Cardioprotective potential of angiotensin converting enzyme inhibitors.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
I Gavras
Publications and source records attributed to I Gavras.
Effects of bradykinin and prostaglandin inhibition on systemic and regional hemodynamics in conscious normotensive rats.
These experiments were designed to study the effects of inhibition of endogenous bradykinin and/or prostaglandins on systemic and regional hemodynamics in conscious normotensive rats, using the radioactive microsphere technique. Administration of either a bradykinin antagonist (50 micrograms/min for 5 min) or indomethacin (10 mg/kg) alone, decreased the cardiac output by an average of 17.58 and 25.94%, respectively (P less than 0.05), without significant change in total peripheral resistance. Regional blood flow decreased and local vascular resistance increased in most organs. Coronary and renal blood flow decreased by an average of 16.45 and 17.26% with bradykinin antagonist and 23.85 and 19.80% with indomethacin, respectively (P less than 0.05). Indomethacin but not bradykinin antagonist also decreased cerebral blood flow by an average of 47.57% (P less than 0.01). Infusion of the bradykinin antagonist following prior prostaglandin inhibition with indomethacin did not induce further changes in either systemic or regional hemodynamics, except in the liver where a significant additional increment in vascular resistance was observed. Our data suggest that most organs have similar patterns of regional vascular sensitivity to bradykinin and prostaglandins (including the heart, kidney, testis, stomach, skin and adrenal). The major differences were in the cerebral vasculature, which was much more sensitive to prostaglandins, and in the liver, spleen and small intestine, which were more sensitive to bradykinin. We conclude that both hormonal systems participate to a varying extent in the maintenance of resting vascular tone in most organs; however, in some cases, their effects may be additive and in others they may work in opposite directions.
Animals↗
Angiotensin converting enzyme inhibitors.
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Angiotensin-Converting Enzyme Inhibitors↗
A novel bradykinin antagonist with improved properties.
Acylation of the N-terminus of [D-Arg0, Hyp3, Thi5,8, D-Phe7] bradykinin with 1-adamantanecarboxylic acid results in an analogue with enhanced potency of at least 33-fold. The new antagonist has potential as a pharmacological tool in the investigation of the role of endogenous bradykinin in cardiovascular regulation.
Adamantane↗
Two highly effective V1/V2 antagonists of vasopressin containing novel thioacids at position 1.
In an attempt to develop more effective and selective V1/V2 antagonists of arginine vasopressin (AVP), two analogues have been designed and synthesized. In position 1 they contain thioacids that include a heteroatom in the cyclohexane ring. The 4-thio-4-tetrahydrothiopyraneacetic acid modification of position 1 used in one of them had advantages over the 1-mercaptocyclohexaneacetic acid substituted compound used as reference. The new compound was weaker at lower doses, but elicited a greater response at higher doses, whereas the reference compound reached its plateau earlier. Although the 4-thio-4-tetrahydropyraneacetic acid substitution used in the second compound resulted in a less potent analogue on a weight basis, this substitution also confers enhanced overall efficacy in terms of magnitude of effect.
Animals↗
Effects of chronic administration of a vasopressin antagonist with combined antivasopressor and antiantidiuretic activities in rats with left ventricular dysfunction.
The present experiments were designed to study the long-term aquaretic effect of [d(CH2)5-D-Tyr(Et)VAVP], an antagonist to arginine vasopressin (AVP) with combined vascular (V1) and renal (V2) receptor inhibiting properties, in rats with left ventricular dysfunction resulting from myocardial infarction (MI). The continuous intravenous infusion of the AVP antagonist (36 micrograms/12 microliters/day) via osmotic minipumps over 11 days resulted in an increase in urine volume and a decrease in urinary osmolality by approximately 10-fold on the first day, but in subsequent days this response decreased in both the post-MI (n = 7) and normal (n = 6) rats. Nevertheless, the daily urine volume remained significantly higher and the urinary osmolality lower in the post-MI rats than in the normal ones throughout the study (p less than 0.05). In two other groups of post-MI (n = 5) and normal (n = 6) rats, intermittent intraperitoneal injections of the AVP antagonist (100 micrograms/kg) every third day resulted in a profound diuresis that was reproducible by each injection and was again significantly greater in the post-MI rats than in the normal rats (p less than 0.05). The cumulative urinary output over the first 10-day period of each treatment was greater with intermittent injections than with continuous infusion in both the post-MI and normal rats, but the difference was significant only in the post-MI rats (398.82 +/- 12.87 ml vs 309.07 +/- 32.44 ml, intermittent vs continuous, respectively, p less than 0.05), even though the cumulative dose of AVP antagonist given intermittently was only about one third of that given continuously.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cardioprotective potential of angiotensin-converting enzyme inhibitors.
Antihypertensive drugs have various effects, both positive and negative, on metabolic and hemodynamic risk factors for coronary artery disease. Cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors have recently been described. The benefits of ACE inhibition include not only a reduction in blood pressure but also improved insulin responsiveness, prevention of potassium loss, diminished myocardial oxygen demand, suppression of catecholamines, and interaction with bradykinin and prostaglandins. These benefits result in improved perfusion of vital organs, diminished cardiac work, and protection of coronary vessels, evident in improved left ventricular systolic and diastolic function, elevation of the anginal threshold in ischemic heart disease, and decreased morbidity and mortality in congestive heart failure.
Angiotensin-Converting Enzyme Inhibitors↗
Effects of a novel renin inhibitor in patients with essential hypertension.
The effects of A-64662, a new specific renin inhibitor, on plasma renin activity (PRA) and blood pressure (BP) were studied for the first time in patients with essential hypertension. A single intravenous bolus of vehicle, 0.001, 0.003, 0.01, 0.03, and 0.1 mg/kg was given to the first four patients, maintained on a constant 100 mEq Na diet. PRA was promptly reduced from 3.4 +/- 2.9 (mean +/- SEM) to 0.2 +/- 0.06 ng/ml/h, a 94% inhibition with the smallest dose, and to undetectable levels (less than 0.1 ng/ml/h) with the larger ones. However, BP did not change within this dose range. The subsequent seven patients received larger doses ranging from 0.2 to 1.0 mg/kg. In three cases, there was reduction in BP on the second dosing day, at doses of 0.4, 0.7, and 1 mg/kg. All responses were late (at 110 min after the injection), transient, and unrelated to baseline PRA. These results strongly suggest that there is a dissociation between the effectiveness of A-64662 in inhibiting PRA and its blood pressure lowering effect in hypertensive patients.
Adult↗
Effect of aging on vasopressin, catecholamines, and alpha 2-adrenergic receptors.
To characterize normal changes with aging, we measured plasma levels of epinephrine, norepinephrine, and vasopressin, as well as alpha 2-adrenergic receptor numbers (Bmax) and the antagonist dissociation constant (Kd) from platelet-derived membranes of white, younger (aged 28 +/- 6 years, n = 30) and older (aged 70 +/- 4 years, n = 41) normotensive, healthy volunteers. There were no differences in resting vasopressin or epinephrine levels at 0.83 +/- 0.83 and 360 +/- 120 pmol/L in the younger versus 1.0 +/- 0.2 and 450 +/- 420 in the older subjects, respectively. However, plasma norepinephrine was significantly higher in the older (2.87 +/- 1.34 nmol/L) versus the younger subjects (1.50 +/- 0.53 nmol/L, P less than .01). Platelet alpha 2-receptor numbers were significantly lower in the older subjects at 289 +/- 79 fmol/mg protein versus 388 +/- 81 fmol/mg protein in the younger subjects (P less than .01), compatible with but not proof of down-regulation by norepinephrine. However, Kd, representing receptor affinity, was similar in both groups. Therefore, studies of hormone and receptor status in various pathologic conditions should always take into account the normal changes attributable to the age of the subject population.
Adult↗
Effects of a vasopressin antagonist with combined antipressor and antiantidiuretic activities in rats with left ventricular dysfunction.
These experiments assessed the hemodynamic and aquaretic effects of an arginine vasopressin (AVP) antagonist with dual V1V2-receptor inhibiting properties in rats with congestive heart failure resulting from ischemic cardiomyopathy. The compound d(CH2)5-D-Tyr(Et)VAVP was used in these studies. Rats with limited or extensive myocardial infarcts (i.e., with less than 50% or greater than 66% necrosis of the left ventricular wall, respectively, induced by left coronary ligation) and sham-operated controls received the AVP antagonist (100 micrograms/kg i.v.) 4 weeks later. This agent produced an 18% increase in cardiac output (p less than 0.05) and 13% decrease in systemic vascular resistance in the severely damaged rats, both changes being significantly different from those seen in the normal controls or the rats with limited infarcts. All animals exhibited increases in urinary output of 4-10-fold over baseline. We conclude that the hemodynamic and renal effects of this agent are beneficial in animals with left ventricular dysfunction.
Animals↗
Pressor hormones in elderly hypertensive persons. Racial differences.
The purpose of this study was to examine pressor hormones and platelet alpha 2-adrenergic receptors in elderly unmedicated free-living subjects. Eighty-seven subjects, 70 +/- 5 years old (mean +/- SD), hypertensive or normotensive (blood pressure less than 160/90 mm Hg) were recruited for measurement of blood levels of norepinephrine, epinephrine, and vasopressin, as well as density and affinity of alpha 2-adrenergic receptors from platelet membranes, assessed by maximal binding (Bmax) and dissociation constant (Kd) of rauwolscine. They were separated into white hypertensive (n = 22) or normotensive (n = 41), and black hypertensive (n = 11) or normotensive (n = 13) groups, with similar age distribution throughout and similar blood pressure levels in the hypertensive and normotensive groups. Vasopressin was higher in the black hypertensive than white hypertensive group (1.5 +/- 1.0 vs. 0.7 +/- 0.5 pg/ml, respectively, p less than 0.005), whereas epinephrine correlated inversely with diastolic blood pressure (r = -0.7, p less than 0.02, in the black hypertensive group). Kd was higher in the black normotensive group than in the other groups (1.6 +/- 0.6 vs. 1.0 +/- 0.2, 1.1 +/- 0.3, or 1.0 +/- 0.3 nM in the white normotensive, black hypertensive, or white hypertensive group, respectively, p less than 0.002). Bmax was no different among groups but was significantly correlated with vasopressin levels for the whole group (r = 0.4, p less than 0.0004) although no such correlation existed within the black hypertensive group. The data suggest that various vasoconstrictor systems participate to different extents in the mechanisms generating and sustaining hypertension in elderly white and black subjects.
Aged↗
Angiotensin-converting enzyme inhibitors in hypertension and congestive heart failure.
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Angiotensin-Converting Enzyme Inhibitors↗
Renin inhibition with A-64662: effect on blood pressure and hormonal response in man.
We studied the effects of intravenous injections of the renin inhibitor A-64662 on blood pressure, plasma renin activity (PRA), angiotensin II (Ang II) and aldosterone levels in patients with essential hypertension. While PRA was completely suppressed with doses as small as 0.001 microgram/kg, blood pressure was affected only in a few instances in doses of 0.4-1.0 mg/kg. In the six patients in whom Ang II and aldosterone results were available these hormones were concomitantly reduced with PRA, although the PRA inhibition lasted much longer (up to 24 h). There was little relationship between the blood pressure changes and plasma levels of renin activity, Ang II and aldosterone, suggesting that the plasma pool of these variables may not be the crucial factor determining blood pressure responses in patients with essential hypertension.
Aldosterone↗
Salt-induced hypertension: the interactive role of vasopressin and of the sympathetic nervous system.
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Animals↗
Hypertension in the aging patient. Implications for the selection of drug therapy.
Although earlier debates had questioned the wisdom of treating hypertension in elderly patients, it is now becoming apparent that such treatment is warranted. Systolic hypertension, which prevails in this population, is more closely correlated to hypertensive complications than is diastolic blood pressure. Recent multicenter trials have demonstrated that in this age group, as in younger patients, control of hypertension can significantly decrease the rate of cardiovascular and cerebrovascular events. Many effective antihypertensive agents are available today, but elderly patients, because of their hemodynamic and biochemical characteristics, are particularly vulnerable to the common side effects of most drugs. However, the two newer classes of drugs (the angiotensin-converting enzyme inhibitors and the calcium channel blockers) offer several advantages in terms of favorable hemodynamic and biochemical profiles, convenience of dosing, and maintenance of quality of life. These characteristics justify choosing these agents as first-line therapy for hypertension.
Aged↗
Bradykinin antagonism and prostaglandins in blood pressure regulation.
These experiments were designed to analyze the interaction of a bradykinin antagonist with prostaglandins in blood pressure regulation of normotensive rats. Male Wistar rats, divided into three groups, received a 5-minute intra-arterial infusion of the bradykinin antagonist [( DArgo-Hyp3-Thi5,8-DPhe7]BK-TFA) at 250 micrograms/min. Groups were either intact rats (group I, n = 5), pretreated with indomethacin (group II, n = 10), or pretreated with both indomethacin and prazosin (group III, n = 8). The bradykinin antagonist infusion, which was shown to inhibit exogenous bradykinin by greater than 76% in intact animals, did not alter mean arterial pressure in group I rats despite a twofold increase in norepinephrine and a threefold increase in epinephrine. Group II rats presented a progressive increase in mean arterial pressure during the bradykinin antagonist infusion (14 +/- 3 mm Hg), with no statistically significant change in plasma catecholamines. Group III, with lower baseline mean arterial pressure due to alpha 1-adrenergic blockade, had an increase in mean arterial pressure comparable with group II during bradykinin antagonist infusion (22 +/- 5 mm Hg), confirming that this response was not sympathetically mediated. We conclude that in normotensive rats bradykinin plays a role in blood pressure regulation that is closely linked to that of prostaglandins and that points to a balance between these systems.
Adrenergic alpha-Antagonists↗
Intravenous dilevalol in the treatment of severe hypertension.
Dilevalol, the stereoisomer of labetalol, was given in repeated incremental intravenous bolus injections to 10 patients with severe hypertension requiring urgent blood pressure lowering. The mean cumulative dose of dilevalol was 445 +/- 165 mg. Blood pressure was reduced from 201 +/- 33/131 +/- 13 to 150 +/- 12/109 +/- 7 mm Hg (p less than 0.01) and heart rate did not change significantly. In only one patient was the study discontinued because of side effects (nausea and dizziness). There were no other clinically significant adverse reactions and no change was observed in electrocardiogram or routine biochemical and hematologic tests. Five of these patients, who achieved diastolic blood pressure of less than or equal to 105 mm Hg, participated in a subsequent outpatient phase of the study with combination of oral dilevalol with hydrochlorothiazide. Of these only one achieved good blood pressure control. We concluded that in such severely hypertensive patients intravenous dilevalol was safe and effective for the short-term lowering of blood pressure. However, long-term outpatient maintenance with this drug needs further evaluation.
Adult↗
Acute effects of the new angiotensin-converting enzyme inhibitor cilazapril: a pilot study.
This study assesses the magnitude and duration of action of three different oral doses of the new orally active angiotensin-converting enzyme (ACE) inhibitor RO 312848 (cilazapril, Hoffman-LaRoche, Nutley, NJ) on blood pressure and plasma ACE levels. Twelve hypertensive patients were separated into two groups: Group A (n = 6) received two single daily doses of 5 and 10 mg, each preceded and followed by two placebo days, and Group B (n = 6) received 10 and 20 mg on an identical protocol. The onset and duration of an appreciable blood pressure lowering effects were at 2 hours and at least for 12 hours, respectively, whereas suppression of ACE levels occurred at 1 hour and lasted for more than 72 hours. Response of these two parameters was partial after 5 mg, but was maximal after 10 mg and did not increase further with the 20-mg dose. A 5-10 mg dose daily may be sufficient to maintain chronic blood pressure control with this agent, but long-term dose trials are necessary to establish its clinical utility.
Adult↗