:  The number of patients with well‐controlled hypertension is alarmingly low worldwide and new approaches to treatment of increased blood pressure (BP) are being sought. Melatonin has a role in blood pressure regulation. The nighttime production of melatonin is found to be reduced in hypertensive individuals. Administration of melatonin decreased BP in several animal models of hypertension, in healthy men and women, and in patients with arterial hypertension. Most promising results were achieved in patients with non‐dipping nighttime pressure, in which the circadian rhythm of BP variation is disturbed. Several potential mechanisms of BP reduction are considered. Melatonin can, via its scavenging and antioxidant nature, improve endothelial function with increased availability of nitric oxide exerting vasodilatory and hypotensive effects. Melatonin seems to interfere with peripheral and central autonomic system, with a subsequent decrease in the tone of the adrenergic system and an increase of the cholinergic system. Melatonin may act on BP also via specific melatonin receptors localized in peripheral vessels or in parts of central nervous system participating in BP control. With a large clinical trial using melatonin in hypertension treatment, many important questions could be answered, such as the dose of melatonin and regimen of its application, the choice of patients with greatest possible benefit from melatonin treatment, the potential of anti‐remodeling effect of melatonin and the interaction of melatonin with other antihypertensive drugs.

The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled receptors. The pleiotropic receptor-independent effects of melatonin with a possible impact on blood pressure involve the reactive oxygen species (ROS) scavenging nature, activation and over-expression of several antioxidant enzymes or their protection from oxidative damage and the ability to increase the efficiency of the mitochondrial electron transport chain. Besides the interaction with the vascular system, this indolamine may exert part of its antihypertensive action through its interaction with the central nervous system (CNS). The imbalance between the sympathetic and parasympathetic vegetative system is an important pathophysiological disorder and therapeutic target in hypertension. Melatonin is protective in CNS on several different levels: It reduces free radical burden, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. The increased level of serum melatonin observed in some types of hypertension may be a counter-regulatory adaptive mechanism against the sympathetic overstimulation. Since melatonin acts favorably on different levels of hypertension, including organ protection and with minimal side effects, it could become regularly involved in the struggle against this widespread cardiovascular pathology.

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of cardioprotective strategies. However, many biological effects of these drugs cannot be explained by the known mode of action. Our comprehension of the RAS is thus far from complete. The RAS represents an ingenious system of “checks and balances”. It incorporates vasoconstrictive, pro-proliferative, and pro-inflammatory compounds on one hand and molecules with opposing action on the other hand. The list of these molecules is still not definitive because new biological properties can be achieved by minor alteration of the molecular structure. The angiotensin A/alamandine-MrgD cascade associates the deleterious and protective branches of the RAS. Its identification provided a novel clue to the understanding of the RAS. Angiotensin A (Ang A) is positioned at the “crossroad” in this system since it either elicits direct vasoconstrictive and pro-proliferative actions or it is further metabolized to alamandine, triggering opposing effects. Alamandine, the central molecule of this cascade, can be generated both from the “deleterious” Ang A as well as from the “protective” angiotensin 1–7. This pathway modulates peripheral and central blood pressure regulation and cardiovascular remodeling. Further research will elucidate its interactions in cardiovascular pathophysiology and its possible therapeutic implications.