Enhanced receptor-dependent inositol phosphate accumulation in hypoxic myocytes.
The arrhythmogenic effects of alpha 1-adrenergic receptor agonists are enhanced in the ischemic myocardium. The present study was designed to determine whether hypoxia influences alpha 1-receptor subtype activation of phosphoinositide hydrolysis in neonatal rat ventricular myocyte cultures. Hypoxia did not alter basal inositol phosphate accumulation, but markedly increased norepinephrine-dependent inositol phosphate accumulation. This effect was apparent within 30 min and readily reversed on 30 min of reoxygenation. The response to norepinephrine reflected activation of a specific alpha 1-adrenergic receptor subtype; it was inhibited by prazosin and WB-4101 but not by chloroethylclonidine or propranolol. The density of alpha 1-adrenergic receptors identified by [125I]IBE-2254 was similar in normoxic and hypoxic myocytes. Consistent with this observation, the response to a maximal concentration of norepinephrine was enhanced by hypoxia, but the half-maximum effective dose for norepinephrine was not modified. The effects of isoproterenol to stimulate adenosine 3',5'-cyclic monophosphate (cAMP) accumulation and of carbachol to inhibit isoproterenol-stimulated cAMP accumulation were not influenced by hypoxia. In contrast, inositol phosphate accumulation in response to carbachol or thrombin was markedly increased in hypoxic myocytes. These results demonstrate an effect of hypoxia to enhance phosphoinositide hydrolysis through a mechanism(s) distal to the receptor that may have important implications with respect to calcium overload and electrical abnormalities during myocardial ischemia.
Department of Medicine, Columbia University, New York, New York 10032.
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Steinberg
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Alter
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D007295:Inositol Phosphates / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology; D009994:Osmolar Concentration; D010100:Oxygen / Q000378:metabolism; D010313:Partial Pressure; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D012016:Reference Values; D013565:Sympatholytics / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D007295:Inositol Phosphates; D011942:Receptors, Adrenergic, alpha; D013565:Sympatholytics; D002217:Carbachol; D000242:Cyclic AMP; D013917:Thrombin; D007545:Isoproterenol; D010100:Oxygen; D009638:Norepinephrine