Steinberg S F, Alter A
Department of Medicine, Columbia University, New York, New York 10032.
Am J Physiol. 1993 Aug;265(2 Pt 2):H691-9. doi: 10.1152/ajpheart.1993.265.2.H691.
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.
α1 - 肾上腺素能受体激动剂的致心律失常作用在缺血心肌中增强。本研究旨在确定缺氧是否影响新生大鼠心室肌细胞培养物中磷酸肌醇水解的α1受体亚型激活。缺氧并未改变基础肌醇磷酸积累，但显著增加了去甲肾上腺素依赖性肌醇磷酸积累。这种效应在30分钟内明显，并在复氧30分钟后迅速逆转。对去甲肾上腺素的反应反映了特定α1 - 肾上腺素能受体亚型的激活；它被哌唑嗪和WB - 4101抑制，但不被氯乙可乐定或普萘洛尔抑制。用[125I]IBE - 2254鉴定的α1 - 肾上腺素能受体密度在常氧和缺氧心肌细胞中相似。与此观察结果一致，缺氧增强了对最大浓度去甲肾上腺素的反应，但去甲肾上腺素的半数最大有效剂量未改变。异丙肾上腺素刺激3',5'-环磷酸腺苷（cAMP）积累的作用以及卡巴胆碱抑制异丙肾上腺素刺激的cAMP积累的作用不受缺氧影响。相反，缺氧心肌细胞中对卡巴胆碱或凝血酶的反应导致肌醇磷酸积累显著增加。这些结果表明缺氧通过受体远端的机制增强磷酸肌醇水解，这可能对心肌缺血期间的钙超载和电异常具有重要意义。
