Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology
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4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / pharmacology
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Animals
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Anions / metabolism
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Anthracenes / pharmacology
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Aorta, Thoracic / drug effects
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Aorta, Thoracic / physiology*
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Bicarbonates / pharmacology
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Cell Membrane Permeability
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Chloride Channels / antagonists & inhibitors
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Chloride Channels / physiology*
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Chlorides / pharmacology*
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In Vitro Techniques
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Indoles / pharmacology
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Isometric Contraction / drug effects
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Isometric Contraction / physiology*
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Male
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Mesylates / pharmacology
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / physiology*
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Niflumic Acid / pharmacology
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Norepinephrine / pharmacology*
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Potassium / pharmacology
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Rats
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Rats, Sprague-Dawley
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Ryanodine / pharmacology
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Sarcoplasmic Reticulum / drug effects
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Sarcoplasmic Reticulum / physiology
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Serotonin / pharmacology
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Vasoconstriction / drug effects
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Vasoconstriction / physiology*
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Vasodilator Agents / pharmacology
Substances
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Anions
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Anthracenes
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Bicarbonates
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Chloride Channels
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Chlorides
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Indoles
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Mesylates
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Vasodilator Agents
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methanesulfonic acid
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Ryanodine
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Serotonin
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Niflumic Acid
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3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
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9-anthroic acid
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4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid
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Potassium
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Norepinephrine
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cyclopiazonic acid