Vascular Effects of Obestatin in Lean and Obese Subjects.
Obese patients have impaired vasodilator reactivity and increased endothelin 1 (ET-1)-mediated vasoconstriction, two abnormalities contributing to vascular dysfunction. Obestatin, a product of the ghrelin gene, in addition to favorable effects on glucose and lipid metabolism, has shown nitric oxide (NO)-dependent vasodilator properties in experimental models. Given these premises, we compared the effects of exogenous obestatin on forearm flow in lean and obese subjects and assessed its influence on ET-1-dependent vasoconstrictor tone in obesity. In both lean and obese participants, infusion of escalating doses of obestatin resulted in a progressive increase in blood flow from baseline (bothP< 0.001). This vasodilation was predominantly mediated by enhanced NO activity, becauseNG-monomethyl-l-arginine markedly blunted the flow response to obestatin in both groups (bothP< 0.05 vs. saline). In obese subjects, antagonism of ETAreceptors by BQ-123 increased forearm flow during saline (P< 0.001) but did not induce additional vasodilation (P> 0.05) during obestatin. Circulating obestatin levels were not different between lean and obese participants (P= 0.41). Our findings indicate that obestatin causes NO-dependent vasodilation in the human circulation. This effect is preserved in obesity, where it is accompanied by reduced ET-1-mediated vasoconstriction. These latter observations make obestatin a promising target for vascular prevention in obesity and diabetes.
Department of Internal Medicine, Catholic University, Rome, Italy.
Francesca
F
Schinzari
Department of Surgery, Catholic University, Rome, Italy.
Augusto
A
Veneziani
Department of Pharmacology, Catholic University, Rome, Italy.
Nadia
N
Mores
Department of Biochemistry, Catholic University, Rome, Italy.
Angela
A
Barini
Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Nicola
N
Di Daniele
Department of Internal Medicine, Catholic University, Rome, Italy carmine.cardillo@unicatt.it.
Carmine
0000-0001-5182-3005
C
Cardillo
Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Manfredi
M
Tesauro
D000328:Adult; D016022:Case-Control Studies; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1; D004730:Endothelium, Vascular / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D054439:Ghrelin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D056128:Obesity, Abdominal; D010456:Peptides, Cyclic / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D054439:Ghrelin; D010456:Peptides, Cyclic; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C072247:cyclo(Trp-Asp-Pro-Val-Leu)