Antihypertensive Effects Of Angiotensin-converting Enzyme Inhibitors Research Articles

Role of race in the pharmacotherapy of heart failure.

To review the literature assessing the differences in response to angiotensin-converting enzyme (ACE) inhibitors and beta-blockers in black patients compared with the response in non-black patients in the management of systolic heart failure. A MEDLINE search (January 1966-May 2001) was performed using heart failure, blacks, Negroid race, adrenergic beta-antagonists, and angiotensin-converting enzyme inhibitors as key words. English-language articles were identified. Additional pertinent articles were identified from review of the references of these articles. All identified references were reviewed. All articles deemed relevant to the subject of this article were included. It has been suggested that the antihypertensive effect of ACE inhibitors and beta-blockers may be less in black patients than in other racial groups. Retrospective reanalyses of major heart failure trials have suggested that black patients may not realize a significant benefit in morbidity or mortality when heart failure is managed with ACE inhibitors or beta-blockers. It has also been suggested that black patients may respond more favorably than non-black patients to the combination of hydralazine and isosorbide dinitrate. Published reanalyses of ACE inhibitor and beta-blocker trials in heart failure provide weak data to support a lack of benefit in black patients. The published literature on this topic is limited by its retrospective nature. Firm conclusions regarding the influence of race on effectiveness of ACE inhibitors and beta-blockers cannot be made until prospective trials, with planned analysis of the effect of race, have been performed.

Effect of aspirin on blood pressure in hypertensive patients taking enalapril or losartan

The ability of angiotensin converting enzyme (ACE) inhibitors to lower blood pressure may in part be due to the formation of vasodilatory prostaglandins. Inhibition of prostaglandin synthesis with aspirin may therefore theoretically attenuate the antihypertensive effect of ACE inhibitors. This trial studied the interaction between aspirin (ASA) and enalapril, an ACE inhibitor, and ASA and losartan, an angiotensin subtype 1 receptor antagonist. Seventeen essential hypertensive patients were studied, maintained on a stable dose of either enalapril (n = 7) or losartan (n = 10) monotherapy for ≥12 weeks before and throughout the study. Each patient received a 2-week course of placebo, 81 mg/day ASA, and 325 mg/day ASA, each treatment separated by a 2-week washout period. Blood pressure (BP) and serum thromboxane B 2 (TXB 2) samples were obtained at the end of each treatment period. Placebo was compared with each dose of ASA for each group. In both the enalapril and losartan groups, mean, systolic, and diastolic BP were unchanged with the addition of ASA. Concentrations of TXB 2 were suppressed to <10% in both groups with ASA. This study demonstrates that 81 to 325 mg/day ASA exerts no significant effect on BP in essential hypertensives taking enalapril or losartan.

Angiotensin I-converting enzyme gene polymorphism and acute response to captopril in essential hypertension.

Insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has been shown to be a determinant for serum ACE level and a marker for several cardiovascular diseases. We investigated whether the ACE gene can predict the therapeutic efficacy of ACE inhibitors in essential hypertensive patients. The response of blood pressure and plasma renin activity (PRA) 1 h after 50 mg captopril administration were evaluated in 82 inpatients with untreated essential hypertension (42 men, 40 women; mean age +/- SD: 52 +/- 13 years; range: 27 to 79 years) in relation to ACE genotypes. There were no differences in age, gender, blood pressure, and PRA in the basal conditions, among essential hypertensive patients with the II, ID, and DD genotypes (n = 36, 34, and 12, respectively). The acute responses of PRA and blood pressure to an ACE inhibitor were similar in the three groups. The blood pressure response was negatively correlated with baseline PRA (r = 0.497). These data suggest that PRA but not the I/D polymorphism of the ACE gene is a useful predictor of the short-term antihypertensive effects of ACE inhibitors.

Neuronal angiotensin-converting enzyme (ACE) gene expression is increased by converting enzyme inhibitors (CEI)

Exposure to angiotensin-converting enzyme (ACE) inhibitors has been associated with increased ACE activity in vivo and in vitro. In the current study, we examined the effects of ACE inhibitors on ACE gene expression and activity in brain and primary neuronal cultures prepared from brains of neonatal spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) controls. ACE mRNA levels were increased in brain and neuronal cultures following ACE inhibitor exposure. A concomitant increase in ACE activity was evident in brain, but ACE activity was decreased in neuronal cultures following ACE inhibitor exposure. Since ACE has been localized to several cell types in the brain, including endothelial cells and glia, as well as neurons, the differences in ACE activity between whole brain and neuronal cultures following exposure to ACE inhibitors may be related to differential regulation of the ACE gene in these cell types. These findings and the observation that ACE mRNA levels are >20-fold higher in cultured neurons from neonatal SHR than in those from WKY support the conclusions that the activity of the brain renin angiotensin system is enhanced in SHR and that blockade of this system by chronic ACE inhibitor treatment contributes to the sustained antihypertensive effect of ACE inhibitors in this model.

ACE Inhibition and Pressor Responsiveness to Norepinephrine in Hypertensive Patients

The pressor response to norepinephrine (NE) was assessed in normal renin essential hypertensive patients before and after they were randomly assigned to receive in parallel groups of treatment a single dose of an angiotensin converting enzyme (ACE) inhibitor (captopril or lisinopril) or a prolonged therapy with lisinopril (30-45 days) or with hydrochlorothiazide (9 days). Blood pressure was significantly reduced by all treatments. The pressor response to NE was unchanged after the single administration of the ACE inhibitors, while it was blunted after chronic administration of lisinopril and after the diuretic. On the basis of these results, it is suggested that the attenuation of the sympathetically mediated vasoconstriction may represent an additional mechanism contributing to the antihypertensive effect of ACE inhibitors administered chronically.

Angiotensin Converting Enzyme Inhibition

With chronic angiotensin converting enzyme (ACE) inhibition, blood pressure remains controlled throughout the day despite intermittent recovery of normal function of the renin-angiotensin system. This has been taken as evidence to suggest that the disappearance of angiotensin II (Ang II) from the circulation is not the main mechanism involved in the blood pressure-lowering action of ACE inhibitors. However, the degree of ACE inhibition is often not reliably estimated by the commonly used measurements of plasma ACE activity in vitro or plasma im-munoreactive Ang II levels. The most appropriate method to assess ACE activity seems to be the measurement of the ratio between circulating angiotensin-) 1–8)octapeptide and angiotensin I (Ang I) concentrations. The octapeptide Ang II can be measured precisely using high pressure liquid chromatography followed by a radioimmunoassay. Even using such improved methods, with long-term ACE inhibi- tion. there exists a clear dissociation between the time course of ACE inhibition and that of the antihypertensive effect. Although it is attractive to speculate on this basis that other pathways such as blockade of tissue renin or enhanced vasodilator activity are responsible for the antihypertensive effect of ACE inhibitors, it is important to remember that the dissociation between the pharmacokinetic profile and the time course of the antihypertensive effect is not specific for ACE inhibitors and is well known with other agents. Since intermittent reduction of circulating Ang II is still an omnipresent feature of ACE inhibition, it seems at present that ACE inhibitors reduce blood pressure predominantly by this mechanism.

Angiotensin Converting Enzyme Inhibition

With chronic angiotensin converting enzyme (ACE) inhibition, blood pressure remains controlled throughout the day despite intermittent recovery of normal function of the renin-angiotensin system. This has been taken as evidence to suggest that the disappearance of angiotensin II (Ang II) from the circulation is not the main mechanism involved in the blood pressure-lowering action of ACE inhibitors. However, the degree of ACE inhibition is often not reliably estimated by the commonly used measurements of plasma ACE activity in vitro or plasma immunoreactive Ang II levels. The most appropriate method to assess ACE activity seems to be the measurement of the ratio between circulating angiotensin-(1-8)octapeptide and angiotensin I (Ang I) concentrations. The octapeptide and angiotensin I (Ang I) concentrations. The octapeptide Ang II can be measured precisely using high pressure liquid chromatography followed by a radioimmunoassay. Even using such improved methods, with long-term ACE inhibition, there exists a clear dissociation between the time course of ACE inhibition and that of the antihypertensive effect. Although it is attractive to speculate on this basis that other pathways such as blockade of tissue renin or enhanced vasodilator activity are responsible for the antihypertensive effect of ACE inhibitors, it is important to remember that the dissociation between the pharmacokinetic profile and the time course of the antihypertensive effect is not specific for ACE inhibitors and is well known with other agents. Since intermittent reduction of circulating Ang II is still an omnipresent feature of ACE inhibition, it seems at present that ACE inhibitors reduce blood pressure predominantly by this mechanism.

Effects of chronic administration of angiotensin converting enzyme (ACE) inhibitors on blood pressure and tissue ACE activity in the SHR.

Although ACE inhibitors have proven clinically effective as antihypertensive agents, the mechanisms by which they lower blood pressure are not clearly understood. While inhibition of circulating enzyme has been thought to be of primary importance, reductions in circulating angiotensin II levels do not appear to mediate the antihypertensive effects of ACE inhibitors in hypertensive animals or man (1,2). As previously demonstrated, inhibition of tissue components of the renin-angiotensin system may be an important factor involved in blood pressure reduction (1,3). In this regard, we have shown in a comparative study of several ACE inhibitors that while inhibition of circulating ACE activity is not well correlated with antihypertensive effects in SHR, changes in aorta and/or brain may be necessary for the acute effects of these compounds (4). In the present study, we have compared the chronic effects of enalapril and two new ACE inhibitors, CGS 14824A and CGS 16617, on blood pressure, tissue ACE activity, and components of the renin-angiotensin system in conscious SHR. CGS 14824A, like enalapril, is an ester pro-drug, while CGS 16617 is a diacid which does not require hydrolysis for in vivo activity.

Effect of acute oral administration of captopril and MK-421 on vascular angiotensis converting enzyme activity in the spontaneously hypertensive rat

Vascular angiotensin converting enzyme (ACE) may be important as a potential site of action for the antihypertensive effect of ACE inhibitors. ACE activity, estimated by hydrolysis of [ 3H] HipGlyGly, was similar in the aorta, mesenteric and carotid arteries of SHR. ACE activity in veins was not as consistent and was significantly lower in the jugular veins and vena cava of SHR than in the arteries. Nevertheless, ACE activity in all the blood vessels examined, although less than lung ACE activity, was higher than ACE activity found in other tissues such as brain, heart and kidney. Equieffective antihypertensive doses of captopril (10 mg/kg p.o.) and MK-421 (1.0 mg/kg p.o.) dramatically inhibited ACE activity in all the arteries and veins examined. Maximal ACE inhibition occured within 15 minutes after the oral administration of captopril. In contrast, maximal ACE inhibition was slower in onset and of longer duration after MK-421 than after captopril for all the vessels. Thus, relatively high ACE activity can be measured in both arteries and veins from the spontaneously hypertensive rat (SHR) and ACE was dramatically inhibited after antihypertensive oral doses of captopril or MK-421. Furthermore, vascular ACE inhibition can be used to compare the onset and duration of activity of ACE inhibitors; MK-421 has a longer onset and duration in SHR than captopril based on inhibition of ACE in blood vessels.