Cibenzoline, a class 1 (local anaesthetic-type) antiarrhythmic drug, was investigated for possible effects upon the myocardial Ca2+ inward current. In voltage-clamp experiments with isolated cardiac myocytes of guinea-pig, cibenzoline caused a concentration-dependent inhibition of the Ca2+ current, with an IC50 of 14 microM. Inhibition of the Ca2+ current by cibenzoline (2 microM) was dependent upon stimulation frequency, with a greater block occurring at 2 Hz (approximately 50%) than at 0.2 Hz (approximately 15%). The magnitude of Ca2+ current block was also potential-dependent. A markedly greater inhibition by cibenzoline (20 microM) was recorded when myocytes were depolarized (to +20 mV) from a holding potential of -35 mV than of -80 mV. At the less negative potential, cibenzoline also caused a reduction in the level of the holding current, which suggests a decrease in the inwardly rectifying K+ current. Cibenzoline also caused a concentration-dependent inhibition of KCl-induced contractures of isolated aortic strips of the rat (IC50 = 55 microM) and a reduction in contractile force of isolated, electrically-stimulated papillary muscles of the guinea-pig (IC50 = 35 microM). Thus, cibenzoline possesses Ca2+ channel blocking (class 4) properties in addition to its local anaesthetic actions.

Tiapamil is a Ca2+ entry blocker that is under development for the treatment of mild to moderate hypertension and angina pectoris. It also possesses antiarrhythmic properties. This review focuses on the pharmacological, toxicological, and clinical properties of tiapamil. A comparison is made of the effects of tiapamil with the effects of some other Ca2+ entry blockers. CHEMISTRYTiapamil (Ro 1 1-178 1 , Larocord) is the hydrochloride monohydrate of N-(3,4-dimethoxyphenethy1)-2-(3,4-dimethoxyphenyl)-N-methyl-rn-dithiane-2-propylamine 1,1,3,3-tetraoxide; it was synthesized by Ramuz (47,48) ( Fig. 1). With a molecular weight of 610.18, it is an odorless white crystalline powder with a bitter taste. It is moderately soluble in water (-1.7% at 25°C) and is a weak base with a pKa of 8.35 at 25°C. Tiapamil lacks an asymmetrical carbon atom; it is thus a single chemical entity. In this respect tiapamil differs from other phenylalkylamine derivatives, which are available only as racemic mixtures. PHARMACOLOGYTiapamil inhibits depolarization-induced transmembrane Ca2+ influx and interferes with excitation-contraction coupling in the heart and vascular smooth muscle (15,27). Inhibitory effects of tiapamil have been demonstrated in isolated vascularpreparations, including rabbit main pulmonary artery, dog coronary artery, and rat mesenteric and renal arteries (15,27,29). Tiapamil was most effective in relaxing high K+ (150 mM) induced contractures of isolated dog coronary artery strips, with a potency (ICSO 0.22 FM) only slightly lower than that of verapamil (ICSO 0.17 p~) . Both compounds also inhibited 45Ca influx induced by K+ depolarization in rabbit main pulmonary artery at concentrations similar to those required for relaxation of contracture. In isolated, depolarized renal arteries of the rat, tiapamil 77

No abstract