Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones.

Objective: Alpha and gamma-melanocyte stimulating hormones (MSH) are peptides 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 mol/kg; the maximum increase, at 10 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 microg/kg intracerebroventricularly, before intravenous gamma-MSH completely prevented the increases in MAP and HR in both strains. Injection of 2 x 10 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 peptides 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.