Transgenic expression of a dominant negative K(ATP) channel subunit in the mouse endothelium: effects on coronary flow and endothelin-1 secretion.
K(ATP) channels are involved in regulating coronary function, but the contribution of endothelial K(ATP) channels remains largely uncharacterized. We generated a transgenic mouse model to specifically target endothelial K(ATP) 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 K(ATP) channel openers, adenosine and levcromakalim, decreased the perfusion pressure whereas the K(ATP) 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 K(ATP) 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 K(ATP) channels to control the coronary blood flow by modulating the release of the vasoconstrictor, endothelin-1.
Malester
Brian
B
Department of Pediatrics, NYU School of Medicine, 560 First Ave., New York, NY 10016, USA.
Tong
Xiaoyong
X
Ghiu
Ioana
I
Kontogeorgis
Andrianos
A
Gutstein
David E
DE
Xu
Jie
J
Hendricks-Munoz
Karen D
KD
Coetzee
William A
WA
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003326:Coronary Circulation / Q000502:physiology*; D003981:Diazoxide / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D004874:Ergonovine / Q000494:pharmacology; D005089:Exocytosis / Q000502:physiology; D005786:Gene Expression Regulation; D005813:Genes, Synthetic; D005905:Glyburide / Q000494:pharmacology; D054086:KATP Channels; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D014044:Tolbutamide / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D054086:KATP Channels; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C092520:uK-ATP-1 potassium channel; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D003981:Diazoxide; D001920:Bradykinin; D005905:Glyburide; D004874:Ergonovine