Regulation of alpha(1)-, beta(1)-, and beta(2)-adrenergic receptors in rat heart by norepinephrine

Previous studies suggest that the desensitization and downregulation of beta(1)-adrenergic receptors (beta(1)-AR) in the failing heart are the result of the elevated plasma catecholamine levels associated with this disease. To examine norepinephrine (NE)-induced regulation of cardiac adrenergic receptors, rats were infused with l-NE (200 mu g . kg(-1). h(-1) for 7 days) or vehicle (0.001 N HCl) by implantation of osmotic minipumps. The technique of coverslip autoradiography was used to quantify alpha(1)-adrenergic receptors (alpha(1)-AR), beta(1)-AR, and beta(2)-AR in different tissue compartments of rat hearts. For measurement of beta-AR binding, sections were incubated with 70 pM [I-125]iodocyanopindolol (ICYP) alone or in the presence of 5 mu M dl-propranolol or 5 x 10(-7) M CGP-20712A (a beta(1)-antagonist) and then set up for autoradiography. [H-s]prazosin (1 nM) with or without phentolamine was used to study alpha-AR binding. Chronic infusion of NE induced a greater downregulation of beta(2)-AR compared with beta(1)-AR in all regions studied, including atrial and ventricular myocytes, coronary arterioles, and connective tissue. An 18% loss of beta(1)-AR was seen only in atrial myocytes; beta(1)-AR density actually increased 28% in ventricular myocytes following NE infusion. There was a 15% decrease in alpha(1)-AR in ventricular myocytes, whereas no change in alpha(1)-AR density was seen in myocardial arterioles. Our study demonstrates that beta(2)-AR are more susceptible to NE-induced downregulation than beta(1)-AR. Thus other mechanisms mag be involved in the selective downregulation of beta(1)-AR in certain forms of heart failure.