title: Differential downregulation of beta 2-adrenergic receptors in tissue compartments of rat heart is not altered by sympathetic denervation.
abstract: With agonist stimulation, cardiac beta 2-adrenergic receptors (beta 2ARs) are downregulated to a much greater extent than are beta 1ARs. It has been hypothesized that this effect is due to sympathetic innervation inhibiting the downregulation of beta 1ARs. To test this hypothesis, the technique of coverslip autoradiography was used to localize and quantify beta 1AR and beta 2AR 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 micrograms.kg-1 x h-1 for 7 days) or vehicle (0.001N HCI) by implantation of osmotic minipumps. Sections were incubated with 70 pmol/L of the beta AR antagonist [125I]iodocyanopindolol (ICYP) alone or in the presence of 5 mumol/L DL-propranolol or 5 x 10(-7) mol/L CGP 20712A (a beta 1AR antagonist). Binding of ICYP to sections of rat hearts was saturable and stereoselective and was displaced by beta AR agonists with the rank order of potency expected for beta ARs. 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 beta 2ARs in atrial and ventricular myocytes, coronary arterioles, and connective tissue but no change in beta 1ARs in these regions in rats with intact sympathetic innervation. Similar changes were seen in denervated animals. There was a marked reduction in beta 2ARs but small insignificant decreases in beta 1ARs, despite the fact that in the denervated animals there was upregulation of beta 1ARs in atrial and ventricular myocytes (approximately 25%). Our study suggests that beta 1ARs 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 beta AR subtypes remains to be elucidated but may be related to differences in the molecular structure between beta 1ARs and beta 2ARs.
authors.affiliation: Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center at Dallas 75235.
authors.forename: M
authors.initials: M
authors.lastname: Zhao
authors.forename: K H
authors.initials: KH
authors.lastname: Muntz
mesh_terms: D000818:Animals; D001345:Autoradiography; D002395:Catecholamines / Q000097:blood; D015536:Down-Regulation; D006321:Heart / Q000294:innervation*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D016627:Oxidopamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000032:analysis; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis*; D013562:Sympathectomy
chemical_list: D002395:Catecholamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D016627:Oxidopamine; D007545:Isoproterenol