Yohimbine blockade of ionic channels in myocardial cells

The effects of yohimbine, an alkaloid shown to have local anesthetic properties on nerve, were determined in isolated perfused chick embryonic (19--21-day-old) hearts. Effects on the fast Na+ channels were studied in hearts perfused with normal Ringer solution by using the maximal upstroke velocity (+Vmax) as an index of the inward current flowing during the rising phase of the normal action potential. Yohimbine (10(-5)--10(-4) M) depressed +Vmax and overshoot and prolonged the action potential. At 5 x 10(-4) M, yohimbine completely blocked the fast Na+ channels, since this dose abolished the action potential when Mn2+ (2 mM) was present to eliminate the slow Ca2+ current. Effects on the slow channels were studied in hearts in which the fast Na+ channels were voltage-inactivated by partial depolarization to about--40 mV with an elevated (25 mM) K+-Ringer solution or blocked by tetrodotoxin (TTX), resulting in loss of excitability. Isoproterenol (10(-6) M) restored excitability by inducing a slowly rising overshooting electrical response (the "slow response") that was accompanied by contractions. At low concentrations (10(-5)--10(-4) M), yohimbine enhanced the isoproterenol-induced slow response; yohimbine induced the slow response in the absence of isoproterenol, even in the presence of a beta-adrenergic blocker. In contrast, at high concentrations (10(-3) M), yohimbine markedly depressed or blocked the slow response. Consistent with this dual action, yohimbine exerted a small positive inotropic action at low doses in hearts perfused with normal Ringer solution and exerted a considerable negative inotropic action at high doses, causing complete blockade of the contractions within 20 min. Cultured reaggregated cells obtained from chick embryo (15--17 day-old) ventricles showed a similar response to yohimbine in that both the normal action potentials and the slow responses were abolished. It is concluded that yohimbine exerts a local anesthetic-like action on myocardial cells, since both fast and slow channels were blocked, but the fast channels were more sensitive to yohimbine.