CORONARY AND CARDIAC SENSITIVITY TO THE VASOSELECTIVE BENZOTHIAZEPINE-LIKE CALCIUM-ANTAGONIST, CLENTIAZEM, IN EXPERIMENTAL HEART-FAILURE

Recent evidence suggests that newer vasoselective dihydropyridine calc ium antagonists are not cardiodepressant and may be useful in the trea tment of heart failure. No data are available on the efficacy of clent iazem, a vasoselective benzothiazepine-like calcium antagonist, in thi s pathological condition. Therefore, our objective was to assess coron ary and cardiac sensitivity to clentiazem in an experimental model of chronic heart failure (cardiomyopsthic hamster, UM-X7.1, >200 day old) . Left ventricular developed pressure (LVP) and coronary flow changes were assessed in isolated, perfused failing hearts and in normal Syria n hamster hearts. Clentiazem dose-response curves for both coronary di lation and negative inotropic effects were determined under control co nditions and in the presence of the nitric oxide (NO) synthase inhibit or, N-G-nitro-L-arginine (L-NAME, 30 mu M), and the cyclooxygenase inh ibitor, indomethacin (10 mu M). Baseline hemodynamics indicate a signi ficant reduction in both LVP and coronary perfusion in failing hearts. Cardiac sensitivity to the negative inotropic effects of clentiazem w ere similar in normal and failing hearts (IC50 = 677 nM and 734 nM, re spectively). However, the clentiazem-induced increase in coronary flow was significantly attenuated in failing hearts (EC50 = 56 +/- 9 nM vs . 15 +/- 3 nM in normal hearts, p < 0.01). To better characterize the reduced coronary sensitivity to clentiazem in the presence of heart fa ilure, the contributions of the NO synthase and the cyclooxygenase pat hways were evaluated. Although coronary sensitivity to clentiazem was significantly reduced in the presence of L-NAME, this attenuation was of the same magnitude in normal and failing hearts, suggesting that co ronary ''desensitization'' to clentiazem in failing hearts does not in volve the NO synthase pathway. Experiments carried in the presence of indomethacin indicate that the reduced coronary sensitivity to clentia zem observed in failing hearts does not involve the cyclooxygenase pat hway. In conclusion, reduced coronary sensitivity to the vasoselective calcium antagonist clentiazem was observed in the failing hamster hea rt, while no exacerbation of clentiazem's cardiodepressant actions was present. Although the mechanisms involved in the vascular desensitiza tion to clentiazem are still unknown, our findings may provide an addi tional explanation for the variable efficacy of calcium antagonists in the treatment of heart failure.