Influence of salmeterol and benzalkonium chloride on G-protein-mediated exocytotic responses of rat peritoneal mast cells

The long-acting beta(2)-adrenoceptor agonist salmeterol and the invert soap benzalkonium chloride share physicochemically important structures, namely a polar head group and a long aliphatic chain. Low concentrations of benza lkonium chloride have been shown to inhibit exocytotic responses in rat per itoneal mast cells by selectively interacting with heterotrimeric G-protein s of the G(i)-type. The present study investigates whether salmeterol inhib its, independently of beta-adrenoceptors, exocytotic responses of rat perit oneal mast cells induced by the direct agonists at G-proteins mastoparan or guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S). Exocytosis was studied by secretion assays ([H-3]5-hydroxytryptamine ([H-3]5-HT)-release) using in tact, streptolysin O-permeabilised or metabolically inhibited (antimycin, d eoxyglucose) rat peritoneal mast cells. Both amphiphilics, salmeterol, and benzalkonium chloride, dose-dependently exerted biphasic effects on mastopa ran-induced [H-3]5-HT release in intact mast cells. In contrast to benzalko nium chloride, the dose-response curves for secretostatic and celltoxic eff ects of salmeterol markedly overlapped. Similar to benzalkonium chloride, s almeterol in non-cytotoxic concentrations (1-25 mu g/ml) dose-dependently i nhibited exocytosis induced by mastoparan (intact cells) or GTP gamma S (pe rmeabilised cells). These findings indicate a direct, adrenoceptor-independ ent affection of G proteins by salmeterol in mast cells. (C) 2000 Elsevier Science B.V. All rights reserved.