Hypoxia Inducible Factor‐1 Improves the Actions of Positive Inotropic Agents in Stunned Cardiac Myocytes

Abstract

We tested hypothesis that upregulation of hypoxia inducible factor‐1 (HIF‐1) would improve the actions of positive inotropic agents in cardiac myocytes after simulated ischemia‐reperfusion. HIF‐1α was upregulated with deferoxamine (150 mg/kg/day for 2 days). Rabbit cardiac myocytes were subjected to simulated ischemia (15 min, 95% N2‐5% CO2) and reperfusion (reoxygenation) and compared to control myocytes. Cell contraction and calcium transients were measured at baseline and after forskolin (10−7, 10−6M) or ouabain (10−5, 10−4M). Under control conditions, high dose forskolin and ouabain increased percent shortening by +20% and +18%. Deferoxamine‐treated control myocytes responded similarly. In stunned myocytes, forskolin (+8%) and ouabain (+9%) did not significant increase shortening. Deferoxamine restored the effects of forskolin (+26%) and ouabain (+28%) in stunning. The results for maximum shortening and relaxation rates were similar. The increased calcium transients caused by forskolin and ouabain were depressed in stunned myocytes, but were maintained after HIF‐1 upregulation. These results suggested that simulated ischemia‐reperfusion impaired the functional and calcium transient effects of positive inotropic agents. Upregulation of HIF‐1 protected cardiac myocyte function after ischemia‐reperfusion by maintaining calcium release.