Modulation of blood pressure by central melanocortinergic pathways

In a recent study by Greenfield and coworkers in patients with a genetic form of obesity, a direct impact of neuronal melanocortins on the development of hypertension was hypothesized. Pharmacological treatment with an MCR agonist supported the observation of a blood pressureregulating effect of the melanocortin system in humans [1]. The discovery of the melanocortin system has been enthusiastically well received in the last two decades. A large number of significant scientific reports demonstrated a large array of physiological functions and molecular mechanisms of this system. The characterization of MCRs and the ensuing synthesis of selective ligands with agonist and antagonist activity are generating a most promising source of innovative drugs for widespread pathological conditions, i.e. nutritional disturbances, myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, diabetic neuropathy, sexual impotence and probably neurodegenerative diseases (for review, see references [2–12]). Melanocortins [melanocyte-stimulating hormones (MSHs)] derive from the precursor proopiomelanocortin (POMC) in the nucleus arcuatus and their expression is strongly connected to leptin as part of the same loop of regulation of food intake and weight control (Figure 1) [13– 17,19,20]. The actions of melanocortins are mediated by a family of five G protein-coupled receptors known as MCRs. MC3R and MC4R are largely distributed in the brain and the CNS (mainly the paraventricular, dorsomedial and lateral nuclei in the hypothalamus). The other MCRs are expressed in tissues apart from the nervous system and mediate the non-neuronal effects of MSH like pigmentation and ACTH-induced steroid synthesis [3–5,12]. The genetic deficiency of MC4R is the most common form of monogenic obesity and is a direct proof for the critical role of the melanocortin system in obesity [18,25]. In addition to hormonal effects and some bizarre effects on behaviour (i.e. excessive yawning, crisis of stretching or spontaneous penile erection), melanocortins have been reported to have a variety of important effects on cerebral function [10,11]. Melanocortins also have a direct effect on cardiovascular function [21–24,28]. Central administration of alpha-MSH increases the mean arterial pressure and heart rate, and animal data propagate that these effects are mediated via interference with autonomic outflow [22,23,29]. Numerous studies suggest that hyperinsulinaemia is involved in obesity-induced hypertension through effects on the activity of the sympathetic nervous system [26,27].