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Pasquale Pagliaro, Nazareno Paolocci, Takayoshi Isoda, Walter F Saavedra, Genshiro Sunagawa, David A Kass, Reversal of glibenclamide-induced coronary vasoconstriction by enhanced perfusion pulsatility: possible role for nitric oxide, Cardiovascular Research, Volume 45, Issue 4, March 2000, Pages 1001–1009, https://doi.org/10.1016/S0008-6363(99)00414-9
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Abstract
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 μg/min/kg, i.c.) lowered mean 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 by NG-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 (−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 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.
