Coronary myogenic constriction antagonizes EDHF-mediated dilation: role of KCa channels.

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.

• Authors: Simone Gschwend, Robert H Henning, Dick de Zeeuw, Hendrik Buikema
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 41 Issue 4 Pg. 912-8 (Apr 2003) ISSN: 1524-4563 [Electronic] United States
• PMID: 12642510 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzimidazoles
• Biological Factors
• Potassium Channels, Calcium-Activated
• endothelium-dependent hyperpolarization factor
• Cromakalim
• NS 1619

Topics

• Animals
• Benzimidazoles (pharmacology)
• Biological Factors (antagonists & inhibitors)
• Coronary Vessels (drug effects, physiology)
• Cromakalim (pharmacology)
• Culture Techniques
• Male
• Mesenteric Arteries (drug effects, physiology)
• Potassium Channels, Calcium-Activated (physiology)
• Rats
• Rats, Sprague-Dawley
• Vasoconstriction (drug effects)
• Vasodilation (drug effects)