Reversal of glibenclamide-induced coronary vasoconstriction by enhanced perfusion pulsatility: possible role for nitric oxide

Objectives: ATP-sensitive potassium channels(K-ATP(+)) prominently contribu te to basal coronary tone; however, flow reserve during exercise remains un changed despite channel blockade with glibenclamide (GLI). We hypothesized that increasing perfusion pulsatility, as accompanies exercise, offsets vas oconstriction from K-ATP(+)-channel blockade, and that this effect is blunt ed by nitric oxide synthase (NOS) inhibition. Methods: In 31 anaesthetized dogs the left anterior descending artery was blood-perfused by computer-con trolled servo-pump, with real-time arterial perfusion pulse pressure (PP) v aried from 40 and 100 mm Hg at a constant mean pressure and cardiac workloa d. Results: At control PP (40 mm Hg), GLI (50 mu g/min/kg, i.c.) lowered me an regional coronary flow from 37+/-5 to 25+/-4 ml/min (P<0.001). However, this was not observed at 100 mm Hg PP (41+/-2 vs. 45+/-4). NOS inhibition b y N-G-monomethyl-L-arginine (L-NMMA) did not alter basal flow at 40 mm Hg P P, but modestly lowered flow (-5%, P<0.001) at higher PP (100 mm Hg), reduc ing PP-flow augmentation by -36%, and acetylcholine (ACh) induced flow elev ation by -39%. Go-infusion of L-NMMA with GLI resulted in net vasoconstrict ion at both PP levels (-60% and -40% at 40 and 100 mm Hg PP, respectively). Unlike GLI, vasoconstriction by vasopressin (-43+/-3% flow reduction at 40 mm Hg PP) or quinacrine (-23+/-7%) was not offset at higher pulsatility (- 44+/-4 and -23+/-6%, respectively). Neither of the latter agents inhibited ACh- or PP-induced flow responses, nor did they modify the effect of L-NMMA on these responses. Conclusions: Increased coronary flow pulsatility offse ts vasoconstriction from K-ATP(+) blockade by likely enhancing NO release. This mechanism may assist exercise-mediated dilation in settings where K-AT P(+) opening is partially compromised. (C) 2000 Elsevier Science B.V. All r ights reserved.