Enhanced inositol trisphosphate response to α1-adrenergic stimulation in cardiac myocytes exposed to hypoxia

G. P. Heathers, A. S. Evers, P. B. Corr

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Myocardial ischemia elicits an enhanced responsivity to α1-adrenergic stimulation and a reversible increase in α1-adrenergic receptor number. In adult cardiac myocytes, α1-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 α1-adrenergic receptor number leads to an enhanced synthesis of inositol trisphosphate, the intracellular second messenger for the α1-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 α1-adrenergic receptor density, also leads to an enhanced production of inositol trisphosphate and could account for the enhanced α1-adrenergic responsivity in the ischemic heart in vivo, which is known to facilitate arrhythmogenesis.

Original languageEnglish
Pages (from-to)1409-1413
Number of pages5
JournalJournal of Clinical Investigation
Issue number4
StatePublished - 1989


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