on March 17, 2003
Published online before print March 17, 2003, doi: 10.1161/01.HYP.0000063883.83470.7B
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Submitted on August 7, 2002
From the Institute of Clinical Pharmacology, University of Groningen, Groningen, The Netherlands. * To whom correspondence should be addressed. E-mail: s.gschwend{at}med.rug.nl.
Abstract--In hypertension, pressure-induced myogenic constriction and impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation may contribute to increased vasomotor tone. Myogenic constriction as well as EDHF-mediated dilation may share common signaling mechanisms, and both may control KCa channel activity to set arterial tone. To investigate a potential relation between the 2 mechanisms, we studied coronary arteries of Sprague-Dawley rats for individual myogenic constriction compared with EDHF-mediated dilation of the same artery. EDHF-mediated dilation was measured as the maximal dilation to acetylcholine (100 µmol/L) after preconstriction, resistant to NO inhibition (NG-methyl-L-arginine acetate salt, L-NMMA, 100 µmol/L), and prostaglandin inhibition (indomethacin, 10 µmol/L) but abolished by charybdotoxin (100 nmol/L) plus apamin (500 nmol/L). Individual coronary myogenic constriction at an intraluminal pressure of 70 mm Hg (n=9) ranged from 6% to 44% (24±4%). EDHF-mediated dilation ranged from 18% to 84% (42±7%). Elevating pressure to 130 mm Hg (n=8) increased myogenic constriction by 2-fold (P<0.01) and decreased EDHF-mediated dilation by 2.6-fold (P<0.01). Interestingly, individual myogenic constriction inversely correlated to individual EDHF-mediated dilation (r=-0.75, P<0.001, n=17). Pretreatment with the KCa channel opener NS1619 (30 µmol/L) prevented coronary myogenic constriction and increased EDHF-mediated dilation by 2.2-fold (P<0.01), whereas the KATP channel opener cromakalim (3 µmol/L) had no effect on EDHF-mediated dilation. For comparison, in mesenteric arteries (at 70 mm Hg) low myogenic constriction (2±1%) was associated with high EDHF-mediated dilation (93±2%), and pretreatment with NS1619 had no effect. Our results demonstrate that myogenic constriction in coronary arteries antagonizes EDHF-mediated dilation. Activation of KCa channels with NS1619 reduces myogenic constriction and profoundly increases EDHF-mediated dilation, specifically in coronary arteries, suggesting a potential therapeutic impact to reduce coronary risk in hypertension.
Revised on September 13, 2002
Coronary Myogenic Constriction Antagonizes EDHF-Mediated Dilation. Role of KCa Channels
Simone Gschwend*;
Key words: acetylcholine • autoregulation • endothelium-derived factors • constriction • potassium channels • vasodilation
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