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-nitrol-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 orl-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'.