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We explored the mechanism of halothane's interaction with the serotoninergic contractile response of isolated canine coronary artery rings. The serotoninergic contractile response of both intact and denuded rings was measured with and without halothane. In some experiments, rings were pretreated with methiothepin, a 5-HT1 and 5-HT2 antagonist, or ketanserin, a 5-HT2 antagonist. The contractile responses to 5-carboxamidotryptamine (5-CT) and alpha-methylserotonin, a 5-HT1 and a 5-HT2 receptor agonist, respectively, were measured with and without halothane. Finally, the response to prostaglandin F2-alpha, another spasm mediator, was also measured with and without halothane. Halothane attenuated the coronary artery response to serotonin (5-hydroxytryptamine, 5-HT), and specific 5-HT1 and 5-HT2 agonists, and prostaglandin F2 alpha (PGF2 alpha). Its inhibitory effect on the serotoninergic response was abolished in vessels pretreated with either 5-HT1 or 5-HT2 blockers. These data suggest that halothane is not a direct smooth muscle depressant, that it is not a specific 5-HT1- or 5-HT2-subtype antagonist in canine coronary arteries, and that it might interfere with intracellular pathways activated by agonist-receptor interactions.

Because controversies surround the increased negative inotropic effects of calcium antagonists in heart failure, other mechanisms may explain their lack of efficacy in this condition. We hypothesized that altered coronary sensitivity through endothelial dysfunctions may be involved. Our goal was to evaluate the effects of heart failure on coronary and cardiac sensitivity to the calcium antagonist diltiazem. Left ventricular developed pressure (LVP) and coronary flow (CF) were assessed in isovolumetrically beating, perfused, failing hearts from cardiomyopathic hamsters (UM-X7.1) and hearts from normal hamsters. Diltiazem concentration-response curves for both coronary dilation and its negative inotropic effects were charted under control conditions and in the presence of the specific nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Diltiazem concentration-response curves for its negative inotropic action were similar in normal and failing hearts (IC50 1.2 and 2.3 microM, respectively). In contrast, the coronary dilator effects of diltiazem were impaired in failing hearts (EC50 for diltiazem-induced coronary dilation increased from 90 nM in normal hearts to 1.1 microM 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 and cyclooxygenase pathways. Diltiazem concentration-response curves from failing hearts were not modified in the presence of L-NAME, whereas indomethacin normalized the coronary response to diltiazem in heart failure. These findings suggest that coronary "desensitization" to diltiazem occurs through parallel production and/or release of a vasoconstricting factor or factors originating from the cyclooxygenase pathway. Heart failure was not associated with increased cardiac sensitivity to diltiazem but rather with altered coronary sensitivity. These findings suggest that coronary desensitization may play a role in the lack of efficacy of diltiazem in heart failure and provide a better understanding of factors modulating the effects of calcium antagonists in heart failure.

Diltiazem is known to exert significant cardioprotection, but its efficacy under hypothermic conditions has not been documented. Because of its lipophilicity and its better tissue penetration, clentiazem, a chlorobenzothiazepine derivative of diltiazem, may offer cytoprotection additive to cold cardioplegia. We investigated the cardioprotective actions of clentiazem and diltiazem (10(-8) and 10(-6) M) when added to cold cardioplegia (myocardial temperature of 10 degrees-12 degrees C), in isolated rabbit heart subjected to 90-min global ischemia. Functional recovery was assessed by measuring left ventricular developed pressure (LVDP), coronary flow (CF) and heart rate (HR). To explore the potential beneficial mechanisms of these agents, we measured myocardial lipids and total calcium at the end of a 30-min period of reperfusion as well as their myocardial accumulation. Addition of 10(-8) M clentiazem to cold cardioplegia resulted in significant improvement in mechanical recovery (postischemic LVDP of 88.5 mm Hg with cardioplegia alone vs. 105.5 mm Hg with added clentiazem at 25 mm Hg diastolic pressure, DP). The additive cardioprotection afforded by clentiazem appeared to be concentration dependent since significant cardiodepression (postischemic LVDP of 79.8 mm Hg and 18% reduction in HR) was observed at a higher concentration (10(-6) M) and these effects were correlated with myocardial accumulation of the drug. The additive cardioprotective effect of clentiazem appeared to be structure related because diltiazem at both 10(-8) and 10(-6) M concentrations offered no benefits in addition to cold cardioplegia. These results indicate that the additive cardioprotection observed with 10(-8) M clentiazem could be related to its coronary vasodilator action since it reversed the cold cardioplegia-induced attenuation of hyperemic CF at reperfusion. Other factors must be involved, however, because addition of 10(-6) M diltiazem resulted in increased postischemic CF but without improving myocardial recovery. The functional protection offered by 10(-8) M clentiazem was associated with preservation of myocardial lipid components. Myocardial cholesterol content, which is essential for maintenance of membrane integrity, was preserved in that group, whereas a loss was observed in groups treated with cardioplegia alone and in the other treated groups. Total myocardial phospholipids were preserved in groups receiving 10(-8) M clentiazem plus cold cardioplegia or cold cardioplegia alone. A reduction in plasmalogen content, the predominant myocardial phospholipid species, and an increase in total myocardial calcium were noted only in ischemic hearts that received neither cardioplegia nor benzothiazepines, suggesting that cold cardioplegia is sufficient to prevent irreversible damage. Clentiazem affords cardioprotective benefits additive to cold cardioplegia.(ABSTRACT TRUNCATED AT 400 WORDS)