Synergistic actions of pentobarbital and dihydropyridine Ca2+ antagonists on guinea pig isolated thoracic aorta†

Summary— In order to elucidate the mechanism(s) behind the interactions between barbiturates and Ca²⁺ antagonists, the effects of pentobarbital combined with three structurally diverse types of Ca²⁺ antagonist on CaCl₂-induced contractile responses of the guinea pig thoracic aorta in Ca²⁺-free and 40 mM K⁺ medium and the effects of pentobarbital on Ca²⁺ antagonist binding to guinea pig aortic membranes were investigated. The dihydropyridine derivatives isradipine (10^?10–10^?8 M) and nifedipine (10^?10–10^?8 M) inhibited CaCl₂-induced contractions concentration-dependently. Treatment with both pentobarbital (10^?4 M) and dihydropyridine Ca²⁺ antagonists (10^?9 M) shifted the CaCl₂ concentration-response curves to the right significantly compared with those after treatment with the Ca²⁺ antagonists and pentobarbital alone. However, no synergistic effects of pentobarbital (10^?4 M) with other types of Ca²⁺ antagonist (verapamil (10^?7 M) and diltiazem (10^?6 M)) were observed. The binding of [³H]isradipine (2 × 10^?9 M) to guinea pig aortic membranes was increased significantly by simultaneous pentobarbital treatment, but no such effect was observed with [³H]verapamil (10^?8 M) or [³H]diltiazem (2 × 10^?8 M). These findings suggest that the synergistic contractile effects of pentobarbital and dihydropyridines were, in part, due to enhancement of dihydropyridine binding to guinea pig aortic membranes (L-type Ca²⁺ channels) by pentobarbital and that the interactions between pentobarbital and Ca²⁺ antagonists may be structurally specific.