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The effects of frequency of contraction and of external calcium and sodium concentration on the inotropic actions of acetylcholine (ACh) on isolated mammalian myocardium were examined. In stimulated left atria of cats, ACh reduced tension development, i.e. exerted a negative inotropic effect, which became more striking as the frequency of contraction was increased and was inhibited by atropine. In cat papillary muscles studied at a low frequency ( 72/min) this positive effect of ACh was abolished. Moreover, at high frequencies, ACh consistently further reduced the normal increment in tension associated with increasing frequency. The magnitude of the positive inotropic action of ACh on papillary muscle was abolished by lowering the extracellular [Na+ ] and varied inversely with the extracellular [Ca2+ ]. These findings were interpreted in terms of a dual action of ACh on the myocardium: (1) an action on the muscarinic receptor that reduces contractility and may be blocked with atropine, and (2) a direct effect on cellular membrane permeability to Ca2+ that stimulates contractility and may be reduced by prior elevation of intracytoplasmic [Ca2+ ].

Effects of Frequency of Contraction and lonic Environment on the Responses of Heart Muscle to Acetylcholine