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1 Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
2 Morinaga Institute of Biological Science, Yokohama, Japan
3 Biomedical Sciences, Hokkaido University Graduate School of Veterinary Medicine, Sapporo, Japan
* To whom correspondence should be addressed. E-mail: jtune{at}lsuhsc.edu.
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 leptin concentration to levels comparable to 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. Further, 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 µg/min) and sodium nitroprusside (1.0 - 100.0 µg/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 (EDHF) as a major mediator of muscarinic coronary vasodilation, as dilation to Ach was abolished by combined pretreatment with L-NAME (150 µg/min i.c.) and indomethacin (10 mg/kg i.v.). 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 EDHF, or changes in coronary leptin receptor mRNA levels.
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