Cardiac Swelling-Induced Chloride Current is Enhanced by Endothelin

Publisher Website
Google Scholar
Abstract
Endothelins (ETs) are a family of peptide hormones that act on G protein-coupled ETA and ETB receptors. ETs exert inotropic and chronotropic actions in the heart. Myocardial ischemia is associated with increased plasma levels of ET and cell swelling. We examined the effect of ETs on dog atrial swelling-induced chloride current (ICl,swell). Whole-cell patch clamp was used; 10 nM ET-1 or ET-2 increased ICl,swell by approximately twofold. ET-2 had no effect if ICl,swell activation was prevented by hypertonic superfusate. Outward ET-2-induced current was blocked by 150 μM DIDS more effectively than inward current. Overnight pretreatment with phorbol 12-myristate 13-acetate (1.6 μM), pertussis toxin (100 ng/ml), or dialysis of the cell with 300 μM 2′-deoxyadenosine 3′-monophosphate, a P-site inhibitor of adenylyl cyclase, did not diminish the effect of ET-2. The effect of ET-2 was blocked by an ETAI - (BQ123), but not an ETB-selective (BQ788) antagonist. ET-2-induced currents were inhibited ∼70% by PD 98059 (30 μM), a selective MAPK kinase (MEK) blocker. PD 98059 did not affect basal whole cell current or ICl,swell before exposure to ET-2. The data suggest that MEK activity is not required for activation of atrial ICl,swell but that ET-2 stimulates ICl,swell by a MEK-dependent pathway.