responses to a close arterial infusion of noradrenaline (29.7-177.9 nmol kg-1 h-1) were measured in rats anaesthetized with pentobarbitone. Systemic blood pressure was unaffected by noradrenaline infusion at this dose level. Renal blood flow was significantly reduced by 16% while glomerular filtration rate remained unchanged. These responses resulted in a rise in filtration fraction of some 10%. 2 In a separate group of animals, noradrenaline infusion in this manner and at similar dose rate increased plasma renin activity approximately 3 fold. 3 Continuous infusion of the angiotensin converting enzyme inhibitor, teprotide (3.36 mumol kg-1 h-1), had no measurable effect on systemic blood pressure, renal blood flow, glomerular filtration rate or filtration fraction. 4 Infusion of noradrenaline into these animals receiving teprotide caused a significant fall in renal blood flow of 16%. There was a fall in glomerular filtration rate of some 17% which was significantly different from the response observed in the animals not receiving teprotide. There was a consequent small but insignificant fall in filtration fraction. 5 These data show that the regulation of glomerular filtration rate in response to the vasoconstrictor drug, noradrenaline, is partly mediated via the renin-angiotensin system. They provide evidence for a role of intrarenal angiotensin II in regulating glomerular filtration by causing efferent arteriolar vasoconstriction.

Angiotensin II↗
PubMed1988

Intrarenal kallikrein-kinin activity in acute renovascular hypertension in dogs.

The intrarenal kallikrein-kinin system was studied during the acute phase of renovascular hypertension induced by renal artery constriction and during teprotide inhibition of kininase II in the dog. Kallikrein-like activity measured by both kininogenase and esterolytic assays, was increased during renal artery constriction (p less than 0.5) and (p less than 0.01). The administration of teprotide resulted in a further increase of renal cortical kallikrein-like activity and inhibited kininase II activity (p less than 0.01). Following the inhibition of kininase II, the plasma concentration of kininogen was also significantly decreased (p less than 0.01). These results suggest that kininase II inhibition may increase levels of intrarenal and plasma kinins and that decreased degradation of kinin peptides may contribute significantly to the acute hypertensive effect of teprotide.

Animals↗
PubMed1978

Role of the renin-angiotensin system in the systemic vasoconstriction of chronic congestive heart failure.

In 15 patients with severe chronic left ventricular failure, plasma renin activity (PRA) ranged widely, from 0.2--39 ng/ml/hr. The level of PRA was unrelated to cardiac output (CO) or pulmonary artery wedge pressure (PWP), but was slightly negatively correlated with mean arterial pressure (MAP) (r = -0.45) and systemic vascular resistance (SVR) (r = -0.40). After infusion of the angiotensin converting enzyme inhibitor teprotide (SQ 20,881) PWP fell from 26.3 +/- 1.3 (SEM) to 20.3 +/- 1.4 mm Hg (P less than 0.001), CO rose from 3.94 +/- 0.23 to 4.75 +/- 0.31 l/min (P less than 0.001), MAP fell from 87.5 +/- 3.8 to 77.9 +/- 4.1 mm Hg (P less than 0.001) and SVR from 1619 +/- 148 to 1252 +/- 137 dyne-sec-cm-5 (P less than 0.001). The fall in MAP and in SVR was significantly correlated with control PRA (r = 0.68 and r = 0.58, respectively). When subjects were divided on the basis of control PRA the hemodynamic response to teprotide was greatest in the high renin group. PRA rose after teprotide (8.7 +/- 3.4 to 37.9 +/- 7.7 ng/ml/hr, P less than 0.05) but plasma norepinephrine fell (619.1 +/- 103.6 to 449.7 +/- 75.7, P less than 0.05). The renin-angiotensin system thus appears to have an important role in the elevated SVR in some patients with heart failure. Chronic inhibition of converting enzyme should be explored as a possible therapeutic approach.

Adult↗
PubMed1982

Renin-angiotensin system inhibition in acute myocardial infarction in dogs. Effects on systemic hemodynamics, myocardial blood flow, segmental myocardial function and infarct size.

Acute left anterior descending coronary artery occlusion was produced in 21 conscious, chronically instrumented dogs. Forty minutes after coronary occlusion, nine dogs were given i.v. teprotide, 25 micrograms/kg/min, followed by oral doses of captopril, 10 mg/kg every 8 hours for 24 hours. The remaining 12 dogs served as saline-infused controls. In all dogs, acute coronary occlusion increased plasma renin activity and peripheral vascular resistance and reduced cardiac output, but did not change mean aortic blood pressure significantly. Teprotide significantly (p less than 0.05) decreased peripheral vascular resistance (from 3804 +/- 1158 to 2876 +/- 816 dy-sec-cm-5) (+/- SD) and mean aortic pressure (from 117 +/- 12 to 107 +/- 15 mm Hg), and increased cardiac output (from 2.63 +/- 0.67 to 3.12 +/- 0.74 l/min). Teprotide also produced a relative increase in flow to the renal and splanchnic circulations compared with the saline-treated controls. There were, however, no differences in segmental systolic shortening, blood flow in the normal or ischemic myocardium, or infarct size. These results indicate that the renin-angiotensin system may play an important role in dogs with acute coronary occlusion and that blockade of this system lowers systemic blood pressure and improves cardiac output. However, direct effects of renin-angiotensin system blockade on the myocardium are lacking; there were no changes in myocardial blood flow, myocardial mechanics or infarct size.

Animals↗
PubMedDate not supplied

Pre- and postjunctional inhibition of vascular sympathetic function by captopril in SHR. Implication of vascular angiotensin II in hypertension and antihypertensive actions of captopril.

The present study was designed to examine the effects of treatment of SHR with captopril, teprotide, and saralasin on vascular and cardiac responses to sympathetic nerve stimulation and angiotensin I and II (AI, AII) and norepinephrine (NE). A single dose of captopril (10 mg/kg i.v. as well as 10 and 100 mg/kg p.o.) caused significant and marked inhibition of pressor responses to sympathetic nerve stimulation in pithed SHR but cardiac responses were unaffected. Pressor responses to AI were abolished but those to AII and NE were not significantly altered. Neither teprotide nor saralasin caused consistent inhibition of sympathetic responses despite total blockade of AI and AII response respectively. Selective inhibition of pressor but not cardiac responses to sympathetic nerve stimulation was obtained after 2 weeks, 3 and 6 months of daily oral doses of captopril. In addition, postjunctional pressor responses to AI, AII, and NE were also significantly inhibited by chronic captopril treatment. Infusion of AII, bilateral nephrectomy, or pretreatment with indomethacin alone in pithed SHR receiving captopril had no effect on the inhibition of pressor responses to sympathetic stimulation. However, the combination of pretreatment of indomethacin and infusion of AII completely restored sympathetic function in SHR receiving captopril. These studies suggest that captopril has a selective inhibitory effect on vascular responses to sympathetic nerve stimulation but not on cardiac responses. Moreover, this effect may have a prejunctional component since, after acute treatment, there is no inhibitory effect on responses to AII or NE. Since, under appropriate conditions, the inhibition can be reversed by AII infusion but not nephrectomy, it is suggested that this inhibition occurs at the vascular level by inhibition of local AII formation by captopril, a site not accessible to teprotide or saralasin.

Angiotensin II↗
PubMed1978

Renin-angiotensin system inhibition in conscious dogs during acute hypoxemia. Effects on systemic hemodynamics, regional blood flows, and tissue metabolism.

The role of the renin-angiotensin system in mediating the circulatory and metabolic responses to hypoxia was studied in three groups of conscious dogs that were infused continuously with normal saline, teprotide (10 mug/kg per min), and saralasin (1 mug/kg per min), respectively. Hypoxia was produced by switching from breathing room air to 5 or 8% oxygen-nitrogen mixture. Plasma renin activity increased from 2.3+/-0.4 to 4.9+/-0.8 ng/ml per h during 8% oxygen breathing, and from 2.8+/-0.4 to 8.4+/-1.8 ng/ml per h during 5% oxygen breathing. As expected, cardiac output, heart rate, mean aortic blood pressure, and left ventricular dP/dt and dP/dt/P increased during both 5 and 8% oxygen breathing in the saline-treated dogs; greater increases occurred during the more severe hypoxia. Teprotide and saralasin infusion diminished the hemodynamic responses to 5% oxygen breathing, but did not affect the responses to 8% oxygen breathing significantly. In addition, the increased blood flows to the myocardium, kidneys, adrenals, brain, intercostal muscle, and diaphragm that usually occur during 5% oxygen breathing were reduced by both agents. These agents also reduced the increases in plasma norepinephrine concentration during 5% oxygen breathing, but had no effects on tissue aerobic or anaerobic metabolism. In dogs pretreated with propranolol and phentolamine, administration of teprotide (0.5 mg/kg) during 5% oxygen breathing reduced mean aortic blood pressure and total peripheral vascular resistance, and increased cardiac output and heart rate, but did not affect left ventricular dP/dt, dP/dt/P, and end-diastolic pressure. Simultaneously, renal and myocardial blood flows increased and myocardial oxygen extraction decreased, while myocardial oxygen consumption did not change significantly. These results suggest that the renin-angiotensin system plays an important role in the hemodynamic responses to severe hypoxia. It appears that angiotensin not only exerts a direct vasoconstrictor action, especially upon the coronary and renal circulations, but also potentiates the cardiovascular effects of sympathetic stimulation that occur during severe hypoxia.

Angiotensins↗