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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Animals, Calcium-Binding Proteins, Carbazoles, Cell Shape, Cyclic GMP-Dependent Protein Kinases, Deferoxamine, Drug Tolerance, Female, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Models, Biological, Myocardial Contraction, Myocardial Stunning, Myocytes, Cardiac, Natriuretic Peptide, Brain, Nitroglycerin, Phosphorylation, Protein Kinase Inhibitors, Rabbits, S-Nitroso-N-Acetylpenicillamine, Up-Regulation.
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Does hypoxia inducible factor-1 protect against nitrate tolerance and stunning in rabbit cardiac myocytes? Context: 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 nitrate exposure and stunning in cardiac myocytes. HIF-1alpha was increased with deferoxamine (150 mg/kg for 2 days). Nitrate tolerance was induced by a chronic nitroglycerin patch (0.3 mg/h for 5 days). We used freshly isolated rabbit ventricular myocytes. Half the myocytes were subjected to simulated ischemia [15 min 95% N(2)-5% CO(2)] and reperfusion [reoxygenation] to produce stunning. Cell function was measured utilizing a video-edge detector. Shortening was examined at baseline and after brain natriuretic peptide (BNP, 10(-8), 10(-7) M) or S-nitroso-N-acetyl-penicillamine (SNAP, 10(-6), 10(-5) M) followed by KT5823 (cyclic GMP protein kinase inhibitor, 10(-6) M). We also measured cyclic GMP protein kinase protein levels and kinase activity. In control, BNP (-29%) reduced percent shortening, while KT5823 partially restored function. Deferoxamine treated control myocytes responded similarly. In patched nonstunned myocytes, BNP (-12%) reduced shortening less and KT5823 did not increase function. However, deferoxamine restored the blunted effects of BNP (-21%) and KT5823. In stunned myocytes, BNP (-11%) reduced shortening less and KT5823 did not affect function. Deferoxamine increased the effects of BNP (-27%) and KT5823 in stunning. Patch combined with stunning also similarly blunted the effects of BNP (-12%) and KT5823. Deferoxamine improved the effects of BNP (-22%) and KT5823. Similar results were observed after SNAP. Stunning reduced cyclic GMP protein kinase activity and deferoxamine restored activity. Deferoxamine had no effect on kinase activity in nitrate tolerance.
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We found that upregulation of HIF-1 could protect isolated cardiac myocytes against nitrate tolerance through a cyclic GMP protein kinase-independent mechanism and through a kinase-dependent mechanism in stunning. Final Decision: yes