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Hypoxia inducible factor‐1 protects against nitrate tolerance and stunning in cardiac myocytes

We tested whether upregulation of hypoxia inducible factor‐1 (HIF‐1) would restore the blunted effects of natriuretic peptides and nitric oxide caused by chronic nitrates and stunning in cardiac myocytes. HIF‐1α was increased with deferoxamine (DFX) and nitrate tolerance was induced with a chronic nitroglycerin patch. We used rabbit ventricular myocytes. Myocytes were subjected to simulated ischemia [15 min 95% N2‐5% CO2] and reperfusion [reoxygenation] to produce stunning. Cell function was measured at baseline and after brain natriuretic peptide (BNP) or S‐nitroso‐N‐acetyl‐penicillamine (SNAP) followed by KT5823 (cGMP protein kinase inhibitor). We also measured cGMP protein kinase protein levels and kinase activity. In control, BNP (−29%) reduced %shortening, while KT5823 partially restored function. DFX treated myocytes responded similarly. In patched myocytes, BNP (−12%) reduced shortening less and KT5823 did not increase function. However, DFX restored the blunted effects of BNP (−21%) and KT5823. In stunned myocytes, BNP (−11%) reduced shortening less and KT5823 did not affect function. DFX increased the effects of BNP (−27%) and KT5823 in stunning. Patch plus stunning also similarly blunted the effects of BNP (−12%) and KT5823, while DFX improved the effects of BNP (−22%) and KT5823. Similar results were seen with SNAP. Stunning reduced cGMP protein kinase activity and DFX restored activity. DFX had no effect on kinase activity in nitrate tolerance. We found that upregulation of HIF‐1 could protect against nitrate tolerance through a cGMP protein kinase‐independent mechanism and through a kinase‐dependent mechanism in stunning.