Abstract 11694: The Gut Hormone Obestatin Induces Nitric Oxide-Dependent Vasodilation and Inhibits Endothelin-1 Activity in Obese Patients

Abstract

Obese patients have vascular dysfunction related to impaired nitric oxide (NO)-dependent vasodilation and increased endothelin (ET)-1 activity. Obestatin is a gastrointestinal peptide with favorable metabolic actions linked to obesity and diabetes; it has also been shown to exert cardiovascular benefits in experimental models by producing vascular relaxation via specific activation of endothelium-dependent NO signaling. Here we tested the hypothesis that obestatin might have advantageous impacts on the NO pathway and the ET-1 system in patients with central obesity. To this purpose, forearm blood flow responses to intra-arterial infusion of graded doses of exogenous obestatin (0.2; 0.4; 0.8; 1,6; 3.2 nmol/min, each dose given for 5 min) were assessed in lean subjects (n=5) and in patients with central obesity (n=14), during the concurrent infusion of saline and after NO inhibition by L-NMMA (4 μmol/min for 15 min). In another group of obese patients (n=10), vascular responses to selective blockade of ET A receptors (BQ-123, 10 nmol/min for 60 min) were measured in the absence and the presence of obestatin (0.8 nmol/min). In lean subjects, before NO synthase inhibition obestatin resulted in a progressive increase in forearm flow (60% at the highest dose; P<0.001 vs. baseline); obestatin-induced vasodilation, however, was completely abolished by L-NMMA (P<0.001 vs. saline). Similarly, in obese patients obestatin induced a significant vasodilation (45%; P<0.001 vs. baseline), which was blunted by L-NMMA (16%; P<0.01 vs. saline). Before obestatin, in obese patients ET A receptor blockade resulted in a marked vasodilation (39% flow increase at 60 min; P<0.001 vs. baseline), which was totally abrogated in the presence of obestatin (P<0.001 vs. absence). In conclusion, obestatin produces vasorelaxation in healthy humans via specific activation of endothelium-dependent NO signaling. This beneficial effect of obestatin is preserved in obese arteries, where it is associated with inhibition of ET-1 signaling. These actions of obestatin, therefore, may be important in the normal regulation of vascular function and are clearly relevant to obesity, a condition characterized by increased prevalence of hypertension and cardiovascular complications.