The inhibitory effect of differently classified calcium antagonists on the calcium- and epinephrine-induced responses of isolated guinea-pig atria.
The effects of calcium antagonists diltiazem, flunarizine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W7) were investigated on the calcium- and epinephrine-induced responses of guinea-pig spontaneously beating atria. All these calcium antagonists showed negative chronotropic and inotropic effects. Diltiazem (3 x 10(-8) M to 1.8 x 10(-7) M) antagonized both the action of epinephrine and calcium in a different manner but at the same concentrations. Flunarizine (1 x 10(-6) M to 1 x 10(-5) M) also antagonized both the action of epinephrine and calcium; but flunarizine weakly inhibits the calcium response at concentrations which have considerable antiadrenergic action. Only at the highest concentrations did both calcium antagonists show a decrease of the epinephrine maximum effect. W7 (1 x 10(-5) M to 1 x 10(-4) M) showed a mainly non-competitive antagonism against epinephrine but was practically ineffective against calcium. The results obtained suggest that a pharmacological prerequisite exists for classifying a calcium antagonist as a calcium entry blocker in the atrial muscle. Such a drug does not produce selective inhibition to calcium- and epinephrine-induced responses. The ability or inability to inhibit the response to calcium represents the discriminant parameter for the action site of the calcium antagonist which are transmembranal fluxes or intracellular mechanisms respectively.