Endothelin-1 receptor antagonist: Effects on endothelin- and cyclosporine-treated mesangial cells

Endothelin-1 receptor antagonist: Effects on endothelin- and cyclosporine-treated mesangial cells. Endothelin-1 (Et) has profound effects on glomerular microcirculation and mesangial cell contraction. A parameter of mesangial cell contraction was examined by measuring myosin light chain phosphorylation (MLCP) in glomerular mesangial cells in the presence and absence of a newly developed endothelin-1 receptor antagonist (Et A ). Addition of Et alone (10 nM) caused a marked increase in MLCP, which, on average, rose by 53 ± 6% above the level in cells exposed to vehicle (P A virtually abolished this Et-induced increase in MLCP, which rose by only 2 ± 3% and -1 ± 4% for doses of Et A of 44 nM and 66 nM, respectively. Examination of the intracellular calcium concentration, [Ca 2+ ] i , revealed that Et A almost completely abolished the transient increase in [Ca 2+ ] i evoked by Et and also suppressed the early portions of the sustained increase in [Ca 2+ ] i . Et A was ineffective in abolishing [Ca 2+ ] i increase in response to arginine vasopressin. Finally, to evaluate Et A 's efficacy in a pathophysiologic setting, we also studied mesangial cells exposed to cyclosporine (Cs). Exposure of mesangial cells to Cs (10 -5 M) for 60 minutes caused a significant increase in MLCP, on average, by 38 ± 6% above control (P A increased MLCP significantly less, by only 15 ± 9%. These data provide further evidence for Et's long-lasting cellular actions, and demonstrate inhibitory effects of an Et receptor antagonist after direct cellular exposure to Et and also after Cs exposure, a pathophysiologic setting which likely involves Et.