Enhanced inositol trisphosphate response to alpha 1-adrenergic stimulation in cardiac myocytes exposed to hypoxia.
Myocardial ischemia elicits an enhanced responsivity to alpha 1-adrenergic stimulation and a reversible increase in alpha 1-adrenergic receptor number. In adult cardiac myocytes, alpha 1-adrenergic receptor number increases two- to threefold after 10 min of hypoxia, an increase similar to that seen during ischemia in vivo. To determine whether this increase in alpha 1-adrenergic receptor number leads to an enhanced synthesis of inositol trisphosphate, the intracellular second messenger for the alpha 1-adrenergic receptor, the mass of inositol trisphosphate was quantified by a novel procedure developed in our laboratory that circumvents problems associated with using labeled precursors. The peak increases in inositol trisphosphate levels of three- to fourfold were measured after 30 s of norepinephrine stimulation and exhibited a 50% effective concentration (EC50) of 7.9 x 10(-8) M. Hypoxia produced a marked leftward shift in the dose-response curve for the production of inositol trisphosphate in response to norepinephrine stimulation (EC50 = 1.2 x 10(-8) M). Hypoxia also induced a 100-fold reduction in the concentration of norepinephrine required to elicit a threshold increase in inositol trisphosphate (10(-9) M), compared with control normoxic myocytes (10(-7) M). Thus, hypoxia, which increases alpha 1-adrenergic receptor density, also leads to an enhanced production of inositol trisphosphate and could account for the enhanced alpha 1-adrenergic responsivity in the ischemic heart in vivo, which is known to facilitate arrhythmogenesis.
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Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
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D000818:Animals; D003327:Coronary Disease / Q000378:metabolism / Q000503:physiopathology; D004285:Dogs; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000096:biosynthesis*; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D013237:Stereoisomerism; D013403:Sugar Phosphates / Q000096:biosynthesis*
D007295:Inositol Phosphates; D011942:Receptors, Adrenergic, alpha; D013403:Sugar Phosphates; D015544:Inositol 1,4,5-Trisphosphate; D009638:Norepinephrine