Leptin-induced endothelium-dependent vasorelaxation of peripheral arteries in lean and obese rats: role of nitric oxide and hydrogen sulfide.
Adipose tissue hormone leptin induces endothelium-dependent vasorelaxation mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHF). Previously it has been demonstrated that in short-term obesity the NO-dependent and the EDHF-dependent components of vascular effect of leptin are impaired and up-regulated, respectively. Herein we examined the mechanism of the EDHF-dependent vasodilatory effect of leptin and tested the hypothesis that alterations of acute vascular effects of leptin in obesity are accounted for by chronic hyperleptinemia. The study was performed in 5 groups of rats: (1) control, (2) treated with exogenous leptin for 1 week to induce hyperleptinemia, (3) obese, fed highly-palatable diet for 4 weeks, (4) obese treated with pegylated superactive rat leptin receptor antagonist (PEG-SRLA) for 1 week, (5) fed standard chow and treated with PEG-SRLA. Acute effect of leptin on isometric tension of mesenteric artery segments was measured ex vivo. Leptin relaxed phenylephrine-preconstricted vascular segments in NO- and EDHF-dependent manner. The NO-dependent component was impaired and the EDHF-dependent component was increased in the leptin-treated and obese groups and in the latter group both these effects were abolished by PEG-SRLA. The EDHF-dependent vasodilatory effect of leptin was blocked by either the inhibitor of cystathionine γ-lyase, propargylglycine, or a hydrogen sulfide (H2S) scavenger, bismuth (III) subsalicylate. The results indicate that NO deficiency is compensated by the up-regulation of EDHF in obese rats and both effects are accounted for by chronic hyperleptinemia. The EDHF-dependent component of leptin-induced vasorelaxation is mediated, at least partially, by H2S.
Department of Pathophysiology, Medical University, Lublin, Poland ; Department of Neurology, Medical University, Lublin, Poland.
Anna
A
Jamroz-Wiśniewska
Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel.
Arieh
A
Gertler
Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel.
Gili
G
Solomon
Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom.
Mark E
ME
Wood
University of Exeter Medical School, St Luke's Campus, Exeter, Devon, United Kingdom.
Matthew
M
Whiteman
Department of Pathophysiology, Medical University, Lublin, Poland.
Jerzy
J
Bełtowski
D000273:Adipose Tissue / Q000098:blood supply / Q000187:drug effects; D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000235:genetics / Q000378:metabolism; D001729:Bismuth / Q000494:pharmacology; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004032:Diet; D004730:Endothelium, Vascular / Q000187:drug effects*; D005786:Gene Expression Regulation; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009942:Organometallic Compounds / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000480:Alkynes; D001685:Biological Factors; D020738:Leptin; D009942:Organometallic Compounds; D054411:Receptors, Leptin; D012459:Salicylates; C067410:endothelium-dependent hyperpolarization factor; D010656:Phenylephrine; D009569:Nitric Oxide; C015715:bismuth subsalicylate; C009055:propargylglycine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D003542:Cystathionine gamma-Lyase; D005998:Glycine; D001729:Bismuth; D006862:Hydrogen Sulfide