DIFFERENTIAL DOWN-REGULATION OF BETA-2-ADRENERGIC RECEPTORS IN TISSUE COMPARTMENTS OF RAT-HEART IS NOT ALTERED BY SYMPATHETIC DENERVATION

With agonist stimulation, cardiac beta2-adrenergic receptors (beta2ARs) are downregulated to a much greater extent than are beta1ARs. It has been hypothesized that this effect is due to sympathetic innervation inhibiting the downregulation of beta1ARs. To test this hypothesis, the technique of coverslip autoradiography was used to localize and quantify beta1AR and beta2AR subtypes in tissue compartments of the heart in rats subjected to sympathetic denervation by two intravenous injections of 6-hydroxydopamine (50 mg/kg per dose). After denervation, the rats were infused with L-isoproterenol (400 mug.kg-1.h-1 for 7 days) or vehicle (0.0001N HCl) by implantation of osmotic minipumps. Sections were incubated with 70 pmol/L of the betaAR antagonist [I-125]iodocyanopindolol (ICYP) alone or in the presence of 5 mumol/L DL-propranolol or 5x10(-7) mol/L CGP 20712A (a beta1AR antagonist). Binding of ICYP to sections of rat hearts was saturable and stereoselective and was displaced by betaAR agonists with the rank order of potency expected for betaARs. There was an 89% reduction in catecholamine concentration in rat ventricles after 1 week of 6-hydroxydopamine treatment, before implantation of the minipumps. Chronic infusion of isoproterenol induced significant downregulation (63% to 74%) of beta2ARs in atrial and ventricular myocytes, coronary arterioles, and connective tissue but no change in beta1ARs in these regions in rats with intact sympathetic innervation. Similar changes were seen in denervated animals. There was a marked reduction in beta2ARs but small insignificant decreases in beta1ARs, despite the fact that in the denervated animals there was upregulation of beta1ARs in atrial and ventricular myocytes (almost-equal-to 25%). Our study suggests that beta1ARs in the heart are not significantly downregulated by chronic agonist exposure and that this is unrelated to sympathetic innervation. The underlying mechanism of preferential regulation of betaAR subtypes remains to be elucidated but may be related to differences in the molecular structure between beta1ARs and beta2ARs.