Chronic norepinephrine elicits desensitization by uncoupling the β-receptor

Abstract

The goal of this study was to determine the mechanism of β-adrenergic receptor desensitization after chronic elevation of circulating NE levels. Osmotic minipumps containing either NE or saline were implanted subcutaneously in dogs for 3-4 wk. Physiologic desensitization to isoproterenol was confirmed in conscious dogs, i.e., left ventricular dP/dt increased in response to isoproterenol (0.4 μg/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 β-adrenergic receptor density as determined with 125I-cyanopindolol binding was 49% higher (P < 0.05) in the NE pump group. However, β-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(s) was also reduced (P < 0.05) in animals with NE pumps. Thus, the process of desensitization in response to chronic elevation of NE levels in intact, normal dogs does not involve a decrease in β-adrenergic receptor density. Rather, it is characterized by reduced adenylate cyclase activation and uncoupling of the β-adrenergic receptor in association with decreased activity of the GTP-coupling protein G(s).