Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, 5-HT7, operational model of agonism, SB-269770, 5-CT, dog, proximal stomach, efficacy distribution, receptor density, quantitative PCR, OPERATIONAL MODEL, PHARMACOLOGICAL AGONISM, FUNCTIONAL DYSPEPSIA, LONGITUDINAL MUSCLE, PROXIMAL STOMACH, SPLICE VARIANTS, SEROTONIN, AFFINITY, 5-HYDROXYTRYPTAMINE, ACCOMMODATION, Alternative Splicing, Animals, Dinoprost, Dogs, Dose-Response Relationship, Drug, Female, Gastric Mucosa, Gene Expression, In Vitro Techniques, Male, Molecular Sequence Data, Muscle Contraction, Muscle Relaxation, Nitroprusside, Phenols, Protein Isoforms, RNA, Messenger, Receptors, Serotonin, Reverse Transcriptase Polymerase Chain Reaction, Serotonin, Serotonin Antagonists, Serotonin Receptor Agonists, Stomach, Sulfonamides, Tetrodotoxin, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

Abstract:

This study aimed to determine, quantify and explain regional differences in the relaxant response to the selective 5-HT(1) and 5-HT(7) receptor agonist 5-carboxamidotryptamine (5-CT) throughout the canine stomach. 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-HT(7) receptor messenger RNA (mRNA) expression was compared by means of quantitative PCR. 5-CT inhibited PGF(2alpha)-induced tonic contraction (corpus) and increase of phasic contraction amplitude (antrum). The consistent antagonism produced by the selective 5-HT(7) 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-HT(7) 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-HT(7) receptor mRNA between the lesser and the greater curvature indicates that differences in receptor density contribute to the observed functional differences. This study illustrates that 5-HT(7) 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-HT(7) receptor expression at least partially explain the functional differences.