Molecular mechanism of penile smooth muscle relaxation. The intracellular second messengers mediating smooth muscle relaxation, cAMP and cGMP, activate their specific protein kinases, which phosphorylate certain proteins to cause opening of potassium channels, closing of calcium channels, and sequestration of intracellular calcium by the endoplasmic reticulum. The resultant fall in intracellular calcium leads to smooth muscle relaxation. Sildenafil inhibits the action of PDE5 and thus increases the intracellular concentration of cGMP. Papaverine is a nonspecific phosphodiesterase inhibitor. eNOS, endothelial nitric oxide synthase. (From Lue TF: Erectile dysfunction. N Engl J Med 2000;342:1802--1813. Copyright “ 2000 Massachusetts Medical Society. All rights reserved.)