Recent evidence suggests that newer vasoselective
dihydropyridine calcium antagonists are not cardiodepressant and may be useful in the treatment of
heart failure. No data are available on the efficacy of
clentiazem, a vasoselective benzothiazepine-like
calcium antagonist, in this pathological condition. Therefore, our objective was to assess coronary and cardiac sensitivity to
clentiazem in an experimental model of chronic
heart failure (cardiomyopathic 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 Syrian hamster hearts.
Clentiazem dose-response curves for both coronary dilation and negative inotropic effects were determined under control conditions and in the presence of the
nitric oxide (
NO) synthase inhibitor,
NG-nitro-L-arginine (
L-NAME, 30 microM), and the
cyclooxygenase inhibitor,
indomethacin (10 microM). Baseline hemodynamics indicate a significant reduction in both LVP and coronary perfusion in failing hearts. Cardiac sensitivity to the negative inotropic effects of
clentiazem were similar in normal and failing hearts (IC50 = 677 nM and 734 nM, respectively). 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 failure, the contributions of the
NO synthase and the
cyclooxygenase pathways 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 coronary "desensitization" to
clentiazem in failing hearts does not involve the
NO synthase pathway. Experiments carried in the presence of
indomethacin indicate that the reduced coronary sensitivity to
clentiazem observed in failing hearts does not involve the
cyclooxygenase pathway. In conclusion, reduced coronary sensitivity to the vasoselective
calcium antagonist
clentiazem was observed in the failing hamster heart, while no exacerbation of
clentiazem's cardiodepressant actions was present. Although the mechanisms involved in the vascular desensitization to
clentiazem are still unknown, our findings may provide an additional explanation for the variable efficacy of
calcium antagonists in the treatment of
heart failure.