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* Department of Pediatrics, NYU School of Medicine, New York, New York; USA;
Department of Pharmacology, NYU School of Medicine, New York, New York, USA;
Department of Physiology and Neuroscience, NYU School of Medicine, New York, New York, USA;
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA;
|| American Cardiovascular Research Institute, Atlanta, Georgia, USA; and
¶ Department of Medicine, NYU School of Medicine, New York, New York, USA
2Correspondence: Pediatric Cardiology, NYU School of Medicine, 560 First Ave., TCH-521, New York, NY 10016, USA. E-mail: william.coetzee{at}med.nyu.edu
KATP channels are involved in regulating coronary function, but the contribution of endothelial KATP channels remains largely uncharacterized. We generated a transgenic mouse model to specifically target endothelial KATP channels by expressing a dominant negative Kir6.1 subunit only in the endothelium. These animals had no obvious overt phenotype and no early mortality. Histologically, the coronary endothelium in these animals was preserved. There was no evidence of increased susceptibility to ergonovine-induced coronary vasospasm. However, isolated hearts from these animals had a substantially elevated basal coronary perfusion pressure. The KATP channel openers, adenosine and levcromakalim, decreased the perfusion pressure whereas the KATP channel blocker glibenclamide failed to produce a vasoconstrictive response. The inducible endothelial nitric oxide pathway was intact, as evidenced by vasodilation caused by bradykinin. In contrast, basal endothelin-1 release was significantly elevated in the coronary effluent from these hearts. Treatment of mice with bosentan (endothelin-1 receptor antagonist) normalized the coronary perfusion pressure, demonstrating that the elevated endothelin-1 release was sufficient to account for the increased coronary perfusion pressure. Pharmacological blockade of KATP channels led to elevated endothelin-1 levels in the coronary effluent of isolated mouse and rat hearts as well as enhanced endothelin-1 secretion from isolated human coronary endothelial cells. These data are consistent with a role for endothelial KATP channels to control the coronary blood flow by modulating the release of the vasoconstrictor, endothelin-1.—Malester, B., Tong, XY., Ghiu, I., Kontogeorgis, A., Gutstein, D. E., Xu, J., Hendricks-Munoz, K. D., Coetzee, W. A. Transgenic expression of a dominant negative KATP channel subunit in the mouse endothelium: effects on coronary flow and endothelin-1 secretion.
Key Words: potassium channels • coronary vasculature • transgenic mouse
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