HYPOXIA-INDUCIBLE FACTOR-1 IMPROVES THE ACTIONS OF POSITIVE INOTROPIC AGENTS IN STUNNED CARDIAC MYOCYTES

作者：Tan Tao; Luciano Jason A; Scholz Peter M; Weiss Harvey R^*

来源：CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 2009, 36(9): 904-911.

DOI：10.1111/j.1440-1681.2009.05165.x

• calcium transients
• cardiac myocytes
• contractility
• hypoxia-inducible factor-1
• ischaemia-reperfusion
• New Zealand white rabbit

P>In the present study, 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 ischaemia-reperfusion (I/R).
Hypoxia-inducible factor-1 alpha was upregulated with deferoxamine (150 mg/kg per day for 2 days). Rabbit cardiac myocytes were subjected to simulated ischaemia (15 min, 95% N(2)-5% CO(2)) and reperfusion (re-oxygenation) and compared with control myocytes. Cell contraction and calcium transients were measured at baseline and after forskolin (10(-7) and 10(-6) mol/L) or ouabain (10(-5) and 10(-4) mol/L).
Under control conditions, high-dose forskolin and ouabain increased percentage shortening by 20 and 18%, respectively. Deferoxamine-treated control myocytes responded similarly. In stunned myocytes, forskolin and ouabain did not significantly increase shortening (increases of 8% and 9%, respectively). 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 also depressed in stunned myocytes, but were maintained by HIF-1 upregulation.
These results suggest that simulated I/R impaired the functional and calcium transient effects of positive inotropic agents. Upregulation of HIF-1 protects cardiac myocyte function after I/R by maintaining calcium release.

• 出版日期2009-9