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Effects of human plasma proteins on endothelin binding and function.

We have previously shown that the endothelin (ET) isoforms ET-1 and ET-3 and ET receptor antagonists exhibit a high degree (> 98%) of binding to plasma proteins, especially serum albumin. This study examines the effects of human plasma proteins on ET-1 binding and ET-1 stimulated biologic responses. When ET-1 binding to rat pituitary MMQ cells was examined, human serum albumin (HSA) inhibited ET-1 binding in a concentration-dependent manner, with 92% inhibition observed at 5% (w/v) HSA. A similar observation was made when human plasma was tested. Surprisingly, addition of human plasma (0-100%) or HSA (0-5%) did not have a significant effect on ET-1-stimulated phosphatidylinositol (PI) hydrolysis in these cells. In human pericardial smooth-muscle cells, HSA again exhibited profound inhibitory effects on ET-1 binding; 5% HSA inhibited ET-1 binding by 84%. However, ET-1-stimulated arachidonic acid release in these cells was not significantly affected by HSA (0-5%). Addition of increasing concentrations of human plasma incrementally decreased the potency of PD-156707, and ETA-selective antagonist, on inhibiting ET-1-stimulated PI hydrolysis in the MMQ cells. These results suggest that, although ET-1 binding to the receptor is inhibited by human plasma proteins, especially HSA, ET-1-induced signal transduction is not significantly affected. Furthermore, plasma proteins decrease the potency of an ET receptor antagonist in inhibiting ET-1-stimulated biologic responses. This study may help to explain the discrepancy between in vitro and in vivo potencies of ET receptor antagonists.