ET-1 MODULATES K-CA-CHANNEL ACTIVITY AND ARTERIAL TENSION IN NORMOXICAND HYPOXIC HUMAN PULMONARY VASCULATURE

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 pul monary 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+ (K-Ca)-channel current [I-K(Ca)] by increasing intracellular Ca2+ concentration, whereas it directly inhi bits I-K(Ca) in isolated membrane patches. At a higher concentration ( 10 nM), ET-l-induced I-K(Ca) inhibition predominates. In hypoxic HPSMC s, ET-1 at 5 nM significantly reduces I-K(Ca). The ETA-receptor antago nist BQ-123 reverses the ET-l-induced decrease in I-K(Ca). Chronic BQ- 123 treatment also prevents the hypoxia-induced decrease in I-K(Ca). I n PA rings obtained from human organ donors, ET-1 causes a concentrati on-dependent increase in tension. The ET-l-mediated increase in tensio n is reversed by a K-Ca-channel agonist. The increase in tension at th e highest concentration studied (9 nM) was more pronounced in PA rings obtained from patients with chronic obstructive pulmonary disease. Th ese results imply that an ET-l-induced decrease in I-K(Ca) contributes to chronic hypoxia-induced pulmonary hypertension.