Yohimbine blockade of ionic channels in myocardial cells

Abstract

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 (+V̇ max) as an index of the inward current flowing during the rising phase of the normal action potential. Yohimbine (10 −5–10 −4 M) depressed +V̇ max and overshoot and prolonged the action potential. At 5 × 10 −4 M, yohimbine completely blocked the fast Na + channels, since this dose abolished the action potential when Mn 2+ (2 mM) was present to eliminate the slow Ca 2+ current. Effects on the slow channels were studied in hearts in which the fast Na + channels were voltage-inactivated 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 β-adrenergic blocker. In contrast, at high concentrations (10 −3 M), yohimbine markedly depressed or blocked the low 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.