IMPAIRED CORONARY SENSITIVITY TO DILTIAZEM IN EXPERIMENTAL HEART-FAILURE - INVOLVEMENT OF THE CYCLOOXYGENASE BUT NOT THE NITRIC OXIDE-SYNTHASE PATHWAY

Because controversies surround the increased negative inotropic effect s of calcium antagonists in heart failure, other mechanisms may explai n their lack of efficacy in this condition, We hypothesized that alter ed coronary sensitivity through endothelial dysfunctions may be involv ed, Our goal was to evaluate the effects of heart failure on coronary and cardiac sensitivity to the calcium antagonist diltiazem. Left vent ricular developed pressure (LVP) and coronary flow (CF) were assessed in isovolumetrically beating, perfused, failing hearts from cardiomyop athic hamsters (UM-X7.1) and hearts from normal hamsters. Diltiazem co ncentration-response curves for both coronary dilation and its negativ e inotropic effects were charted under control conditions and in the p resence of the specific nitric oxide (NO) synthase inhibitor, N-G-nitr o-L-arginine methyl ester (L-NAME, 30 mu M), and the cyclooxygenase in hibitor, indomethacin (10 mu M) Diltiazem concentration-response curve s for its negative inotropic action were similar in normal and failing hearts (IC50 1.2 and 2.3 mu M, respectively). In contrast, the corona ry dilator effects of diltiazem were impaired in failing hearts (EC(50 ) for diltiazem-induced coronary dilation increased from 90 nM in norm al hearts to 1.1 mu M in failing hearts, p < 0.01). The involvement of endothelial dysfunctions in the observed coronary ''desensitization'' to diltiazem in heart failure was evaluated through the NO-synthase a nd cyclooxygenase pathways. Diltiazem concentration-response curves fr om Failing hearts were not modified in the presence of L-NAME, whereas indomethacin normalized the coronary response to diltiazem in heart f ailure. These findings suggest that coronary ''desensitization'' to di ltiazem occurs through parallel production and/or release of a vasocon stricting factor or factors originating from the cyclooxygenase pathwa y. Heart failure was not associated with increased cardiac sensitivity to diltiazem but rather with altered coronary sensitivity. These find ings suggest that coronary desensitization may play a role in the lack of efficacy of diltiazem in heart failure and provide a better unders tanding of factors modulating the effects of calcium antagonists in he art failure.