Chronic Norepinephrine Elicits Desensitization by Uncoupling

The goal of this study was to determine the mechanism of ,/-adrenergic receptor desensitization after chronic elevation of circulating NE levels. Osmotic minipumps containing either NE or saline were implanted subcutaneously in dogs for 34 wk. Physiologic desensitization to isoproterenol was confirmed in conscious dogs, i.e., left ventricular dP/dt increased in response to isoproterenol (0.4 ug/kg per min) by 5,625±731 mmHg/s in control dogs with saline pumps, and significantly less, P < 0.01, by 2,093±263 mmHg/s in dogs with NE pumps. Myocardial 13-adrenergic receptor density as determined with 1251-cyanopindolol binding was 49% higher (P < 0.05) in the NE pump group. However, 13-adrenergic receptor agonist binding with isoproterenol demonstrated a significant shift into the low affinity state for the animals with NE pumps. Basal, GTP plus isoproterenol, 5'-guanylylimidodiphosphate, sodium fluoride, and forskolin-stimulated adenylate cyclase activity in the NE pump group were significantly depressed (P < 0.05) by amounts ranging from 20 to 40%. The functional activity of the guanine nucleotide binding protein G. was also reduced (P < 0.05) in animals with NE pumps. Thus, the process of desensitization in response to chronic elevation ofNE levels in intact, normal dogs does not involve a decrease in fi-adrenergic receptor density. Rather, it is characterized by reduced adenylate cyclase activation and uncoupling of the 63adrenergic receptor in association with decreased activity of the GTP-coupling protein G,.