title: SK&F S-106203 inhibits leukotriene C4, leukotriene D4 and leukotriene E4 vasopressor responses in the conscious rat.
abstract: 1. The purpose of these experiments was to investigate the effects of the selective peptidoleukotriene receptor antagonist, SK&F S-106203, on leukotriene C4 (LTC4), LTD4 and LTE4 vasopressor responses in the conscious, normotensive rat. SK&F S-106203 was administered as a bolus followed by a continuous infusion in order to provide information on the relationship between antagonism of leukotriene responses and steady-state plasma concentrations. 2. Infusion of SK&F S-106203 at doses of 0.2 mgkg-1 + 1 mgkg-1 h-1, 1 mgkg-1 + 3 mgkg- h-1 or 2 mgkg-1 + 10 mgkg-1 h-1 produced dose-dependent steady-state plasma drug concentrations of 1.0, 3.2 and 23.8 micrograms ml-1, respectively. Plasma SK&F S-106203 concentrations appeared to increase in a linear fashion at doses of 1 and 3 mgkg-1 h-1; at the highest dose the increment in plasma drug concentrations (i.e., 7-8 fold) was greater than the increment in dose (i.e., 3 fold), suggesting saturation of the primary clearance mechanism(s) at this dose. 3. SK&F S-106203 (2 mgkg-1 + 10 mgkg-1 h-1) had no effect on noradrenaline-, vasopressin-, isoprenaline-, or U 46619-induced responses. 4. SK&F S-106203 produced dose-dependent rightward shifts in the LTC4 and LTE4 dose-response curves. Administration of SK&F S-106203 at doses of 0.2mg kg1 + 1 mg kg1 h-, mg kg' + 3mgkg-'h-1, or 2mgkg-' + lOmgkg-1h'- produced dose-ratios of 1.0, 3.1 and 19.9, respectively, against LTC4 responses, and dose-ratios of 1.6, 3.8 and 9.1, respectively, against LTE4 responses. 5. Against LTD4 responses, SK&F S-106203 at doses of 0.2mgkg- + mgkg-1 h-, mg kg' + 3 mg kg- 1h - ', or 2 mg kg- + 10 mg kg- h- produced dose-ratios of 2.5, 2.8, and 11.4, respectively. Administration of D-penicillamine, a non-competitive LTD4 dipeptidase inhibitor, had no effect on LTD4 responses. 6. The similarity in the LTD4 dose-ratios at the two lower infusion rates, despite increases in the plasma drug concentrations, suggests the existence of pharmacologically heterogeneous LTD4 receptors. These results indicate that SK&F S-106203 is a potent, selective and apparently competitive antagonist of LTC4, LTD4 and LTE4 vascular responses in the intact rat.
authors.affiliation: SmithKline Beecham Pharmaceuticals plc, Department of Pharmacology, King of Prussia, PA 19406.
authors.forename: E F
authors.initials: EF
authors.lastname: Smith
authors.forename: M J
authors.initials: MJ
authors.lastname: Slivjak
authors.forename: J W
authors.initials: JW
authors.lastname: Egan
authors.forename: R D
authors.initials: RD
authors.lastname: Eckardt
authors.forename: J F
authors.initials: JF
authors.lastname: Newton
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003998:Dicarboxylic Acids / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007545:Isoproterenol / Q000494:pharmacology; D017999:Leukotriene E4; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010396:Penicillamine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D003998:Dicarboxylic Acids; D013189:SRS-A; C065234:SK&F S-106203; D017999:Leukotriene E4; D010396:Penicillamine; D007545:Isoproterenol; D009638:Norepinephrine