Direct Effects of Cholinergic Stimulation on Ventricular Automaticity in Guinea Pig Myocardium

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 (10M) in control, reserpine-pretreated animals, and in the presence of increased norepinephrine release induced by superfusion of tyramine (10 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 M) produced a 23% slowing in rate in control animals and an 8% slowing in reserpine pretreated animals (P < 0.01), suggesting basal secretion of norepinephrine. Tyramine (10 M) produced a 28% increase in rate in control animals (P < 0.05) and tyramine (10 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.