Chronic hypoxia increases beta 1-adrenergic receptor mRNA and density but not signaling in neonatal rat cardiac myocytes.
BACKGROUND
It is well recognized that the beta-adrenergic receptor-adenylylcyclase system is altered during myocardial ischemia/hypoxia. However, there are no data regarding either regulation of beta-adrenergic receptors, particularly at the mRNA level, or adenylylcyclase activity in isolated cardiac myocytes exposed to chronic hypoxia.


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) beta 1-mRNA and receptor expression and adenylylcyclase activity and (2) beta 1-mRNA and receptor downregulation and adenylylcyclase desensitization induced by prolonged norepinephrine incubation. We found that hypoxia for 72 hours increased myocardial membrane beta 1-adrenergic receptor density by 44%. This increase was not associated with a corresponding decrease in cytosolic beta 1-adrenergic receptors. RNase protection assays demonstrated that hypoxia increased the steady-state levels of beta 1-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 beta 1-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 beta 1-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 beta 1-mRNA and receptor downregulation and desensitization of the adenylylcyclase response.
Li
H T
HT
Cardiology Section, Veterans Affairs Medical Center, San Francisco, CA 94121, USA.
Honbo
N Y
NY
Karliner
J S
JS
D000262:Adenylyl Cyclases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000096:biosynthesis*; D015398:Signal Transduction; D014158:Transcription, Genetic
D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D020120:Iodocyanopindolol; D010869:Pindolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D009638:Norepinephrine