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

Objectives: ATP-sensitive potassium channels (K⁺(ATP)) prominently contribute to basal coronary tone; however, flow reserve during exercise remains unchanged despite channel blockade with glibenclamide (GLI). We hypothesized that increasing perfusion pulsatility, as accompanies exercise, offsets vasoconstriction from K⁺(ATP)-channel blockade, and that this effect is blunted by nitric oxide synthase (NOS) inhibition. Methods: In 31 anaesthetized dogs the left anterior descending artery was blood-perfused by computer-controlled servo-pump, with real-time arterial perfusion pulse pressure (PP) varied from 40 and 100 mm Hg at a constant mean pressure and cardiac workload. Results: At control PP (40 mm Hg), GLI (50 �g/min/kg, i.c.) lowered mean regional coronary flow from 375 to 254 ml/min (P<0.001). However, this was not observed at 100 mm Hg PP (412 vs. 454). NOS inhibition by N(G)-monomethyl-L-arginine (L-NMMA) did not alter basal flow at 40 mm Hg PP, but modestly lowered flow (-5%, P<0.001) at higher PP (100 mm Hg), reducing PP-flow augmentation by -36%, and acetylcholine (ACh) induced flow elevation by -39%. Co-infusion of L-NMMA with GLI resulted in net vasoconstriction at both PP levels (-60% and -40% at 40 and 100 mm Hg PP, respectively). Unlike GLI, vasoconstriction by vasopressin (-433% flow reduction at 40 mm Hg PP) or quinacrine (-237%) was not offset at higher pulsatility (-444 and -236%, 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 offsets vasoconstriction from K(ATP)/⁺ blockade by likely enhancing NO release. This mechanism may assist exercise-mediated dilation in settings where K(ATP)/⁺ opening is partially compromised. (C) 2000 Elsevier Science B.V.