Erythropoietin protects the heart from ventricular arrhythmia during ischemia and reperfusion via neuronal nitric-oxide synthase.
Erythropoietin (EPO) is a potent cardioprotective agent in models of myocardial ischemia and reperfusion (I/R). It has been suggested recently that EPO may also reduce ventricular arrhythmia after I/R. The present study investigated the role of neuronal nitric oxide synthase (nNOS) on the antiarrhythmic effects of EPO. EPO treatment increased nNOS expression in isolated neonatal mouse ventricular myocytes. Cotreatment with the phosphatidylinositol 3 (PI3)-kinase inhibitor, LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], or treatment of cardiomyocytes infected with a dominant negative adenovirus targeted to Akt1 (ADV-dnAkt1) blocked the effects of EPO on nNOS expression, suggesting that EPO regulates nNOS expression via PI3-kinase and Akt. To examine the in vivo antiarrhythmic effects of EPO, wild-type (WT) and nNOS(-/-) mice were anesthetized and, after a baseline measurement, subjected to myocardial I/R to provoke ventricular arrhythmias. Pretreatment with EPO 24 h before ischemia increased nNOS expression and significantly reduced the number of premature ventricular contractions (PVCs) and the incidence of ventricular tachycardia (VT) in WT mice. In contrast, treatment with EPO had no effect on PVCs or the incidence of VT in nNOS(-/-) mice. Furthermore, EPO treatment after ischemia significantly reduced the threshold dose of cesium chloride (CsCl) to induce VT. We conclude that EPO via nNOS protects the heart from spontaneous and CsCl-induced ventricular arrhythmia during myocardial I/R.
Burger
Dylan E
DE
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A 5C1.
Xiang
Fu-Li
FL
Hammoud
Lamis
L
Jones
Douglas L
DL
Feng
Qingping
Q
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D002478:Cells, Cultured; D002586:Cesium / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D018879:Ventricular Premature Complexes / Q000503:physiopathology / Q000517:prevention & control
D002586:Cesium; D002712:Chlorides; D004791:Enzyme Inhibitors; D004921:Erythropoietin; D052248:Nitric Oxide Synthase Type I; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C496321:Nos1 protein, mouse; C028019:cesium chloride