The endothelium modulates the contribution of chloride currents to norepinephrine-induced vascular contraction.
Activation of a Cl- current is critical to agonist-induced activation of rat aortic smooth muscle contraction. Substituting extracellular Cl- with 130 mM methanesulfonate (8 mM Cl-) increases the contractile response to norepinephrine (NE) but not to KCl. We hypothesized that endothelial factors modulate this effect. Removing the endothelium (rubbing) or treatment with N-nitro L-arginine (L-NNA) markedly increased the potentiation of NE-induced contraction by low-Cl- buffer. Indomethacin had no effect. The previously demonstrated ability of Cl--channel blockers (DIDS, anthracene-9-carboxylic acid, niflumic acid) or Cl- transport inhibitors (bumetanide, bicarbonate-free buffer) to inhibit responses to NE was not altered by L-NNA. Low-Cl- buffer alone did not contract intact rings but produced nifedipine-sensitive contractile responses after rubbing or L-NNA treatment. These data suggest that the Cl- conductance of smooth muscle in intact blood vessels is low but increases with withdrawal of reduced nitric oxide (NO') or agonist stimulation. Rubbing or L-NNA increased the sensitivity of rings to KCl but not to NE. Nifedipine reduced both sensitivity and maximum response to NE in intact vessels. L-NNA increased the maximum response to NE in nifedipine-treated rings without changing sensitivity. We conclude that although NO' affects both the voltage-dependent and voltage-independent components of contraction, sensitivity to NE is determined by the voltage-dependent portion. The voltage change required for a full response to NE is dependent on activation of a Cl- current that may be under the tonic regulatory influence of NO'.
Lamb
F S
FS
Department of Pediatrics, University of Iowa, Iowa City, Iowa, 52242, USA.
Barna
T J
TJ
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D009544:Niflumic Acid / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects
D000873:Anthracenes; D018118:Chloride Channels; D019335:Nitroarginine; D009569:Nitric Oxide; D009544:Niflumic Acid; C010030:9-anthroic acid; D009543:Nifedipine; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D009638:Norepinephrine; D007213:Indomethacin