Transgenic expression of a dominant negative KATPchannel subunit in the mouse endothelium: effects on coronary flow and endothelin‐1 secretion

Abstract

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 dom- inant negative Kir6.1 subunit only in the endothelium. These animals had no obvious overt phenotype and no early mortality. Histologically, the coronary endothe- lium in these animals was preserved. There was no evidence of increased susceptibility to ergonovine-in- duced coronary vasospasm. However, isolated hearts from these animals had a substantially elevated basal coronary perfusion pressure. The KATP channel open- ers, adenosine and levcromakalim, decreased the per- fusion pressure whereas the KATP channel blocker glibenclamide failed to produce a vasoconstrictive re- sponse. 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 (endo- thelin-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. Pharmacologi- cal blockade of KATP channels led to elevated endothe- lin-1 levels in the coronary effluent of isolated mouse and rat hearts as well as enhanced endothelin-1 secre- tion 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, endothe- lin-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 endothe- lium: effects on coronary flow and endothelin-1 secre- tion. FASEB J. 21, 2162-2172 (2007)