Endothelin-1 Stimulates Eicosanoid Production in Cultured Human Nasal Mucosa

Abstract

Endothelin (ET) has been shown to contract both vascular and nonvascular smooth muscle and to stimulate human nasal glandular secretion of serous and mucous cell products. Some effects of ET are thought to be mediated by eicosanoid production. To explore the direct effect of ET on arachidonate metabolism in cultured human nasal mucosal explants, eicosanoids were measured after ET-1 stimulation. After labeling the explants with [3H]arachidonic acid (AA), supernatant from control and ET-1-treated explants were fractionated by reverse-phase high-performance liquid chromatography (HPLC). The resulting elution pattern suggested the release of prostaglandin (PG) E2 and AA in response to ET-1 stimulation. Radioimmunoassay after HPLC resolution confirmed that ET-1 induced a significantly increased release of PGE2 as well as PGD2, PGF2 alpha, thromboxane B2, and 15-hydroxyeicosatetraenoic acid (15-HETE). Although significant amounts of 15-HETE were generated, cyclooxygenase product generation was most remarkable. Eicosanoid release after ET-1 exposure (10 to 0.1 microM) is concentration dependent and occurs within 1 h. Whereas 15-HETE release was maximal at 4 h, prostanoid production was maximal 1 h after exposure to ET-1. Other assayed AA metabolites, including the peptidoleukotrienes, did not significantly change after ET-1 stimulation. We conclude that ET-1 induces the release of predominantly cyclooxygenase products from cultured human nasal mucosal explants.