TY - JOUR
T1 - Leptin resistance extends to the coronary vasculature in prediabetic dogs and provides a protective adaptation against endothelial dysfunction
AU - Knudson, Jarrod D.
AU - Dincer, Ü Deniz
AU - Dick, Gregory M.
AU - Shibata, Haruki
AU - Akahane, Rie
AU - Saito, Masayuki
AU - Tune, Johnathan D.
PY - 2005/9
Y1 - 2005/9
N2 - 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.
AB - 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.
KW - Coronary circulation
KW - Metabolic syndrome
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=23944484926&partnerID=8YFLogxK
U2 - 10.1152/ajpheart.00244.2005
DO - 10.1152/ajpheart.00244.2005
M3 - Article
C2 - 15894577
AN - SCOPUS:23944484926
SN - 0363-6135
VL - 289
SP - H1038-H1046
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 3 58-3
ER -