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Reversal of glibenclamide-induced coronary vasoconstriction by enhanced perfusion pulsatility: possible role for
P Pagliaro1, N Paolocci, T Isoda
1Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Insights
Increased blood flow pulsatility counteracts coronary artery constriction from ATP-sensitive potassium (K+ATP) channel blockade, likely via nitric oxide (NO) release. This mechanism may aid exercise-induced dilation when K+ATP channels are compromised.
Area of Science:
- Cardiovascular Physiology
- Vascular Biology
- Pharmacology
Background:
- ATP-sensitive potassium (K+ATP) channels influence basal coronary tone.
- Glibenclamide (GLI) blockade of K+ATP channels does not affect exercise-induced coronary flow reserve.
- Exercise increases coronary perfusion pulsatility.
Purpose of the Study:
- To test if increased perfusion pulsatility offsets K+ATP channel-mediated vasoconstriction.
- To investigate if nitric oxide synthase (NOS) inhibition blunts this compensatory effect.
- To determine if this pulsatility effect is specific to K+ATP channel blockade.
Main Methods:
- Anesthetized dogs with computer-controlled coronary artery perfusion.
- Varied perfusion pulse pressure (PP) from 40 to 100 mm Hg.
- Administered glibenclamide (GLI), NG-monomethyl-L-arginine (L-NMMA), vasopressin, and quinacrine.
Main Results:
- GLI-induced vasoconstriction was abolished at high PP (100 mm Hg) but present at low PP (40 mm Hg).
- NOS inhibition blunted the pulsatility-induced flow augmentation and acetylcholine-induced dilation.
- Vasopressin and quinacrine caused vasoconstriction that was not offset by increased pulsatility.
Conclusions:
- Increased coronary flow pulsatility likely enhances nitric oxide (NO) release, offsetting K+ATP channel blockade.
- This pulsatility-mediated NO release may be a key mechanism supporting exercise hyperemia.
- The findings suggest a protective role for pulsatility in maintaining coronary flow during compromised K+ATP channel function.
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 micrograms/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.