Alteration in sensitivity to isoproterenol and acetylcholine in the rat heart after repeated administration of isoproterenol

Y Nomura, H Kajiyama and T Segawa

Alteration of sensitivity to the inotropic responses to isoproterenol and acetylcholine (ACh) and of saturation constants for the specific binding of [3H]dihydroalprenolol and [3H]quinuclidinyl benzilate to particulate fractions were investigated in rat hearts chronically treated with isoproterenol. The EC50 value for the inotropic response to isoproterenol in the atria of rats injected i.p. with isoproterenol (0.01 or 0.1 mg/kg) twice a day for 10 days, was 9.0-fold higher than in controls. Isoproterenol (0.17 mg/kg i.p.)-induced stimulation of cardiac ornithine decarboxylase activity was significantly (P less than .05) attenuated in atria from animals of the treated groups. Scatchard analysis of specific binding of [3H]dihydroalprenolol revealed that repeated isoproterenol injection produced a significant decrease in the maximum number of binding sites (Bmax), but not in the dissociation constant (KD) for this antagonist. In comparison to the isoproterenol- induced changes in beta adrenergic positive inotropic response, repeated treatment with isoproterenol decreased 2-fold the EC50 value for the negative inotropic response to ACh in isolated atria. Scatchard analysis of specific [3H]quinuclidinyl benzilate binding, however, indicated a significant (P less than .01) decrease in Bmax. Repeated isoproterenol injections also elicited a significant increase in cardiac weight. It is suggested that repeated administration of isoproterenol induces a decrease in density of beta adrenergic receptors which may in part underlie a cardiac hyposensitivity to isoproterenol and an increase in the number of muscarinic ACh receptors and inotropic responsiveness to ACh.

Volume 220, Issue 2, pp. 411-416, 02/01/1982
Copyright © 1982 by American Society for Pharmacology and Experimental Therapeutics

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