The Effect of Milrinone (Win 47203) on the In Vitro Electropharmacological Properties of Mammalian Cardiac Tissue

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Abstract
The electropharmacological effects of milrinone (Win 47203), a new positive inotropic agent of the bipyridine class, were studied on dog and guinea pig cardiac muscle by means of microelectrode techniques. In dog Purkinje fibers perfused with a Krebs solution containing 4 mM K+, milrinone did not produce any changes in action potential configuration. However, rat of discharge from spontaneously active Purkinje fibers was increased by milrinone. In dog auricular and ventricular trabeculae, milrinone increased action potential amplitude, overshoot, and phase 2 of the action potential. The duration of the action potential and the effective refractory period were decreased. In guinea pig papillary muscle, the changes in the action potential produced by milrinone consisted of a slight increase in overshoot and a reduction in the duration of the action potential. Dog Purkinje fibers depolarized with 20 mM K+ did not respond to milrinone. When such depolarized Purkinje tissue was treated with norepinephrine, slow action potentials appeared, and these could be increased by milrinone. Depolarized dog trabeculae were quiescent and addition of milrinone produced a slow action potential; the amplitude, rate of depolarization, and duration of the slow action potentials were dependent on the milrinone concentration. In depolarized guinea pig papillary muscles, milrinone induced dose-dependent slow action potentials and contractions which could be reversed on washing. Preexisting slow action potentials inducd by tetraethylammonium plus high [Ca]o were potentiated by milrinone in a dose-dependent manner. The changes in phase 2 and the induction of the slow action potential in depolarized muscle suggest that Ca2+ entry via the calcium channels plays a role in the positive inotropic effects of milrinone as well as in the initiation or abolition of an arrhythmia.