Overview on the Pharmacological and Toxicological Characterization of the Calcium Antagonist Tiapamil

Abstract

The results obtained in a variety of isolated organ preparations characterize tiapamil as a calcium antagonist or calcium entry blocker. 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 and reduced ⁴⁵Ca influx into depolarized vascular smooth muscle cells. The inhibitory effects of tiapamil were surmountable by an elevation of the extracellular calcium concentration. Calcium-mediated, slowly rising potentials in partially depolarized guinea pig papillary muscle, evoked by electrical stimulation in the presence of isoprenaline, were also antagonized by tiapamil. As in vascular muscle, the tiapamil effects in cardiac muscle were reduced by elevation of external calcium.Tiapamil altered haemodynamic parameters in a characteristic sequence, with an increase in coronary flow appearing at the lowest effective doses, followed by decreases in blood pressure, total peripheral vascular resistance and, eventually, heart rate. A depression of myocardial contractility was not found at doses which are considered to be therapeutic. After cardiac autonomic denervation, tiapamil produced a dose-dependent bradycardia. However, cardiac denervation did not alter the extent of tiapamil-induced decreases in coronary vascular resistance and did not unmask a potential negative inotropic effect of the drug. A comparison of various vascular preparations suggested a certain degree of selectivity for coronary arteries in the calcium antagonistic action of tiapamil. The haemodynamic findings are in line with these in vitro results.A coronary segmental analysis revealed that tiapamil acts on small coronary arteries. It differs in this respect from nitroglycerin which dilates large coronary arteries. Tiapamil increased pO₂ in the subendocardial layers of the myocardium percentagewise more than in the subepicardial layers. Furthermore, it reduced experimentally-induced myocardial ischaemia as determined by a reduction of the S-T segment elevation of the epicardial ECG after ligation of a coronary artery.