Related Experiment Videos
Experimental cardiovascular benefits of angiotensin-converting enzyme inhibitors: beyond blood pressure reduction
B A Schölkens1, W Linz, P A Martorana
1BU Cardiovascular Agents, Hoechst AG Frankfurt/Main, Germany.
Insights
Converting-enzyme (CE) inhibitors like ramipril offer cardiac benefits beyond blood pressure reduction. Low doses protect against cardiac hypertrophy and ischemia-reperfusion injury, suggesting local cardiac effects.
Area of Science:
- Cardiovascular Pharmacology
- Renal Physiology
- Cardiac Metabolism
Background:
- Converting-enzyme (CE) inhibitors are widely used for hypertension and heart failure.
- Their cardiovascular benefits are often attributed to systemic blood pressure reduction.
- Potential direct cardiac effects independent of systemic hemodynamics remain less understood.
Purpose of the Study:
- To investigate the direct cardiac effects of CE inhibition separate from blood pressure reduction.
- To determine if sub-antihypertensive doses of ramipril can confer cardioprotection.
- To explore the mechanisms underlying potential local cardiac actions of CE inhibitors.
Main Methods:
- Experiments in rats and dogs using non-antihypertensive doses of ramipril and its active metabolite, ramiprilat.
- Assessment of left ventricular hypertrophy in rats with aortic constriction.
- Evaluation of ex vivo ischemia-reperfusion arrhythmias and cardiodynamic parameters in rats.
- Direct intracoronary infusion of ramiprilat in dogs with experimentally induced myocardial infarction.
Main Results:
- Non-antihypertensive doses of ramipril prevented and regressed cardiac hypertrophy in rats.
- Low-dose ramipril protected against ischemia-reperfusion arrhythmias and improved cardiac function in rats.
- Direct cardiac administration of ramiprilat reduced infarct size in dogs, an effect mimicked by bradykinin and blocked by a bradykinin antagonist.
Conclusions:
- CE inhibition provides cardioprotective effects independent of systemic blood pressure lowering.
- Local cardiac actions, potentially involving bradykinin and the kinin system, contribute to the cardiovascular benefits of CE inhibitors.
- These findings suggest paracrine and/or autocrine roles for the renin-angiotensin system and kinins within the heart.
Abstract:
In an attempt to separate the cardiac effects of converting-enzyme (CE) inhibition from those on blood pressure, experiments were performed in rats and dogs with nonantihypertensive (subhypotensive) doses of the CE inhibitor ramipril. (a) Left ventricular hypertrophy: Rats with aortic constriction treated with a nonantihypertensive dose of ramipril (10 micrograms/kg/day) for 6 weeks showed the same prevention and regression of cardiac hypertrophy as groups receiving the antihypertensive dose of 1 mg/kg/day. Comparable results were obtained in animals treated for 1 year. (b) Ischemia-reperfusion injuries: In rats, subchronic oral administration of ramipril in a subhypotensive dose (10 micrograms/kg/day) prevented ex vivo postischemic reperfusion arrhythmias and improved cardiodynamic and metabolic parameters. Almost complete inhibition of cardiac CE was achieved with this low dose. (c) Acute myocardial infarction: Ramiprilat (40 ng/kg/min) was infused for 6 h into the left coronary artery of anesthetized dogs with a ligation of the descending branch of this artery. This route and the low dose were chosen to achieve local cardiac effects without affecting systemic hemodynamics. Ramiprilat significantly reduced the infarct area expressed as a percentage of the area at risk. This cardioprotective effect of ramiprilat was mimicked by bradykinin and abolished by coadministration of a bradykinin antagonist. Thus, factors beyond blood pressure reduction and load changes may add to the cardiovascular benefits of CE inhibitors. This may indicate local (cardiac) paracrine and/or autocrine effects of the renin-angiotensin system and/or participation of kinins.