Abstract P341: Melanocortin Receptor 4 Activation Mediates Leptin-Induced Sensitization of the Angiotensin II-Elicited Hypertensive Response in Mice

Abstract

Obesity has been shown to promote the renin-angiotensin system (RAS) activity and inflammation in the hypothalamus that increase BP and sympathetic activity. Our previous studies using an Induction-Delay-Expression (IND-DEL-EXP) experimental design demonstrated that in the rats high-fat diet (HFD) or central leptin pretreatment resulted in an enhanced hypertensive response to subsequent treatment with angiotensin (ANG) II. The present study tested whether the leptin sensitization of ANG II-induced hypertension is mediated by activation of brain melanocortin receptor 4 (MC4R) in mice. The animals pretreated with either 3-week HFD or systemic leptin during IND responded with enhanced hypertension to ANG II (1000 ng/kg/min, sc.; HFD, Δ44.0±2.1 mmHg vs. Δ29.4±3.2 mmHg; leptin, Δ43.0±1.7 mmHg vs. Δ29.4±2.0 mmHg). This sensitized ANG II hypertensive response produced by systemic leptin given during IND was blocked by co-administration of icv SHU9119, a MCR4 antagonist (Δ24.0±2.9 mmHg). Moreover, a similar sensitization of the ANG II-induced hypertensive response was produced by icv pretreatment with MT II, a MC4R agonist (Δ39.6±2.1 mmHg). The results indicate that leptin-induced sensitization of ANG II-elicited hypertension is mediated by activation of brain MC4R.