Pieter Janssen(1,2), Nicolaas H. Prins(2), Pieter J. Peeters(2), Klaas P. Zuideveld(3) and Romain A. Lefebvre(1)
(1)Ghent University, Ghent, Belgium; (2)Johnson & Johnson Pharmaceuticals, Beerse, Belgium; (3)F. Hoffmann-La Roche, Basel, Switzerland
Objectives This study aimed to determine, quantify and explain regional differences in 5-HT7 receptor efficacy throughout the canine stomach using the relaxant response of the selective 5-HT1/7 receptor agonist 5‑carboxamidotryptamine (5-CT).
Methods From 6 dogs, longitudinal muscle strips from 8 gastric corpus regions and 6 antrum regions were mounted for isotonic measurement. The 5-CT-induced relaxation was examined on a prostaglandinF2a-induced submaximal contraction. The resulting concentration-effect relationships were subsequently analyzed using the Hill equation and the operational model of agonism to estimate the operational affinity (pKA) and efficacy (log t) in a population approach (nlme, S-PLUS). The efficacy estimate (log t; ratio of receptor density and coupling efficiency) obtained was compared with estimates of 5-HT7 receptor mRNA expression.
Results 5-CT inhibited PGF2a-induced tonic contraction (corpus) and increase of phasic contraction amplitude (antrum). The consistent antagonism produced by the selective 5-HT7 receptor antagonist SB-269970 (10 nM, pA2 estimates 8.2-8.9) confirmed that in every region, the inhibition by 5-CT was 5-HT7 receptor-mediated. Differences in the maximum effect (61-108%) and potency (pEC50 6.4-8.6) were consistent by region in all animals. Using the operational model of agonism these differences could be quantified by estimating the efficacy parameter t (log t estimates ranging from 0.1-2.1). The log t decreases going from the lesser to the greater curvature. A proportional difference (68%) in the relative expression of 5-HT7 receptor mRNA between the lesser and the greater curvature indicates that differences in receptor density contribute to the observed functional differences.
Conclusions This study illustrates that 5-HT7 receptors are present throughout the ventral wall of the canine stomach but the efficacy is clearly greater close to the lesser curvature. Regional differences in intrinsic efficacy are likely to be due to changes in receptor density as shown by 5-HT7 mRNA receptor expression. Regional differences in efficacy support the hypothesis that using partial agonists for the 5-HT7 receptor it may be possible to obtain pharmacological and physiological selectivity.
Reference: PAGE 13 () Abstr 523 [www.page-meeting.org/?abstract=523]
Poster: poster