The gastrointestinal peptide obestatin induces vascular relaxation via specific activation of endothelium-dependent NO signalling

BACKGROUND AND PURPOSE Obestatin is a recently discovered gastrointestinal peptide with established metabolic actions, which is linked to diabetes and may exert cardiovascular benefits. Here we aimed to investigate the specific effects of obestatin on vascular relaxation. EXPERIMENTAL APPROACH Cumulative relaxation responses to obestatin peptides were assessed in rat isolated aorta and mesenteric artery (n >= 8) in the presence and absence of selective inhibitors. Complementary studies were performed in cultured bovine aortic endothelial cells (BAEC). KEY RESULTS Obestatin peptides elicited concentration-dependent relaxation in both aorta and mesenteric artery. Responses to full-length obestatin(1-23) were greater than those to obestatin(1-10) and obestatin(11-23). Obestatin(1-23)-induced relaxation was attenuated by endothelial denudation, L-NAME (NOS inhibitor), high extracellular K+, GDP-beta-S (G-protein inhibitor), MDL-12,330A (adenylate cyclase inhibitor), wortmannin (PI3K inhibitor), KN-93 (CaMKII inhibitor), ODQ (guanylate cyclase inhibitor) and iberiotoxin (BKCa blocker), suggesting that it is mediated by an endothelium-dependent NO signalling cascade involving an adenylate cyclase-linked GPCR, PI3K/PKB, Ca2+-dependent eNOS activation, soluble guanylate cyclase and modulation of vascular smooth muscle K+. Supporting data from BAEC indicated that nitrite production, intracellular Ca2+ and PKB phosphorylation were increased after exposure to obestatin(1-23). Relaxations to obestatin(1-23) were unaltered by inhibitors of candidate endothelium-derived hyperpolarizing factors (EDHFs) and combined SKCa/IKCa blockade, suggesting that EDHF-mediated pathways were not involved. CONCLUSIONS AND IMPLICATIONS Obestatin produces significant vascular relaxation via specific activation of endothelium-dependent NO signalling. These actions may be important in normal regulation of vascular function and are clearly relevant to diabetes, a condition characterized by endothelial dysfunction and cardiovascular complications.