Article date: August 2001
By: Magnus Bäck, Maria Kumlin, Ian A Cotgreave, Sven‐Erik Dahlén in Volume 133, Issue 7, pages 1134-1144
Contractions of guinea‐pig tracheal preparations to cysteinyl‐leukotrienes (LTC4, LTD4 and LTE4) were characterized in organ baths, and cysteinyl‐leukotriene metabolism was studied using radiolabelled agonists and RP‐HPLC separation.
In the presence of S‐hexyl GSH (100 μM) the metabolism of [3H]‐LTC4 into [3H]‐LTD4 was inhibited and the LTC4‐induced contractions were resistant to CysLT1 receptor antagonism but inhibited by the dual CysLT1/CysLT2 receptor antagonist BAY u9773 (0.3–3 μM) with a pA2‐value of 6.8±0.2.
In the presence of L‐cysteine (5 mM), the metabolism of [3H]‐LTD4 into [3H]‐LTE4 was inhibited and the LTD4‐induced contractions were inhibited by the CysLT1 receptor antagonist ICI 198,615 (1–10 nM) with a pA2‐value of 9.3±0.2. However, at higher concentrations of ICI 198,615 (30–300 nM) a residual contraction to LTD4 was unmasked, and this response was inhibited by BAY u9773 (1–3 μM).
In the presence of the combination of S‐hexyl GSH with L‐cysteine, the LTD4‐induced contractions displayed the characteristics of the LTC4 contractile responses, i.e. resistant to CysLT1 receptor antagonism, increased maximal contractions and slower time‐course. This qualitative change of the LTD4‐induced contraction was also observed in the presence of S‐decyl GSH (100 μM), GSH (10 mM) and GSSG (10 mM).
S‐hexyl GSH, S‐decyl GSH, GSH and GSSG all stimulated a formation of [3H]‐LTC4 from [3H]‐LTD4.
In conclusion, GSH and GSH‐related compounds changed the pharmacology of the LTD4‐induced contractions by stimulating the conversion of LTD4 into LTC4. Moreover, the results indicate that, in addition to the metabolism of LTC4 into LTD4 and LTE4, also the formation of LTC4 from LTD4 may regulate cysteinyl‐leukotriene function.
Contractions of guinea‐pig tracheal preparations to cysteinyl‐leukotrienes (LTC4, LTD4 and LTE4) were characterized in organ baths, and cysteinyl‐leukotriene metabolism was studied using radiolabelled agonists and RP‐HPLC separation.
In the presence of S‐hexyl GSH (100 μM) the metabolism of [3H]‐LTC4 into [3H]‐LTD4 was inhibited and the LTC4‐induced contractions were resistant to CysLT1 receptor antagonism but inhibited by the dual CysLT1/CysLT2 receptor antagonist BAY u9773 (0.3–3 μM) with a pA2‐value of 6.8±0.2.
In the presence of L‐cysteine (5 mM), the metabolism of [3H]‐LTD4 into [3H]‐LTE4 was inhibited and the LTD4‐induced contractions were inhibited by the CysLT1 receptor antagonist ICI 198,615 (1–10 nM) with a pA2‐value of 9.3±0.2. However, at higher concentrations of ICI 198,615 (30–300 nM) a residual contraction to LTD4 was unmasked, and this response was inhibited by BAY u9773 (1–3 μM).
In the presence of the combination of S‐hexyl GSH with L‐cysteine, the LTD4‐induced contractions displayed the characteristics of the LTC4 contractile responses, i.e. resistant to CysLT1 receptor antagonism, increased maximal contractions and slower time‐course. This qualitative change of the LTD4‐induced contraction was also observed in the presence of S‐decyl GSH (100 μM), GSH (10 mM) and GSSG (10 mM).
S‐hexyl GSH, S‐decyl GSH, GSH and GSSG all stimulated a formation of [3H]‐LTC4 from [3H]‐LTD4.
In conclusion, GSH and GSH‐related compounds changed the pharmacology of the LTD4‐induced contractions by stimulating the conversion of LTD4 into LTC4. Moreover, the results indicate that, in addition to the metabolism of LTC4 into LTD4 and LTE4, also the formation of LTC4 from LTD4 may regulate cysteinyl‐leukotriene function.
British Journal of Pharmacology (2001) 133, 1134–1144; doi:10.1038/sj.bjp.0704180
DOI: 10.1038/sj.bjp.0704180
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