Direct Positive Inotropic Effect of Acetylcholine on Myocardium

The effects of acetylcholine and nicotine on isometric tension, in the presence and absence of atropine, hexamethonium, and endogenous norepinephrine stores, were examined in isolated cat atria and papillary muscles. Acetylcholine exerted a negative inotropic effect, competitively inhibited by atropine, in atrial and papillary muscle; in higher concentrations in papillary muscles, it produced a positive inotropic effect that was independent of cardiac norepinephrine stores and that was not blocked by atropine or hexamethonium. Nicotine, in addition to releasing norepinephrine, was found to exert, in higher concentrations, a direct positive inotropic effect, not antagonized by hexamethonium. These data are compatible with the existence of two distinct cholinergic receptors in the myocardium: a muscarinic receptor intimately associated with vagal nerve endings; and a spatially separate receptor, whose stimulation produces responses similar to those produced by nicotine. This hypothesis allows for the reconciliation of much apparently contradictory data concerning acetylcholine and parasympathetic control of the heart; it accounts for the opposite inotropic effects of acetylcholine on atria (negative) and ventricles (positive) and for the opposite effects of vagal nerve stimulation (negative) and exogenous acetylcholine (positive) on ventricular myocardium.