Bioelectrical and mechanical effects of tiapamil (Ro 11-1781) on isolated guinea pig myocardium

Abstract

In isolated electrically stimulated guinea pig papillary muscles tiapamil exerts a negative inotropic action that corresponds to its presumptive inhibitory effects on the slow-channel-mediated transmembrane Ca2+ influx. However, contractile depression is always accompanied by marked alterations of the normal Na+-carried action potential. Thus Na+-dependent upstroke velocity (dV/dtmax) declines while the length of the plateau phase increases. These observations indicate that tiapamil, besides inhibiting Ca2+ inflow, also interferes with the fast inward Na+ current and possibly also reduces the repolarising K+ efflux. After partial depolarisation with a K+-rich tyrode solution (19 mmol X litre-1 K+). tiapamil lowers the Ca2+-dependent contractile force as it reduces the bioelectric parameters (upstroke velocity, amplitude, duration) of the Ca2+-mediated action potentials. Moreover, in partially depolarised myocardium, the Mg2+-induced bioelectric membrane activity is suppressed by tiapamil. Tiapamil probably operates as an agent with mixed Na+-, K+-, Ca2+- and Mg2+-antagonistic effects and, in this respect, differs considerably from the more specific Ca2+ antagonists such as verapamil, D 600 (gallopamil), nifedipine (and other 1,4-dihydropyridines) or diltiazem. However, tiapamil by virtue of its combined damping actions on both transmembrane Na+ and Ca2+ conductivities (together with prolongation of the action potential plateau), is a drug which exerts, simultaneously, the fundamental myocardial membrane effects of antiarrhythmic agents of group I, III and IV, according to the classification of Singh and Vaughan Williams. Thus these bioelectrical observations are in accordance with the results of clinical studies on tiapamil, which have demonstrated directly its antiarrhythmic efficacy.