Central and Peripheral Inhibition of Angiotensin Converting Enzyme (ACE) in the Shr: Correlation with the Antihypertensive Activity of ACE Inhibitors

Norman, Jon; Lehmann, Monique; Goodman, Frank R.; Barclay, B W; Zimmerman, Mark

doi:10.3109/10641968709164213

Cited by 18 publications

(13 citation statements)

References 3 publications

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“…In their experiments, TPR and aortic pressure were reduced to 76% and 81%, respectively. These results were in agreement with the potency of these two drugs as inhibitors of ACE assessed in vitro (10). It is interesting to examine whether the hemodynamic effects of ACE inhibitors in the ALVF differ from those in the normal animal.…”

Section: Discussionsupporting

confidence: 77%

“…Like enalapril or other recently found ACE inhibitors, the biological action of benazepril is considered to be exerted through benazeprilat, its active metabolite, because be nazepril had a very low inhibitory activity on ACE (9). As regards to ACE inhibition, be nazeprilat is nearly equipotent to enalaprilat in vitro or in vivo when injected intravenously (10).…”

mentioning

confidence: 99%

“…Benazepril is a newly synthesized orally ac tive and long acting ACE inhibitor with no SH group (8)(9)(10)(11)(12). Like enalapril or other recently found ACE inhibitors, the biological action of benazepril is considered to be exerted through benazeprilat, its active metabolite, because be nazepril had a very low inhibitory activity on ACE (9).…”

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confidence: 99%

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Hemodynamic Effects of Benazeprilat in the Anesthetized Dog with Acute Left Ventricular Failure.

et al. 1991

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ABSTRACT-To examine the hemodynamic effects of benazepril, an angiotensin con verting enzyme inhibitor, in left ventricular failure, its active metabolite benazeprilat was administered during acute ischemic left ventricular failure in anesthetized open chest dog induced by repeated injections of plastic microspheres into the left coronary artery. The coronary embolization with microspheres resulted in a moderate and stable left ventricular pump failure characterized by increased left ventricular end diastolic pressure (LVEDP) and decreased cardiac output (CO). Benazeprilat (30 ug/kg) administered intravenously after a stabilization period lowered LVEDP and maintained CO. The total peripheral resistance was reduced with benazeprilat. The oxygen consumption and the coronary blood flow were reduced with benazeprilat be cause of a decrease in wall tension and afterload. These results suggest that benazepri lat (benazepril) has beneficial effects for the treatment of acute left ventricular failure.

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Section: Discussionsupporting

confidence: 77%

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confidence: 99%

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Hemodynamic Effects of Benazeprilat in the Anesthetized Dog with Acute Left Ventricular Failure.

et al. 1991

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“…Because it has been shown that SHR have an impaired baroreflex control of heart rate compared with WKY (24,25), the increment in baroreflex control of heart rate may contribute to the depressor effect of captopril in SHR. In addition, oral administration of ACE inhibitors has been have shown to inhibit brain ACE activity (6,26,27). Our previous study has further shown that early treatment with captopril inhibited the pressor and drinking responses to central administration of All as well as AI suggesting that captopril produced a decrease in the number of central All receptors (20) .…”

Section: Discussionmentioning

confidence: 99%

Effects of Early Treatment of Spontaneously Hypertensive Rats with an Angiotensin Converting Enzyme Inhibitor on Blood Pressure, Baroreflex Function and Cardiac Hypertrophy.

Edwards

Zhang

et al. 1994

Hypertens Res

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The purpose of the current study was to define the critical phase in the development of genetic hypertension during which time application of an angiotensin converting enzyme inhibitor, captopril, would produce long-term antihypertensive effects. In addition, we evaluated two potential mechanisms underlying the long-term antihypertensive effect of early treatment with captopril: alterations in baroreflex sensitivity and cardiovascular remodeling. Separate groups of SHR were placed on captopril in utero, or at 1, 7 or 30 days post birth. The length of therapy was 1-2 months. We also removed captopril from SHR treated in utero at 1, 7 and 30 days post birth. Mean arterial pressures and heart weights were monitored in all rats between 3-4 months of age. Tests of baroreflex function (control of heart rate) were performed in 4-and 9-month old rats using intravenous infusion of phenylephrine and nitroprusside to raise and lower blood pressure, respectively. Mean arterial pressures of SHR placed on captopril at 1 (145 ± 9), 7(141 ± 4) and 30 days (129 ± 4) for 1 month were significantly lower than control SHR (176 ± 7, mmHg), but higher than SHR treated in utero with captopril and maintained on therapy for two months (114 ± 4 mmHg). Similarly, SHR treated with captopril in utero with treatment discontinued at 1, 7 or 30 days post birth showed significantly lower mean arterial pressures than untreated SHR. None of these groups showed blood pressures as low as SHR treated in utero until 2 months of age. These rats continued to show normotensive mean arterial pressures even at 9 months of age. In 4-and 9-month-old captopril treated SHR the sensitivities of baroreflex control of heart rate (slope of the relationship between changes in mean arterial pressure and change in pulse interval) were significantly greater than in untreated SHR. Additionally, the heart weight to body weight ratios of these rats were significantly lower than control rats. These results indicate that early treatment with captopril enhances baroreflex control of heart rate in SHR. This enhancement of baroreflex function may be permanent since it persisted even after captopril had been stopped for 7 months; moreover, the effect of captopril on baroreflex sensitivity may be due to mechanisms other than lowering arterial blood pressure. Our data suggest that captopril treatment applied in short-term intervals from in utero to 2 months of age is effective in lowering the magnitude of hypertension in SHR. Augmentation of baroreflex function and prevention of remodeling of the cardiovascular system may contribute to the permanent prevention of the evelopment of hypertension in SHR treated with captopril. (Hypertens Res 1994; 17: 243-251) Key Words: angiotensin converting enzyme inhibitor, spontaneously hypertensive rats The brain has been found to possess a tissue reninangiotensin system (RAS) independent of the plasma RAS (1-4). Anatomical and functional studies have suggested that enhanced RAS activity in the central nervous system may be involved in t...

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“…With increasing interest in self-contained renin-angiotensin systems within organs such as blood vessels, kidney, heart, and brain, differences in the actions of ACE inhibitors have begun to become apparent, the most likely basis for which would be differences in the distribution of these drugs into various tissues. Most investigators, however, who have attempted to correlate differences in potency and tissue distribution of ACE inhibitors with important actions in vivo did not investigate a very large or diverse array of inhibitors, or a very extensive group of tissues (Chevillard et al, 1988;Cohen & Kurz, 1982;Inada et al, 1986;Jackson et al, 1987a,b;Norman et al, 1987;Sakaguchi et al, 1988;Unger etal., 1984Unger etal., , 1985Unger etal., , 1986a.…”

Section: Introductionmentioning

confidence: 99%

Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE).

Dw¹,

Wang²,

Fung³

et al. 1989

Brit J Clinical Pharma

108

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1. Seven drugs (captopril, zofenopril, enalapril, ramipril, lisinopril, fosinopril, and SQ 29,852) were compared in vitro in homogenates of aorta, brain, heart, lung, and kidney and in sera of spontaneously hypertensive rats (SHR) both with respect to potencies of their active moieties as inhibitors of angiotensin‐converting enzyme (ACE), and, where applicable, rates of hydrolysis of their prodrug ester functions. 2. In ex vivo dose‐response and time‐course studies, the inhibitory effects of the seven drugs on tissue ACEs and their relative distributions to SHR tissues were compared following oral administration. 3. The relative potencies of the inhibitory moieties of the drugs (in parentheses) and the normalized ‘equiactive’ oral doses employed for time‐course studies were: SQ 29,852 (1.0), 100 mg kg‐1; captopril (3.5), 30 mg kg‐1; enalapril (12), 20 mg kg‐1; fosinopril (13), 25 mg kg‐1; zofenopril (20), 10 mg kg‐1; lisinopril (24), 10 mg kg‐1; and ramipril (51), 5 mg kg‐1. 4. Following oral administration of the drugs to SHR, the degree and duration of ACE inhibition in aorta and lung correlated with the antihypertensive actions, with ramipril, lisinopril, and zofenopril producing effects of the greatest magnitude and duration. 5. Ramipril and enalapril did not inhibit brain ACE ex vivo; captopril and zofenopril had modest but short‐lasting effects; and fosinopril, lisinopril, and SQ 29,852 had long‐lasting inhibitory actions, which, with the latter two, were delayed in onset. 6. All of the drugs produced significant inhibition of kidney ACE, with ramipril and fosinopril having somewhat weaker effects, perhaps due to biliary routes of excretion. 7. Captopril, fosinopril, and particularly zofenopril inhibited cardiac ACE ex vivo with degrees and durations that were marked compared with those of the other drugs; preliminary studies with isolated hearts suggest a possible relationship between inhibition of cardiac ACE and preservation of cardiac function subsequent to ischaemia.

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Central and Peripheral Inhibition of Angiotensin Converting Enzyme (ACE) in the Shr: Correlation with the Antihypertensive Activity of ACE Inhibitors

Cited by 18 publications

References 3 publications

Hemodynamic Effects of Benazeprilat in the Anesthetized Dog with Acute Left Ventricular Failure.

Hemodynamic Effects of Benazeprilat in the Anesthetized Dog with Acute Left Ventricular Failure.

Effects of Early Treatment of Spontaneously Hypertensive Rats with an Angiotensin Converting Enzyme Inhibitor on Blood Pressure, Baroreflex Function and Cardiac Hypertrophy.

Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE).

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