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The use of receptor desensitization to analyse CCK A and CCK B /gastrin receptors coupled to contraction in guinea‐pig stomach muscle
Author(s) -
Bishop L.A.,
Gerskowitch V.P.,
Hull R.A.D.,
Shankley N.P.,
Black J.W.
Publication year - 1995
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.1476-5381.1995.tb13232.x
Subject(s) - receptor , guinea pig , contraction (grammar) , gastrin , endocrinology , desensitization (medicine) , medicine , muscle contraction , chemistry , biology , secretion
1 The results of previous studies have been in conflict with respect to the involvement of specific cholecystokinin (CCK A ) and CCK B /gastrin receptors in guinea‐pig gastric muscle. Here, in an in vitro , guinea‐pig gastric muscle assay, pentagastrin (PG) and tetragastrin (TG) behaved as high potency agonists and produced symmetrical concentration‐effect curves. In contrast, cholecystokinin‐octapeptide (CCK‐8), while also behaving as a high potency agonist, produced flat asymmetrical curves. Unlike recent data reported using this tissue (Boyle et al. , 1993), the CCK A receptor‐selective antagonist, devazepide (3, 10, 30 n m ) produced a rightward shift of the upper region of the CCK‐8 curve rendering it biphasic. The lower phase was abolished by the CCK B /gastrin receptor‐selective antagonist, L‐365260 (300 n m ) indicating that the contractile effects of CCK‐8 in this tissue are mediated by both receptor types. 2 L‐365260 produced a concentration‐dependent, parallel rightward displacement of PG concentration‐effect curves. However, a flat Schild plot slope parameter (0.77 ± 0.06) was obtained. Therefore, an empirical pA 2 value of 8.64 ± 0.21 was estimated from the smallest dose ratio. This value is consistent with published values characteristic of an interaction at CCK B /gastrin receptors. 3 TG (1 μ m ) was used to densensitize selectively the CCK B /gastrin receptors in the gastric muscle assay and thereby expose a population of receptors capable of responding to subsequent stimulation by CCK‐8 but not by PG. The selectivity of TG for CCK B /gastrin‐ over CCK A receptors was demonstrated by its low efficacy compared to CCK‐8 in the guinea‐pig gallbladder assay, a tissue shown previously to contain a homogeneous population of CCK A receptors. In TG‐desensitized gastric muscle, CCK‐8 concentration‐effect curves were symmetrical and could be displaced in a simple parallel fashion by devazepide at nanomolar concentrations consistent with an interaction at CCK A receptors (p K B ∼ 10). 4 These results indicate that the guinea‐pig gastric muscle contains both CCK A ‐ and CCK B /gastrin receptors and the effects of CCK‐8 are mediated via both of these receptors. Notwithstanding the complexity of the behaviour of L‐365260, it was possible to obtain a reasonable description of the system using a simple 2‐receptor model in which the effects of individual receptor activation were assumed to be additive. The absence of a simple competitive interaction of PG with L‐365260 may indicate, for example, non‐homogeneity of CCK B /gastrin receptors or lack of concentration equilibrium between the bath and the receptor biophase.