Coronary myogenic constriction antagonizes EDHF-mediated dilation: role of KCa channels.
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 micromol/L) after preconstriction, resistant to NO inhibition (NG-methyl-l-arginine acetate salt, L-NMMA, 100 micromol/L), and prostaglandin inhibition (indomethacin, 10 micromol/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 micromol/L) prevented coronary myogenic constriction and increased EDHF-mediated dilation by 2.2-fold (P<0.01), whereas the KATP channel opener cromakalim (3 micromol/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.
Gschwend
Simone
S
Department of Clinical Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. s.gschwend@med.rug.nl
Henning
Robert H
RH
de Zeeuw
Dick
D
Buikema
Hendrik
H
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001685:Biological Factors / Q000037:antagonists & inhibitors*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D019806:Cromakalim / Q000494:pharmacology; D046508:Culture Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D001562:Benzimidazoles; D001685:Biological Factors; D024681:Potassium Channels, Calcium-Activated; C067410:endothelium-dependent hyperpolarization factor; D019806:Cromakalim; C086491:NS 1619