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The purpose of these experiments was to determine whether muscarinic cholinergic agonists exerted a negative chronotropic effect in the absence of endogenous norepinephrine in isolated guinea pig ventricular myocardial strips. The chronotropic response to physostigmine (10(-6) M) in control, reserpine-pretreated animals, and in the presence of increased norepinephrine release induced by superfusion of tyramine (10(-5) M), was studied. The control rates in the control, reserpine-pretreated, and tyramine-treated groups were 106 +/- 40, 93 +/- 31, 109 +/- 28/min, respectively. Propranolol (10(-6) M) produced a 23% slowing in rate in control animals and an 8% slowing in reserpine pretreated animals (P less than 0.01), suggesting basal secretion of norepinephrine. Tyramine (10(-5) M) produced a 28% increase in rate in control animals (P less than 0.05) and tyramine (10(-4) M) produced no increase in reserpine-pretreated animals. Physostigmine produced similar negative chronotropic response in control, reserpine-pretreated, and tyramine-treated groups of 45, 49, and 28%, respectively. Physostigmine produced no change in measured Purkinje fiber action potential characteristics, except for a decreased rate of spontaneous diastolic depolarization. Our results demonstrate that physostigmine slows the spontaneous rate in control, reserpine-pretreated and tyramine-treated groups, indicating that muscarinic cholinergic agonists exert a direct negative chronotropic effect at postjunctional cell surface receptors, independent of the presence or level of adrenergic tone.

Direct effects of cholinergic stimulation on ventricular automaticity in guinea pig myocardium.