The beneficial effects of PDE5is for experimental ischemia/reperfusion, cardiac hypertrophy, and heart failure [9-19,46] have been ascribed to mechanisms as varied as nitric oxide generation by upregulation of iNOS or eNOS, protein kinase C activation, opening of mitochondrial ATP-sensitive potassium channels, or inhibition of the RhoA-Rho kinase pathway in cardiac tissue, or even distal effects reducing peripheral resistance and aortic and large artery stiffness. The gene discussed is NOS2; the disease is heart failure.