Activation of the central sympathetic nervous system has proved to be a definitive pathophysiological feature in cardiovascular diseases such as primary arterial hypertension, heart failure and arrhythmogenesis during myocardial ischemia. In fact, experimental and clinical evidence suggests sudden cardiac death in ischemic patients to be, at least in part, mediated by the central sympathetic nervous system. In addition to the use of peripherally acting sympatholytic agents, sympathetic overactivity can also be modulated by drugs acting directly on its site of origin, i.e. the central nervous system. In this context, clonidine, a centrally acting antihypertensive drug that displays alpha2-adrenergic agonistic properties, has long been used in the protection of the ischemic heart during surgery in patients with coronary artery disease. Using an experimental model associating central sympathetic overactivity with myocardial ischemia in rabbits, we demonstrated that clonidine and rilmenidine present protective effects of central origin against ventricular arrhythmia, myocardial ischemia and sudden death. Moreover, the protective effects of rilmenidine, a second-generation antihypertensive drug devoid of significant sedative effects, can also be obtained at subhypotensive doses. Finally, we investigated the central cardioprotective effects resulting from the activation of the opioid receptors in the above mentioned experimental model. We showed that clinically relevant doses of fentanyl, an opioid agonist widely used in anesthetic procedures, also elicited significant cardioprotective effects. Clinically, these results are relevant because they confirm the usefulness of opioids in the prevention of arrhythmia and myocardial ischemia in the perioperative period in patients with coronary artery disease. In conclusion, inhibition of central sympathetic overactivity in patients presenting with coronary artery disease emerges as an attractive pharmacological target to the development of cardioprotective drugs.