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 benzalkonium chloride have been shown to inhibit exocytotic responses in rat peritoneal mast cells by selectively interacting with heterotrimeric G-proteins of the G(i)-type. The present study investigates whether salmeterol inhibits, independently of beta-adrenoceptors, exocytotic responses of rat peritoneal 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 ([3H]5-hydroxytryptamine ([3H]5-HT)-release) using intact, streptolysin O-permeabilised or metabolically inhibited (antimycin, deoxyglucose) rat peritoneal mast cells. Both amphiphilics, salmeterol, and benzalkonium chloride, dose-dependently exerted biphasic effects on mastoparan-induced [3H]5-HT release in intact mast cells. In contrast to benzalkonium chloride, the dose-response curves for secretostatic and celltoxic effects of salmeterol markedly overlapped. Similar to benzalkonium chloride, salmeterol in non-cytotoxic concentrations (1-25 microg/ml) dose-dependently inhibited exocytosis induced by mastoparan (intact cells) or ++GTP gamma S (permeabilised cells). These findings indicate a direct, adrenoceptor-independent affection of G proteins by salmeterol in mast cells.
Seebeck
J
J
Department of Pharmacology, University of Kiel, Hospitalstrasse 4, D-24105, Kiel, Germany. jseebeck@pharmakologie.uni-kiel.de
Krebs
D
D
Ziegler
A
A
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001426:Bacterial Proteins; D001548:Benzalkonium Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000187:drug effects*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides; D010529:Peritoneal Cavity / Q000166:cytology; D051381:Rats; D000068299:Salmeterol Xinafoate; D012701:Serotonin / Q000378:metabolism; D013301:Streptolysins / Q000494:pharmacology; D014316:Tritium; D014862:Wasp Venoms / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D001426:Bacterial Proteins; D001548:Benzalkonium Compounds; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D013301:Streptolysins; D014862:Wasp Venoms; C025964:streptolysin O; D014316:Tritium; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000068299:Salmeterol Xinafoate; C037500:mastoparan; D019204:GTP-Binding Proteins; D000420:Albuterol