Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones

Objective Alpha and gamma-melanocyte stimulating hormones (MSH) are pepticles that possess potent hypertensinogenic actions when injected intravenously or intracerebroventricularly. We sought to define the central receptor(s) mediating these cardiovascular actions. Methods We gave bolus injections of synthetic alpha or gamma-MSH intravenously or intracerebroventricularly to anesthetized wild-type (Mc3r+/+, Mc4r+/+) mice and mice with targeted disruption of the gamma-MSH receptor (Mc3r-/-) or the melanocortin 4 receptor (Mc4r-/-). Results gamma-MSH injected intravenously increased mean arterial pressure (MAP) and heart rate (HR) dose-dependently, with the effect being evident at 10(-9) mol/kg; the maximum increase, at 10(-7) mol/kg, was 38 mmHg in both strains from similar control MAP. Parallel increases in HR also occurred. Injection of the sodium channel blocker, benzamil, 4 mu g/kg intracerebroventricularly, before intravenous gamma-MSH completely prevented the increases in MAP and HR in both strains. Injection of 2 x 10(-8) mol/g body weight alpha-MSH intravenously had no effect on MAP or HR in Mc4r wild-type or -/- mice. However, the same dose given intracerebroventricularly to wild-type mice increased MAP from 76 4 to 95 5 mmHg at 10 min (P < 0.01) and HR from 416 15 to 480 +/- 15 beats/min (P < 0.01). In Mc4r-/- mice, the intracerebroventricular administration of the peptide did not alter these variables, in contrast to the results in wild-type mice. Conclusion Both MSH pepticles exert their hypertensinogenic effects through central sites of action, which probably reflect the activation of sympathetic outflow. The actions of intracerebroventricular alpha-MSH appear to be mediated via Mc4r, whereas those of gamma-MSH are independent of its receptor Mc3r, but reflect the activation of a sodium channel in the central nervous system. These results help to reconcile the hypertensive action of gamma-MSH injections with the hypertension observed in states of gamma-MSH deficiency.