ENHANCED RECEPTOR-DEPENDENT INOSITOL PHOSPHATE ACCUMULATION IN HYPOXIC MYOCYTES

The arrhythmogenic effects of alpha1-adrenergic receptor agonists are enhanced in the ischemic myocardium. The present study was designed to determine whether hypoxia influences alpha1-receptor subtype activati on of phosphoinositide hydrolysis in neonatal rat ventricular myocyte cultures. Hypoxia did not alter basal inositol phosphate accumulation, but markedly increased norepinephrine-dependent inositol phosphate ac cumulation. This effect was apparent within 30 min and readily reverse d on 30 min of reoxygenation. The response to norepinephrine reflected activation of a specific alpha1-adrenergic receptor subtype; it was i nhibited by prazosin and WB-4101 but not by chloroethylclonidine or pr opranolol. The density of alpha1-adrenergic receptors identified by [I -125] IBE-2254 was similar in normoxic and hypoxic myocytes. Consisten t with this observation, the response to a maximal concentration of no repinephrine was enhanced by hypoxia, but the half-maximum effective d ose 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 accum ulation in response to carbachol or thrombin was markedly increased in hypoxic myocytes. These results demonstrate an effect of hypoxia to e nhance phosphoinositide hydrolysis through a mechanism(s) distal to th e receptor that may have important implications with respect to calciu m overload and electrical abnormalities during myocardial ischemia.