© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Reversal of glibenclamide-induced coronary vasoconstriction by enhanced perfusion pulsatility: possible role for nitric oxide
The Division of Cardiology, Department of Medicine, and Department of Bioengineering, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
* Corresponding author. Present address: Halsted 500, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287, USA. Tel.: +1-410-955-7153; fax: +1-410-955-0852 dkass{at}bme.jhu.edu
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.
KEYWORDS Coronary circulation; Vasoconstriction/vasodilation; Nitric oxide; K-ATP channels; Blood pressure
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