Role of calcium-activated chloride current in regulating pulmonary vasomotor tone.
Many agonists induce vasoconstriction by releasing intracellularly stored Ca2+ and promoting Ca2+ influx. Activation of Ca(2+)-activated Cl- (ClCa) channels may be a critical mechanism by which a rise in intracellular free Ca2+ concentration ([Ca2+]i) causes membrane depolarization that serves to sustain the elevated [Ca2+]i and maintain vascular tone. In this study the biophysical and pharmacological properties of ClCa currents [ICKCa] were characterized in rat pulmonary artery (PA) smooth muscle cells, and their relationship to the regulation of pulmonary vascular tone was determined. When K+ currents were eliminated by using Cs(+)-containing internal solution, depolarization elicited an inward Ca2+ current followed by a time-dependent outward Cl- current that reversed near Cl- equilibrium potential. Repolarizing voltage steps produced a large inward tail Cl- current that also reversed at a potential close to Cl- equilibrium potential. Replacement of extracellular Ca2+ with Ba2+ significantly augmented the Ca2+ current but abolished the Cl- currents. The Cl- channel blocker niflumic acid (10-50 microM) diminished the time-dependent outward Cl- current and the inward tail Cl- current, decreased serotonin-induced membrane depolarization, and inhibited agonist-induced PA contraction. In the absence of extracellular Ca2+, cyclopiazonic acid, which releases Ca2+ from sarcoplasmic reticulum, elicited an inward Cl- current at a holding potential of -70 mV. These results indicate that rat PA myocytes possess ClCa channels that are activated by depolarization-induced Ca2+ influx and agonist-induced Ca2+ release. This Cl- current contributes to agonist-induced pulmonary vasoconstriction via membrane depolarization.
Yuan
X J
XJ
Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.
D000818:Animals; D002118:Calcium / Q000502:physiology*; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D004553:Electric Conductivity; D004594:Electrophysiology; D007425:Intracellular Membranes / Q000378:metabolism; D009544:Niflumic Acid / Q000494:pharmacology; D009994:Osmolar Concentration; D010656:Phenylephrine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000502:physiology*
D018118:Chloride Channels; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D012701:Serotonin; D009544:Niflumic Acid; D002118:Calcium