title: Openers of SKCa and IKCa channels enhance agonist-evoked endothelial nitric oxide synthesis and arteriolar vasodilation.
abstract: Recent data have led us to hypothesize that selective activation of endothelial small- and/or intermediate-conductance, calcium-activated potassium channels (SK(Ca) and IK(Ca) channels, respectively) by the opener compounds NS309 and DCEBIO would augment stimulated nitric oxide (NO) synthesis and vasodilation in resistance arteries. Experimentally, ATP-evoked changes in membrane potential, cytosolic Ca(2+), and NO synthesis were recorded by patch clamp and microfluorimetry in single human endothelial cells. Agonist-evoked inhibition of myogenic tone in isolated, pressurized arterioles from rat cremaster skeletal muscle was analyzed by video microscopy. NS309 and DCEBIO enhanced ATP-evoked membrane hyperpolarization and cytosolic Ca(2+) transients, along with acute NO synthesis in isolated endothelial cells. The acetylcholine-mediated inhibition of myogenic tone (IC(50)=237 nM) was left-shifted in the presence of NS309 and DCEBIO (10, 100, and 1000 nM) to IC(50) values of 101, 78, and 43 nM; endothelial denudation inhibited this drug effect. L-NAME attenuated the acetylcholine-induced inhibition of myogenic tone but did not interfere with NS309 and DCEBIO-evoked vasodilation. Collectively, our data demonstrate that drug-induced enhancement of endothelial SK(Ca) and IK(Ca) channel activities represents a novel cellular mechanism to increase vasodilation of small-resistance arterioles, thereby highlighting these channels as potential therapeutic targets in cardiovascular disease states associated with compromised NO signaling.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jian-zhong
authors.initials: JZ
authors.lastname: Sheng
authors.forename: Srikanth
authors.initials: S
authors.lastname: Ella
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davis
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hill
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Braun
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005021:Ethylamines / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D005470:Fluorometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D010091:Oximes / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists / Q000378:metabolism*; D051381:Rats; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: C527813:3-amino-4-monomethylamino-2',7'-difluorofluorecein; C507351:5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one; C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D001562:Benzimidazoles; D005021:Ethylamines; D005452:Fluoresceins; D007211:Indoles; D010091:Oximes; D024681:Potassium Channels, Calcium-Activated; D051640:Small-Conductance Calcium-Activated Potassium Channels; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D000109:Acetylcholine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester