Analysis of the variation in the action of L‐365,260 at CCK_B/gastrin receptors in rat, guinea‐pig and mouse isolated gastric tissue assays

Abstract

8.70. 3 Overall, the data could be accounted for by assuming the variable expression of two receptor subtypes across the assays. The rat stomach appeared to express a single receptor characterized by a low affinity constant for L-365,260 (pKB-7.5). The guinea-pig gastric muscle and mouse stomach data could be explained by the presence of this receptor and a second one characterized by a high affinity constant for ). The activity of the two proposed receptor subtypes was consistent between experiments in the guinea-pig and the high affinity receptor appeared to be predominant. In contrast, the mouse stomach data could only be simulated by assuming that the proportion and absolute number of each subtype varied significantly between the replicate experiments. 4 The L-365,260 affinity estimates at the inferred receptor subtypes were indistinguishable from those obtained in a corresponding analysis of the behaviour of L-365,260 in CCKB/gastrin receptor radioligand binding experiments in guinea-pig gastric gland and mouse and rat cerebral cortex preparations.

Analysis of variation in L‐365,260 competition curves in radioligand binding assays

“…However, as discussed above, CCK8S does not appear to discriminate between the two sites in these particular assays and, similarly, pentagastrin did not appear to discriminate between the sites identified using L-365,260 in three isolated, intact tissue assays (Roberts et al, 1996). In terms of pharmacological significance, the L-365,260 affinity estimates at the two sites are indistinguishable from those estimated in isolated gastric tissue assays prepared from the same three species.…”

“…The quoted affinities of L-365,260 in the other two rat neuronal tissues were both low suggesting the predominant presence of GI-binding sites. Interestingly, Patel & Spraggs (1992) and Roberts et al (1996) also obtained evidence for a homogeneous population of receptors with a low affinity for L-365,260 in rat gastric secretory assays. Although in this study the guinea-pig gastric mucosa appeared to express both G1-and G2-binding sites, only one low affinity value for L-365,260 is presented in Table 2.…”

“…The preceding paper (Roberts et al, 1996) describes an analysis of replicate data sets obtained from the interaction between pentagastrin and a selective cholecystokinin (CCK)B/ gastrin receptor antagonist, L-365,260, on isolated, gastrointestinal tissue assays. In the isolated, lumen-perfused, immature rat stomach assay, L-365,260 behaved as a simple competitive antagonist acting at a homogeneous population of receptors.…”

Antagonist inhibition curves and the measurement of dissociation constants

“…5 to 100 or more) and the results used to calculate a single estimate for the tissue. Taking the average of estimates of log affinity constant for each concentration is the same as making a ‘Schild‐plot’(Arunlakshana & Schild, 1957) with ‘the slope constrained to one’ a procedure used, for instance, by Roberts et al (1996). The condition for a least‐squares fit of N results to the equation…”

“…5 to 100 or more) and the results used to calculate a single estimate for the tissue. Taking the average of estimates of log anity constant for each concentration is the same as making a`Schild-plot' (Arunlakshana & Schild, 1957) with`the slope constrained to one' a procedure used, for instance, by Roberts et al (1996). The condition for a least-squares ®t of N results to the equation The main aim of this work was to investigate the relation between Q and [B] and the experimental design, with alternate small and large responses, was chosen because with tissues, such as ileum, it is known that the response obtained with an agonist is aected by the previous response (Ste-phenson, 1956), particularly if this has produced a very small or a very large eect (Barlow, 1975).…”