Simultaneous assessment of effects of calmodulin antagonists and Ca++ channel blockers on the electrophysiological and mechanical characteristics in excised guinea-pig papillary muscles.

The purpose of this study was to assess whether known calmodulin (CaM) antagonists might have an ability to modify slow action potentials and mechanical functions of the isolated guinea-pig myocardium, in comparison with that of Ca++ channel blockers. Their effects on high K+-induced contraction of the canine femoral artery were also examined. In the guinea-pig myocardium, trifluoperazine and W-7, suppressed mechanical contraction as a measure of the over-all Ca++ movement flowing through the sarcolemma to the myofibrils with the IC30 values of 1.6 x 10(-5) M and 2.9 x 10(-5) M, respectively, whereas calmidazolium showed a weak action at concentrations up to 3 x 10(-5) M. The maximum rate of rise (Vmax) of Ca++-mediated slow action potential, a measure of transmembrane Ca++ influx, was clearly suppressed by trifluoperazine and less extently by W-7, but not by calmidazolium. Ca++ channel blockers nicardipine, diltiazem and verapamil, significantly reduced both tension development and Vmax. There was a good correlation between the inhibitory effects of trifluoperazine and these Ca++ channel blockers on tension development and Vmax (r = 0.85-0.96). Such a high correlation was not observed with W-7 and calmidazolium. In the canine femoral artery tensed up with high K+, all of these 3 CaM antagonists and 3 Ca++ channel blockers produced concentration-dependent vasorelaxation and relative potencies determined on the basis of concentrations producing IC30 were in the descending order: nicardipine greater than diltiazem greater than verapamil greater than calmidazolium greater than or equal to trifluoperazine greater than W-7. The present results suggest that the clear negative inotropic effect of trifluoperazine is attributable presumably to its additional inhibitory action on slow inward Ca++ current, while W-7 and calmidazolium elicit their weak negative inotropic effects beyond the process of the transmembrane Ca++ influx. In conclusion, there might be less crucial role of CaM-activated phosphorylation in the regulation of beat-to-beat myocardial contractility than that of transmembrane Ca++ influx.