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Am J Physiol Lung Cell Mol Physiol 275: L729-L739, 1998;
1040-0605/98 $5.00
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Vol. 275, Issue 4, L729-L739, October 1998

ET-1 modulates KCa-channel activity and arterial tension in normoxic and hypoxic human pulmonary vasculature

Wei Peng, John R. Michael, John R. Hoidal, S. V. Karwande, and Imad S. Farrukh

Division of Respiratory, Critical Care, and Occupational Medicine, Department of Internal Medicine, The University of Utah Health Sciences Center, Salt Lake City, Utah 84132

The molecular mechanisms by which endothelin (ET)-1 induces pulmonary hypertension are poorly understood. We investigated the effects of ET-1 on outward K+ currents of normoxic and chronically hypoxic human pulmonary arterial (PA) smooth muscle cells (HPSMCs). In normoxic HPSMCs, ET-1 has dual effects. In intact cells, 5 nM ET-1 activates the large-conductance and Ca2+-activated K+ (KCa)-channel current [IK(Ca)] by increasing intracellular Ca2+ concentration, whereas it directly inhibits IK(Ca) in isolated membrane patches. At a higher concentration (10 nM), ET-1-induced IK(Ca) inhibition predominates. In hypoxic HPSMCs, ET-1 at 5 nM significantly reduces IK(Ca). The ETA-receptor antagonist BQ-123 reverses the ET-1-induced decrease in IK(Ca). Chronic BQ-123 treatment also prevents the hypoxia-induced decrease in IK(Ca). In PA rings obtained from human organ donors, ET-1 causes a concentration-dependent increase in tension. The ET-1-mediated increase in tension is reversed by a KCa-channel agonist. The increase in tension at the highest concentration studied (9 nM) was more pronounced in PA rings obtained from patients with chronic obstructive pulmonary disease. These results imply that an ET-1-induced decrease in IK(Ca) contributes to chronic hypoxia-induced pulmonary hypertension.

endothelin-1; calcium-activated potassium channel; pulmonary hypertension; chronic hypoxia; potassium currents; BQ-123; human lung


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