Hypoxia inducible factor-1 improves the actions of positive inotropic agents in stunned cardiac myocytes.
1. 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). 2. Hypoxia-inducible factor-1α 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% CO2) 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). 3. 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. 4. 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.
Tan
Tao
T
Heart and Brain Circulation Laboratory, Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School Piscataway, NJ 08854, USA.
Luciano
Jason A
JA
Scholz
Peter M
PM
Weiss
Harvey R
HR
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000077768:Ciclopirox; D005576:Colforsin / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D017682:Myocardial Stunning / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011817:Rabbits; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors; D015854:Up-Regulation
D000935:Antifungal Agents; D002316:Cardiotonic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D011728:Pyridones; D000077768:Ciclopirox; D005576:Colforsin; D010042:Ouabain; D003676:Deferoxamine