Abstract 3204: Direct Vascular Effects of Ghrelin to Improve Endothelial Function by Restoring the Endothelin/Nitric Oxide Balance in Patients with Central Obesity
Ghrelin, a peptide hormone with central orexigenic actions, may improve endothelial dysfunction in patients with metabolic syndrome by increasing bioavailability of nitric oxide (NO). Obesity is associated with both decreased circulating ghrelin levels and increased endothelin (ET-1)-mediated vasoconstrictor tone that may importantly contribute to endothelial dysfunction. Therefore, we tested the hypothesis that administration of exogenous ghrelin may have benefits to improve the balance between ET-1 and NO in arterial vessels of patients with central obesity (COb). Vasoactive actions of ET-1 and NO were assessed in 8 males with COb (waist circumference >102 cm) and matched controls by evaluating forearm blood flow (FBF; strain gauge plethysmography) in response to intra-arterial infusion of BQ-123 (selective ETA receptor antagonist; 10 nmol/min for 60 min), followed by L-NMMA (NO biosynthesis inhibitor; 4 μmol/min for 15 min). In patients with COb, these experiments were repeated following local infusion of human ghrelin (200 ng/min for 60 min). In the absence of ghrelin, vasodilator responses induced by BQ-123 were greater in patients with COb than in controls (60 ± 7% [mean ± SEM] vs. 8 ± 9% at 60 min; P=0.001), indicative of enhanced ET-1 vasoconstrictor activity in COb. Under similar conditions, infusion of L-NMMA induced a smaller FBF decrease in patients with COb than in controls (−12 ± 3% vs. −31 ± 5%; P=0.006), consistent with decreased bioavailability of NO in arterial vessels of patients with COb. Importantly, acute intra-arterial infusion of ghrelin in these patients decreased vasodilator responses to BQ-123 (36 ±5%; P=0.007 vs. saline) and enhanced the magnitude of changes in FBF induced by L-NMMA (−40 ± 3%; P=0.003 vs. saline). These results indicate that, in arteries of patients with COb, ghrelin has beneficial effects to normalize the balance between vasoconstrictor (ET-1) and vasodilating (NO) mediators, thereby ameliorating endothelial dysfunction and subsequent atherogenic changes associated with COb. We conclude that, in addition to central metabolic functions, ghrelin has important peripheral vascular actions that may help couple and coordinate metabolic and vascular homeostasis.