title: Leptin resistance extends to the coronary vasculature in prediabetic dogs and provides a protective adaptation against endothelial dysfunction.
abstract: Hyperleptinemia, associated with prediabetes, is an independent risk factor for coronary artery disease and a mediator of coronary endothelial dysfunction. We previously demonstrated that acutely raising the leptin concentration to levels comparable with those observed in human obesity significantly attenuates coronary dilation/relaxation to acetylcholine (ACh) both in vivo in anesthetized dogs and in vitro in isolated canine coronary rings. Accordingly, the purpose of this investigation was to extend these studies to a model of prediabetes with chronic hyperleptinemia. In the present investigation, experiments were conducted on control and high-fat-fed dogs. High-fat feeding caused a significant increase (131%) in plasma leptin concentration. Furthermore, in high-fat-fed dogs, exogenous leptin did not significantly alter vascular responses to ACh in vivo or in vitro. Coronary vasodilator responses to ACh (0.3-30.0 microg/min) and sodium nitroprusside (1.0-100.0 microg/min) were not significantly different from those observed in control dogs. Also, high-fat feeding did not induce a switch to an endothelium-derived hyperpolarizing factor as a major mediator of muscarinic coronary vasodilation, because dilation to ACh was abolished by combined pretreatment with N(omega)-nitro-l-arginine methyl ester (150 microg/min ic) and indomethacin (10 mg/kg iv). Quantitative, real-time PCR revealed no significant difference in coronary artery leptin receptor gene expression between control and high-fat-fed dogs. In conclusion, high-fat feeding induces resistance to the coronary vascular effects of leptin, and this represents an early protective adaptation against endothelial dysfunction. The resistance is not due to altered endothelium-dependent or -independent coronary dilation, increased endothelium-derived hyperpolarizing factor, or changes in coronary leptin receptor mRNA levels.
authors.affiliation: Department of Physiology, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112-1393, USA.
authors.forename: Jarrod D
authors.initials: JD
authors.lastname: Knudson
authors.forename: U Deniz
authors.initials: UD
authors.lastname: Dincer
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dick
authors.forename: Haruki
authors.initials: H
authors.lastname: Shibata
authors.forename: Rie
authors.initials: R
authors.lastname: Akahane
authors.forename: Masayuki
authors.initials: M
authors.lastname: Saito
authors.forename: Johnathan D
authors.initials: JD
authors.lastname: Tune
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000758:Anesthesia; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D003331:Coronary Vessels / Q000473:pathology / Q000502:physiology; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004730:Endothelium, Vascular / Q000502:physiology*; D020738:Leptin / Q000097:blood* / Q000235:genetics / Q000494:pharmacology; D008297:Male; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D011236:Prediabetic State / Q000378:metabolism* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D004041:Dietary Fats; D020738:Leptin; D012333:RNA, Messenger