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

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Abstract
1 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 trabecular 2 Bayk 8644 (10−7−10−5m) produced a slowly developing increase in developed tension which reached a maximum at 10−6m. A small decrease in the positive inotropic effect of Bay k 8644 at 10−5m was probably due to the negative inotropic effect of the solvent, 0.5% ethanol. 3 Bay k 8644 (10−7−10−5m) produced a rightward parallel shift of the concentration-response curves for the negative inotropic effects of nifedipine (10−8−10−5m) and verapamil (10−7−3 × 10−5m). The slopes of the Schild plots were −0.92 for nifedipine (pA2 value = 6.58) and −0.48 for verapamil. 4 Bay k 8644 (10−6 and 10−5m) produced only a slight rightward shift of the concentration-response curves for the negative inotropic effect of diltiazem (10−7−3 × 10−5m) and did not affect the negative inotropic effect of Mn2+ (10−4−10−2m). 5 Addition of 2.5 × 10−3m Ca2+ (5.05 × 10−3m 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 × 10−3m 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, Bayk 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. Bayk 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+