Chronic reserpine pretreatment has been shown to produce postjunctional beta-adrenergic supersensitivity in cardiac tissue. The present investigation was undertaken to determine whether chronic reserpine administration also alters the heart's sensitivity to muscarinic cholinoceptor agonists. The direct and indirect (antiadrenergic) negative inotropic effects of muscarinic agonists were examined in isolated rat left atria at various times after initiation of reserpine pretreatment (1.0 mg.kg-1 x day-1 for 7 days). Supersensitivity to the positive inotropic effects of isoproterenol was demonstrated at 1, 2, and 3 wk after initiation of treatment. Concentration-response curves were then obtained for the muscarinic agonist carbachol and the adenosine A1 receptor agonist (-)-N6-(2-phenylisopropyl)-adenosine (PIA) in reducing the inotropic response to isoproterenol (3.16 microM). The potency of carbachol was increased by approximately 2.0-fold at 1, 2, and 3 wk. Also, sensitivity to the direct negative inotropic effects of carbachol was increased 1.7-fold at 1 wk but not at 2 and 3 wk. At 1 wk, reserpine pretreatment did not alter either the direct or the indirect negative inotropic effects of PIA. These results show that postjunctional beta-adrenergic supersensitivity produced by chronic reserpine pretreatment is accompanied by a reciprocal increase in sensitivity of isolated rat left atria to the negative inotropic effects of muscarinic agonists.

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