Functional antagonism by salbutamol suggests differences in the relative efficacies and dissociation constants of the peptidoleukotrienes in guinea pig trachea.
To assimilate information about the relative efficacies and affinities of the peptidoleukotrienes, the ability of the beta adrenoceptor agonist salbutamol to antagonize functionally contractions produced by leukotrienes (LT)C4, LTD4 and LTE4 was examined in the guinea pig trachea. There was a marked gradation in the sensitivity of LT-induced responses to antagonism by pretreatment with salbutamol (0.01-1.0 microM): LTC4 less than LTD4 less than LTE4. These data suggest marked differences in the receptor reserve for the LTs. However, this postulate is not supported by the finding that the magnitude of the ratio for the estimated dissociation constant, KA, and EC50 values, which provides an indirect measure of the relative receptor reserve, were similar: LTC4 = 4.50, LTD4 = 10.54 and LTE4 = 3.18. Substantial differences were apparent in the estimated KA values: LTC4 = 2.88 nM, LTD4 = 11.8 and LTE4 = 46.4 nM. In the presence of a maximally effective concentration of LTE4 (1 or 10 microM), addition of LTD4 (1 or 10 microM) produced further contraction of the tissue whereas the reverse was not the case. Furthermore, in the presence of salbutamol (70 nM), LTE4 (0.1 microM) produced a 3.6-fold rightward shift in LTD4 concentration-response curves with no effect on the maximum contractile response; a pKB of 7.42 was calculated for LTE4. The results suggest that the large differences in the ability of pretreatment with salbutamol to inhibit contractions produced by LTC4, LTD4 or LTE4 are not attributable solely to corresponding differences in receptor reserve for the individual LTs.(ABSTRACT TRUNCATED AT 250 WORDS)
Hay
D W
DW
Department of Pharmacology, Smith Kline & French Laboratories, King of Prussia, Pennsylvania.
Muccitelli
R M
RM
Wilson
K A
KA
Wasserman
M A
MA
Torphy
T J
TJ
D000420:Albuterol / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D017999:Leukotriene E4; D008297:Male; D008433:Mathematics; D009119:Muscle Contraction / Q000187:drug effects; D009599:Nitroprusside / Q000494:pharmacology; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
D013189:SRS-A; D009599:Nitroprusside; D017999:Leukotriene E4; D000420:Albuterol