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1 Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
2 Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA; Anesthesiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
* To whom correspondence should be addressed. E-mail: jtune{at}lsuhsc.edu.
Obesity is associated with marked increases in plasma leptin concentration, and hyperleptinemia is an independent risk factor for coronary artery disease. As a result, the purpose of this investigation was to test the following hypotheses: 1) leptin receptors are expressed in coronary endothelial cells; 2) hyperleptinemia induces coronary endothelial dysfunction. RT-PCR analysis revealed that the leptin receptor gene (db) is expressed in canine coronary arteries and human coronary endothelium. Further, immunocytochemistry demonstrated that the long form leptin receptor protein (ObRb) is present in human coronary endothelium. The functional effects of leptin were determined using pressurized coronary arterioles (< 130 µm) isolated from Wistar rats, Zucker rats and dogs. Leptin induced pharmacologic vasodilation that was abolished by denudation and the NOS inhibitor L-NAME and was absent in obese Zucker rats. Intracoronary leptin dose-response experiments were conducted in anesthetized dogs. Normal and obese concentrations of leptin (0.1 - 3.0 µg/min i.c.) did not significantly change coronary blood flow or myocardial oxygen consumption; however, obese concentrations of leptin significantly attenuated dilation to graded intracoronary doses of acetylcholine (0.3 - 30.0 µg/min). Additional experiments were performed in canine coronary rings, and relaxation to acetylcholine (6.25 nmol/L - 6.25 µmol/L) was significantly attenuated by obese concentrations of leptin (625 pmol/L), but not by physiologic concentrations of leptin (250 pmol/L). The major findings of this investigation are: 1) the long form leptin receptor is present in coronary arteries and coupled to pharmacologic, nitric oxide-dependent vasodilation; 2) hyperleptinemia produces significant coronary endothelial dysfunction.
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