Related Experiment Videos
Coronary myogenic constriction antagonizes EDHF-mediated dilation: role of KCa channels
Simone Gschwend1, Robert H Henning, Dick de Zeeuw
1Department of Clinical Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. s.gschwend@med.rug.nl
Insights
In hypertension, myogenic constriction in coronary arteries opposes endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation. Activating KCa channels with NS1619 reduces constriction and boosts EDHF dilation, offering potential hypertension therapy.
Area of Science:
- Cardiovascular Physiology
- Vascular Biology
- Hypertension Research
Background:
- Hypertension is associated with increased vasomotor tone due to myogenic constriction and impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation.
- Both myogenic constriction and EDHF-mediated dilation may involve common signaling pathways and regulate KCa channel activity to control arterial tone.
Purpose of the Study:
- To investigate the relationship between myogenic constriction and EDHF-mediated dilation in coronary arteries.
- To determine the role of KCa channels in these vascular responses.
Main Methods:
- Studied individual myogenic constriction and EDHF-mediated dilation in the same coronary arteries of Sprague-Dawley rats.
- Measured EDHF-mediated dilation as acetylcholine-induced dilation resistant to NO and prostaglandin inhibition, but sensitive to charybdotoxin and apamin.
- Examined the effects of pressure changes and KCa channel opener NS1619 on vascular tone and dilation.
Main Results:
- Coronary myogenic constriction inversely correlated with EDHF-mediated dilation (r=-0.75, P<0.001).
- Increased intraluminal pressure elevated myogenic constriction and reduced EDHF-mediated dilation.
- NS1619 prevented myogenic constriction and significantly increased EDHF-mediated dilation in coronary arteries (P<0.01), while cromakalim had no effect.
Conclusions:
- Myogenic constriction antagonizes EDHF-mediated dilation in coronary arteries.
- KCa channel activation with NS1619 ameliorates myogenic constriction and enhances EDHF-mediated dilation, suggesting a therapeutic strategy for hypertension-related coronary risk.
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 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.