Tiapamil, a new calcium antagonist. 1. Demonstration of calcium antagonistic activity and related studies.
N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride (tiapamil, Ro 11-1781), a new homoveratrylamine derivative, was studied under various experimental conditions which allow the recognition of calcium antagonistic activity, and compared with the reference calcium antagonist verapamil. Similar to verapamil, tiapamil inhibited in a concentration-dependent manner calcium-induced contractions in isolated, potassium-depolarized preparations of rat renal artery, dog coronary artery and rabbit main pulmonary artery. The inhibitory effects of tiapamil and verapamil were overcome by raising the calcium concentration of the bath fluid and a competitive antagonism between calcium ions and both compounds was found. In the rabbit main pulmonary artery both tiapamil and verapamil reduced 45Ca influx into the potassium-depolarized vascular smooth muscle cells. Calcium-mediated slowly rising potentials were evoked in partially depolarized guinea-pig papillary muscles by electrical stimulation in the presence of isoprenaline. Tiapamil, like verapamil, inhibited the slow potentials, an effect which was antagonized by elevation of the concentration of calcium or isoprenaline in the bath fluid. Both tiapamil and verapamil decreased contractile force in isolated guinea-pig atria and papillary muscles as well as in isolated cat hearts. In the last preparation the two compounds also reduced heart rate and increased coronary flow. These results characterize tiapamil as a calcium antagonist in both vascular smooth muscle and cardiac muscle. A comparison between tiapamil and verapamil indicated that both drugs are of approximately equal calcium antagonistic potency in coronary vascular smooth muscle, but verapamil is 5--10 times more potent in smooth muscle of other arterial beds and in cardiac muscle. Thus tiapamil appears to be a calcium antagonist with some preference for coronary vascular smooth muscle.
D000779:Anesthetics, Local; D000818:Animals; D002121:Calcium Channel Blockers; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D011437:Propylamines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013976:Tiapamil Hydrochloride
D000779:Anesthetics, Local; D002121:Calcium Channel Blockers; D011437:Propylamines; D013976:Tiapamil Hydrochloride