Nitric oxide is a fundamental regulator of vessels and cardiac muscle function. It is produced by a family of enzymes, the nitric oxide synthases (NOS), all of which are represented in the diverse cell types composing the myocardial tissue. As such, they participate in short-term regulation of contractility and perfusion, and long-term regulation of angiogenesis, myocardial remodeling and regeneration by cardiac stem cells. All of the above are desirable targets for pharmacologic regulation by drugs commonly used in cardiovascular diseases. Indeeed, recent understanding of the regulation of the cardiac NOS has unveiled pleiotropic effects of cardiovascular drugs that could be exploited for improved therapeutic efficacy. We will illustrate such "pleiotropism" for new generation beta-blockers for which we demonstrated the ability to promote NO-dependent beneficial effects in the vasculature and in the myocardium. Elucidation of the pharmacodynamic mechanisms underlying these effects, through activation of beta3-adrenergic receptors, open the way for the development new therapeutic approaches of cardiovascular diseases.