title: Simultaneous assessment of effects of calmodulin antagonists and Ca++ channel blockers on the electrophysiological and mechanical characteristics in excised guinea-pig papillary muscles.
abstract: 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.
authors.affiliation: Department of Pharmacology, Nippon Roche Research Center, Kamakura, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Koyama
authors.forename: N
authors.initials: N
authors.lastname: Himori
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D004110:Diltiazem / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008297:Male; D009529:Nicardipine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D002147:Calmodulin; D014700:Verapamil; D009529:Nicardipine; D004110:Diltiazem