Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle.

Antagonism between either the dihydropyridine calcium agonist, Bay k 8644, or high external Ca2+ and the calcium antagonists, nifedipine, verapamil and diltiazem, and Mn2+ was investigated in canine isolated ventricular trabeculae. Bay k 8644 (10(-7)-10(-5)M) produced a slowly developing increase in developed tension which reached a maximum at 10(-6)M. A small decrease in the positive inotropic effect of Bay k 8644 at 10(-5)M was probably due to the negative inotropic effect of the solvent, 0.5% ethanol. Bay k 8644 (10(-7)-10(-5)M) produced a rightward parallel shift of the concentration-response curves for the negative inotropic effects of nifedipine (10(-8)-10(-5)M) and verapamil (10(-7)-3 X 10(-5)M). The slopes of the Schild plots were -0.92 for nifedipine (pA2 value = 6.58) and -0.48 for verapamil. Bay k 8644 (10(-6) and 10(-5)M) produced only a slight rightward shift of the concentration-response curves for the negative inotropic effect of diltiazem (10(-7)-3 X 10(-5)M) and did not affect the negative inotropic effect of Mn2+ (10(-4)-10(-2)M). Addition of 2.5 X 10(-3)M Ca2+ (5.05 X 10(-3)M Ca2+) to the medium produced a greater maximum positive inotropic effect than Bay k 8644. The concentration-response curves for the negative inotropic effects of nifedipine, verapamil and diltiazem obtained under these conditions were not essentially different from those under control conditions (2.55 X 10(-3)M Ca2+). 6 These results indicate that Bay k 8644, while producing a positive inotropic effect, antagonizes the negative inotropic effect of nifedipine by competing with the latter for the same site closely associated with the calcium channel. In contrast, Bay k 8644 antagonizes the negative inotropic effects of verapamil and diltiazem by interfering allosterically with the binding of these calcium antagonists to their sites of action. Bay k 8644 does not antagonize the negative inotropic effect of Mn2+. No pharmacological antagonism was observed between the three organic calcium antagonists and high external Ca2+_