5-HT7 receptor efficacy distribution throughout the canine stomach

1 This study aimed to determine, quantify and explain regional differences in the relaxant response to the selective 5-HT1 and 5-HT7 receptor agonist 5-carboxamidotryptamine (5-CT) throughout the canine stomach. 2 Longitudinal muscle strips from eight gastric corpus regions and six antrum regions were mounted for isotonic measurement. The 5-CT-induced relaxation was examined on a prostaglandin F-2alpha-induced submaximal response, expressed as percentage of this response and fitted to the operational model of agonism (OMOA). 5-HT7 receptor messenger RNA (mRNA) expression was compared by means of quantitative PCR. 3 5-CT inhibited PGF(2alpha)-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, pA(2) estimates 8.2 - 8.9) confirmed that in every region, the inhibition by 5-CT was 5-HT7 receptor mediated. However, variation in the maximum effect (61 - 108%) and pEC(50) (6.4 - 8.6) was observed throughout the different regions. The OMOA explained these differences as differences in the efficacy parameter tau ( ratio of receptor density and coupling efficiency; log tau estimates ranging from 0.1 to 2.1). The log tau gradient 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. 4 This study illustrates that 5-HT7 receptors are present throughout the ventral wall of the canine stomach, but the efficacy ( expressed as log tau) is clearly greater close to the lesser curvature. Differences in 5-HT7 receptor expression at least partially explain the functional differences.