Guinea pig gall bladder contains a single peptide leukotriene receptor which resembles that present in human conducting airway smooth muscle.
The peptide leukotrienes (LTs), LTC4, LTD4 and LTE4, produced concentration-related contraction of isolated strips of guinea pig gall bladder (GPGB) with pD2 values of 8.48 +/- 0.11, 8.26 +/- 0.22 and 7.28 +/- 0.08, respectively. In the presence of propranolol and indomethacin in epithelium-denuded GPGB, pKB values for the LT antagonist ICI198,615 vs. LTC4, LTD4 and LTE4 were, respectively: 8.61 +/- 0.12, 8.89 +/- 0.13 and 8.70 +/- 0.17. Similarly, pKB values for the LT antagonist SKF104,353 were 7.28 +/- 0.19, 7.88 +/- 0.17 and 7.45 +/- 0.17. Previous studies have shown that inhibition of LTC4 metabolism can alter the apparent affinity of the LT, especially LTC4; consequently, metabolism of [3H]LTC4 in chopped GPGB was investigated. [3H]LTC4 was converted rapidly by gamma-glutamyl transpeptidase to [3H]LTD4 with little accumulation of [3H]LTE4. The combination of acivicin (ACI) and reduced glutathione (GSH) provided complete inhibition of gamma-glutamyl transpeptidase. pD2 values for LTC4 in the presence of ACI/GSH were 8.54 +/- 0.16. pKB values for ICI198,615 and SKF104353 in the presence of ACI/GSH were, i.e., 8.42 +/- 0.14 and 7.53 +/- 0.12, respectively, vs. LTC4 and identical to those obtained in the absence of inhibitors. The mechanism(s) underlying LT-induced contraction was evaluated using the calcium channel blockers diltiazem, nifedipine and verapamil. Noncompetitive antagonism was observed against all LTs indicating the involvement of voltage-sensitive calcium channels in the contractile response. Similarly, all LTs increased polyphosphoinositide hydrolysis. These data indicate: 1) GPGB contains a single type of LT receptor similar to that in human airways and 2) LT-induced contraction appears to involve both polyphosphoinositol formation and voltage-dependent Ca++ channels.
Falcone
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RC
Department of Pharmacology, ICI Pharmaceuticals Group, A Business Unit of ICI Americas Inc., Wilmington, Delaware.
Krell
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RD
D000818:Animals; D005704:Gallbladder / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000032:analysis*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
D007191:Indazoles; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C054217:ICI 198615