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SK&F S‐106203 inhibits leukotriene C 4 , leukotriene D 4 and leukotriene E 4 vasopressor responses in the conscious rat
Author(s) -
Smith Edward F.,
Slivjak Mark J.,
Egan John W.,
Eckardt R.D.,
Newton J.F.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb15781.x
Subject(s) - leukotriene d4 , endocrinology , leukotriene , medicine , antagonist , chemistry , vasopressin , isoprenaline , dose–response relationship , leukotriene c4 , antagonism , pharmacology , receptor , stimulation , asthma
1 The purpose of these experiments was to investigate the effects of the selective peptidoleukotriene receptor antagonist, SK&F S‐106203, on leukotriene C 4 (LTC 4 ), LTD 4 and LTE 4 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 mg kg −1 + 1 mg kg −1 h −1 , 1 mg kg −1 + 3 mg kg −1 h −1 or 2 mg kg −1 + 10 mg kg −1 h −1 produced dose‐dependent steady‐state plasma drug concentrations of 1.0, 3.2 and 23.8 μg ml −1 , respectively. Plasma SK&F S‐106203 concentrations appeared to increase in a linear fashion at doses of 1 and 3 mg kg −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 mg kg −1 + 10 mg kg −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 LTC 4 and LTE 4 dose‐response curves. Administration of SK&F S‐106203 at doses of 0.2 mg kg −1 + 1 mg kg −1 h −1 , 1 mg kg −1 + 3 mg kg −1 h −1 , or 2 mg kg −1 + 10 mg kg −1 h −1 produced dose‐ratios of 1.0, 3.1 and 19.9, respectively, against LTC 4 responses, and dose‐ratios of 1.6, 3.8 and 9.1, respectively, against LTE 4 responses. 5 Against LTD 4 responses, SK&F S‐106203 at doses of 0.2 mg kg −1 + 1 mg kg −1 h −1 , 1 mg kg −1 + 3 mg kg −1 h −1 , or 2 mg kg −1 + 10 mg kg −1 h −1 produced dose‐ratios of 2.5, 2.8, and 11.4, respectively. Administration of d ‐penicillamine, a non‐competitive LTD 4 dipeptidase inhibitor, had no effect on LTD 4 responses. 6 The similarity in the LTD 4 dose‐ratios at the two lower infusion rates, despite increases in the plasma drug concentrations, suggests the existence of pharmacologically heterogeneous LTD 4 receptors. These results indicate that SK&F S‐106203 is a potent, selective and apparently competitive antagonist of LTC 4 , LTD 4 and LTE 4 vascular responses in the intact rat.