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ATP-sensitive K+(KATP) channels couple cellular energy status to membrane excitability. Although it is established that KATP channels regulate coronary blood vessel tone, the specific role of endothelial KATP channels is unknown. We transgenically targeted endothelial KATP channels by expressing a dominant-negative Kir6.1 subunit under the control of the Tek promoter. Histologically, the coronary endothelium was preserved in transgenic (TG) mice. Ergonovine did not induce coronary vasospasm and the mean blood pressure was not detectably different in these mice. The nitric oxide pathway was intact since bradykinin decreased the coronary perfusion pressure (CPP). Levcromakalim also decreased the CPP, most likely by acting on smooth muscle KATP channels. In contrast, the CPP of isolated hearts was substantially elevated in TG mice. Pre-treatment of mice with bosentan [an endothelin-1 (ET-1) receptor antagonist] normalized the CPP, suggestive of an enhanced ET-1 release. Indeed, ET-1 levels (measured by RIA) were elevated in the coronary effluent of TG hearts. KATP channel blockers (e.g. tolbutamide) similarly elevated ET-1 release; both from isolated rat hearts and 'from cultured human coronary artery endothelial cells. In conclusion, our data suggest a novel role for endothelial KATP channels in regulating coronary vessel tone by controlling regulated exocytosis of the vasoconstrictor ET-1. [ABSTRACT FROM AUTHOR]