Basic FGF reduces stunning via a NOS2-dependent pathway in coronary-perfused mouse hearts

1 Cardiovascular Division and 4 Angiogenesis Research Center, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215; 2 Department of Cardiology, Medical University, D-30625 Hannover, Germany; and 3 Department of Surgery University of Virginia Health Sciences Center, Charlottesville, Virginia 22908 Basic fibroblast growth factor (FGF-2) may protect the heart from ischemia-reperfusion injury (stunning) by stimulating nitric oxide (NO) production. To test this hypothesis, we pretreated coronary-perfused mouse hearts with 1 µg/ml FGF-2 or vehicle control before the onset of ischemia. Intracellular calcium (Ca i 2+ ) was estimated by aequorin, and NO release was measured with an NO-selective electrode. Hearts perfused with FGF-2 maintained significantly better left ventricular (LV) function during ischemia than hearts perfused with vehicle. FGF-2 significantly delayed the onset of ischemic contracture and improved LV recovery during reperfusion. Ca i 2+ was similar in both groups at baseline during ischemia and reperfusion. L - N 6 -(1-iminoethyl)lysine, a selective inhibitor of inducible NO synthase (NOS2), obliterated the protective effects of FGF-2. In transgenic hearts deficient in the expression of NOS2 (NOS2 / ), FGF-2 did not attenuate ischemia-induced LV dysfunction. Measurements of NO release demonstrated that FGF-2 perfusion significantly increased NO in wild-type but not in NOS2 / hearts. We conclude that basic FGF attenuates myocardial stunning independent of alterations in Ca i 2+ by stimulating NO production via an NOS2-dependent pathway. ischemia; nitric oxide; intracellular calcium; myocardial function