Leptin resistance extends to the coronary vasculature in prediabetic dogs and provides a protective adaptation against endothelial dysfunction

Jarrod D. Knudson, Ü Deniz Dincer, Gregory M. Dick, Haruki Shibata, Rie Akahane, Masayuki Saito, Johnathan Tune

Research output: Contribution to journalArticle

55 Citations (Scopus)

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 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 as a major mediator of muscarinic coronary vasodilation, because dilation to ACh was abolished by combined pretreatment with Nω-nitro-L- arginine methyl ester (150 μg/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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume289
Issue number3 58-3
DOIs
StatePublished - Sep 2005
Externally publishedYes

Fingerprint

Leptin
Fats
Dogs
Acetylcholine
Endothelium
Prediabetic State
Leptin Receptors
Dilatation
Blood Vessels
Nitroprusside
Vasodilator Agents
Vasodilation
Indomethacin
Cholinergic Agents
Canidae
Real-Time Polymerase Chain Reaction
Coronary Artery Disease
Coronary Vessels
Obesity
Gene Expression

Keywords

  • Coronary circulation
  • Metabolic syndrome
  • Obesity

ASJC Scopus subject areas

  • Physiology

Cite this

Leptin resistance extends to the coronary vasculature in prediabetic dogs and provides a protective adaptation against endothelial dysfunction. / Knudson, Jarrod D.; Dincer, Ü Deniz; Dick, Gregory M.; Shibata, Haruki; Akahane, Rie; Saito, Masayuki; Tune, Johnathan.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 289, No. 3 58-3, 09.2005.

Research output: Contribution to journalArticle

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