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.

Animals↗

PubMedDate not supplied

Study of the negative inotropic action of somatostatin.

Somatostatin was evaluated as a chronotropic and inotropic agent in isolated, spontaneously beating guinea-pig atria. Somatostatin (3 x 10(-5)-1 x 10(-3) mM) caused a concentration-dependent negative inotropic effect and a small reduction of atrial rate. The negative inotropic effect of somatostatin was evaluated at different concentrations of extracellular calcium, on the positive inotropic response induced by calcium and on the positive chronotropic response induced by adrenaline. Small, nonsignificant changes in atria response to somatostatin were found both with the lowest (1.25 mM) and with the highest (5 mM) calcium concentration in the medium. Somatostatin (1 x 10(-4)-1 x 10(-3) mm) did not substantially modify the positive inotropic action of calcium; this substance (1 x 10(-3 mM) caused a parallel shift to the right of the adrenaline concentration-response curve. These results suggest that the negative inotropic and chronotropic actions of somatostatin do not appear to be due to an action on the voltage-sensitive calcium channels, but rather to an action on the calcium channels excited by the stimulation of beta-receptors, whose function is probably cooperative with that of the voltage-sensitive channels.

Animals↗