© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Combined effects of angiotensin converting enzyme inhibition and angiotensin II receptor antagonism in conscious pigs with congestive heart failure
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
* Corresponding author. Tel.: 001-215-652-2640; Fax: 001-215-652-4692.
Objective: The goal of this study was to determine if the hemodynamic effects of the combined administration of an angiotensin converting enzyme (ACE) inhibitor and angiotensin II type 1 (AT1) receptor antagonist are greater than those produced by either of these agents administered individually during heart failure. Methods: Ten farm pigs were chronically instrumented with aortic, left atrial and right atrial catheters, a left ventricular (LV) pressure gauge, LV dimension crystals, coronary occluders, an ascending aortic flow probe and pacing leads. Heart failure was induced by serial myocardial infarctions followed by repeated rapid ventricular pacing. Results: Heart failure was manifested by significant (p<0.01) decreases in LV dP/dt (–38±5%, from 2943±107 mmHg/s) and cardiac output (–27±4%, from 4.1±0.2 l/min) and increases in left atrial pressure (+18±1 mmHg, from 4±1 mmHg) and total peripheral resistance (TPR)(+40±8%, from 23±2 mmHg/l/min). The effects of an ACE inhibitor (enalaprilat) and an AT1 receptor antagonist (L-158,809), administered in maximally effective doses, either individually or concomitantly, were examined on different days in conscious pigs with heart failure. There were no differences in any of the baseline hemodynamic measurements among the groups studied. Thirty minutes after administration, enalaprilat (4 mg/kg i.v.) increased (p<0.05) cardiac output by 8±2% and reduced (p<0.05) mean arterial pressure and TPR by 5±1 and 12±1%, respectively, while the changes in LV dP/dt (0±2%), LV fractional shortening (+4±3%) and heart rate (+1±1%) were not statistically significant. Similarly, L-158,809 (4 mg/kg, i.v.) increased cardiac output by 9±2% and reduced mean arterial pressure and TPR by 4±1 and 11±3%, respectively, while the changes in LV dP/dt (+3±3%), LV fractional shortening (+3±1%) and heart rate (0±1%) were not significant. However, enalaprilat (1 mg/kg, i.v.) and L-158,809 (1 mg/kg, i.v.), administered concomitantly, reduced TPR by 21±3%, an effect greater (p<0.05) than when either of these agents was administered individually at a dose of 4 mg/kg, i.v. The changes in mean arterial pressure (–9±2%), cardiac output (+15±4%) and LV fractional shortening (+11±3%) also tended to be greater with concomitant administration. In addition, in a sequential dosing protocol, when L-158,809 (1 mg/kg, i.v.) was administered 30 min after enalaprilat (1 mg/kg, i.v.), TPR was reduced by 20±4% compared to only a 6±3% reduction (p<0.05) when the enalaprilat was followed 30 min later by a second dose of enalaprilat (1 mg/kg, i.v.). The changes in mean arterial pressure and cardiac output for the combined treatment group also tended to be greater than those for the group given two sequential doses of enalaprilat. Conclusion: In conscious pigs with heart failure, the combined vasodilatory effects of an ACE inhibitor and AT1 receptor antagonist are greater than those produced when only one of these agents is administered, suggesting that independent mechanisms of ACE inhibition and AT1 receptor antagonism could be partly responsible for the improved vascular dynamics during heart failure.
KEYWORDS Cardiac function; Vascular resistance; Dose–response effects; Myocardial ischemia
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