Chloride ion currents contribute functionally to norepinephrine-induced vascular contraction.
Norepinephrine (NE) increases Cl- efflux from vascular smooth muscle (VSM) cells. An increase in Cl- conductance produces membrane depolarization. We hypothesized that if Cl- currents are important for agonist-induced depolarization, then interfering with cellular Cl- handling should alter contractility. Isometric contraction of rat aortic rings was studied in a bicarbonate buffer. Substitution of extracellular Cl- with 130 mM methanesulfonate (MS; 8 mM Cl-) did not cause contraction. NE- and serotonin-induced contractions were potentiated in this low-Cl- buffer, whereas responses to K+, BAY K 8644, or NE in the absence of Ca2+ were unaltered. Substitution of Cl- with I- or Br- suppressed responses to NE. Inhibition of Cl- transport with bumetanide (10(-5) M) or bicarbonate-free conditions (10 mM HEPES) inhibited NE- but not KCl-induced contraction. The Cl--channel blockers DIDS (10(-3) M), anthracene-9-carboxylic acid (10(-3) M), and niflumic acid (10(-5) M) all inhibited NE-induced contraction, whereas tamoxifen (10(-5) M) did not. Finally, disruption of sarcoplasmic reticular function with cyclopiazonic acid (10(-7) M) or ryanodine (10(-5) M) prevented the increase in the peak response to NE produced by low-Cl- buffer. We conclude that a Cl- current with a permeability sequence of I- > Br- > Cl- > MS is critical to agonist-induced contraction of VSM.
Department of Pediatrics, University of Iowa, Iowa City, Iowa, 52242, USA.
F S
FS
Lamb
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TJ
Barna
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D000838:Anions / Q000378:metabolism; D000873:Anthracenes / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D001639:Bicarbonates / Q000494:pharmacology; D002463:Cell Membrane Permeability; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D002712:Chlorides / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008698:Mesylates / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009544:Niflumic Acid / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D000838:Anions; D000873:Anthracenes; D001639:Bicarbonates; D018118:Chloride Channels; D002712:Chlorides; D007211:Indoles; D008698:Mesylates; D014665:Vasodilator Agents; C045880:methanesulfonic acid; D012433:Ryanodine; D012701:Serotonin; D009544:Niflumic Acid; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C010030:9-anthroic acid; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D011188:Potassium; D009638:Norepinephrine; C000543:cyclopiazonic acid