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(Circulation. 1996;94:3303-3310.)
© 1996 American Heart Association, Inc.

Articles

Chronic Hypoxia Increases ß₁-Adrenergic Receptor mRNA and Density but Not Signaling in Neonatal Rat Cardiac Myocytes

Hong-Tai Li, MD; Norman Y. Honbo, MA; Joel S. Karliner, MD

the Cardiology Section, Veterans Affairs Medical Center; the Cardiovascular Research Institute; and the Department of Medicine, University of California, San Francisco.

Correspondence to Joel S. Karliner, MD, Cardiology Section (111C), Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121. E-mail Karliner.Joel-S@SanFrancisco.VA.Gov.

Background It is well recognized that the ß-adrenergic receptor–adenylylcyclase system is altered during myocardial ischemia/hypoxia. However, there are no data regarding either regulation of ß-adrenergic receptors, particularly at the mRNA level, or adenylylcyclase activity in isolated cardiac myocytes exposed to chronic hypoxia.

Methods and Results In a chronic hypoxia model in which neonatal rat ventricular myocytes were exposed to a 1% O₂ environment for 72 hours, we investigated (1) ß₁-mRNA and receptor expression and adenylylcyclase activity and (2) ß₁-mRNA and receptor downregulation and adenylylcyclase desensitization induced by prolonged norepinephrine incubation. We found that hypoxia for 72 hours increased myocardial membrane ß₁-adrenergic receptor density by 44%. This increase was not associated with a corresponding decrease in cytosolic ß₁-adrenergic receptors. RNase protection assays demonstrated that hypoxia increased the steady-state levels of ß₁-mRNA by 109%. Adenylylcyclase activity stimulated by isoproterenol, sodium fluoride, guanyl-5'-imidodiphosphate, and forskolin in hypoxic membranes was not altered compared with normoxic controls. Hypoxia for 72 hours also did not affect norepinephrine-induced ß₁-mRNA and receptor downregulation and adenylylcyclase desensitization in response to isoproterenol, guanyl-5'-imidodiphosphate, or forskolin.

Conclusions In neonatal rat cardiac myocytes, chronic hypoxia (1) increases ß₁-mRNA and receptor expression but does not alter adenylylcyclase activity stimulated at either the receptor or the postreceptor level and (2) does not affect agonist-induced ß₁-mRNA and receptor downregulation and desensitization of the adenylylcyclase response.

Key Words: receptors, adrenergic, beta • myocytes • hypoxia • norepinephrine • mRNA • signal transduction

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