COMBINED EFFECTS OF ANGIOTENSIN-CONVERTING ENZYME-INHIBITION AND ANGIOTENSIN-II RECEPTOR ANTAGONISM IN CONSCIOUS PIGS WITH CONGESTIVE-HEART-FAILURE

Objective: The goal of this study was to determine if the hemodynamic effects of the combined administration of an angiotensin converting en zyme (ACE) inhibitor and angiotensin II type 1 (AT(1)) receptor antago nist are greater than those produced by either of these agents adminis tered individually during heart failure. Methods: Ten farm pigs were c hronically instrumented with aortic, left atrial and right atrial cath eters, a left ventricular (LV) pressure gauge, LV dimension crystals, coronary occluders, an ascending aortic flow probe and pacing leads. H eart failure was induced by serial myocardial infarctions followed by repeated rapid ventricular pacing. Results: Heart failure was manifest ed 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). T he effects of an ACE inhibitor (enalaprilat) and an AT(1) receptor ant agonist (L-158,809), administered in maximally effective doses, either individually or concomitantly, were examined on different days in con scious pigs with heart failure. There were no differences in any of th e baseline hemodynamic measurements among the groups studied. Thirty m inutes after administration, enalaprilat (4 mg/kg i.v.) increased (p<0 .05) cardiac output by 8+/-2% and reduced (p<0.05) mean arterial press ure and TPR by 5+/-1 and 12+/-1%, respectively, while the changes in L V 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 arteria l pressure and TPR by 4+/-1 and 11+/-3%, respectively, while the chang es 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 ch anges in mean arterial pressure (-9+/-2%), cardiac output (+15+/-4%) a nd LV fractional shortening (+11+/-3%) also tended to be greater with concomitant administration. In addition, in a sequential dosing protoc ol, when L-158,809 (1 mg/kg, i.v.) was administered 30 min after enala prilat (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 lat er by a second dose of enalaprilat (1 mg/kg, i.v.). The changes in mea n arterial pressure and cardiac output for the combined treatment grou p also tended to be greater than those for the group given two sequent ial doses of enalaprilat. Conclusion: In conscious pigs with heart fai lure, the combined vasodilatory effects of an ACE inhibitor and AT, re ceptor antagonist are greater than those produced when only one of the se agents is administered, suggesting that independent mechanisms of A CE inhibition and AT(1) receptor antagonism could be partly responsibl e for the improved vascular dynamics during heart failure. (C) 1998 El sevier Science B.V. All rights reserved.