Influence of fenoldopam and quinpirole in the guinea-pig stomach

1 The influence of the selective DA1-agonist fenoldopam and the selective DA2-agonist quinpirole was investigated in the guinea-pig intact stomach model and in guinea-pig gastric corpus muscle strips. 2 In the intact stomach model, quinpirole induced a relaxation from 10(-6) M on. The relaxation by quinpirole (3 x 10(-5) M) was significantly inhibited by rauwolscine (10(-7) M), yohimbine (10(-7) M) and domperidone (10(-6) M). In the presence of tetrodotoxin, quinpirole (3 x 10(-5) M) induced a contraction. 3 In the same model, fenoldopam induced a relaxation but only at 3 x 10(-5) M. The relaxation by fenoldopam (3 x 10(-5) M) was not inhibited by SCH 23390 (10(-6) M). The relaxant effect of dopamine (3 x 10(-6) M) was significantly inhibited by rauwolscine (10(-7) M), yohimbine (3 x 10(-7) M), haloperidol (10(-6) M) and domperidone (10(-6) M). 4 In circular muscle strips of the gastric corpus, the electrically induced cholinergic contractions were inhibited by dopamine but not consistently influenced by quinpirole or fenoldopam. 5 Dopamine, fenoldopam and quinpirole induced an increase in basal tone of the strips. The contraction by dopamine (10(-5) M) was significantly antagonized by prazosin and methysergide. 6 No evidence was thus found for the presence of DA1-receptors in both guinea-pig stomach models. Equally, no evidence for the presence of DA2-receptors was found when studying quinpirole in the strips. Although the relaxant effect of quinpirole in the intact stomach seems predominantly mediated via alpha-2-adrenoceptors, an involvement of DA2-receptors cannot be excluded

Selective desensitization of the 5-HT4 receptor-mediated response in pig atrium but not in stomach

Background and purpose: The time dependency of the effect of 5-HT4 receptor agonists depends on many specific regulatory mechanisms, which vary between tissues. This has important implications with regard to the effects of endogenous 5-HT, as well as to the clinical use of 5-HT4 receptor agonists, and might contribute to tissue selectivity of agonists. Experimental approach: The progression and desensitization of 5-HT4 receptor-mediated responses were evaluated in an organ bath set-up using two, clinically relevant, porcine in vitro models: gastric cholinergic neurotransmission and atrial contractility. Key results: Exposure of gastric tissue to 5-HT or to the selective 5-HT4 receptor agonists prucalopride and M0003 results in a sustained non-transient effect during exposure; after washout, the response to a subsequent challenge with 5-HT shows no clear desensitization. Incubation of left atrial tissue with 5-HT resulted in a transient response, leading after washout to a marked desensitization of the subsequent response to 5-HT. The selective 5-HT4 receptor agonists prucalopride and M0003 induce only very weak atrial responses whereas they are very effective in desensitizing the atrial response to 5-HT. The observations also suggest that the properties of prucalopride and M0003 to bind to and/or activate the 5-HT4 receptor differ from those of 5-HT. This difference might have contributed to the observed desensitization. Conclusions and implications: The high potency of prucalopride and M0003 in desensitizing the response to 5-HT together with their low efficacy in the atrium emphasizes the cardiac safety of this class of 5-HT4 receptor agonists

Differential effects of 5-hydroxytryptamine(4) receptor agonists at gastric versus cardiac receptors: An operational framework to explain and quantify organ-specific behavior

Quantification of different levels of 5-hydroxytryptamine4 (5-HT4) receptor agonism expression across animal species as well as across organs within the same animal species offers substantial potential for the separation of desired gastrointes-tinal versus undesired cardiac pharmacological activity of com-pounds in development. Since a detailed investigation of such properties is lacking to date, we set out to quantify gastric and cardiac effects of 5-HT4 receptor ligands in the pig, a model considered to be representative for the human situation. An in vitro test was developed to study the potentiating effect of 5-HT, prucalopride, tegaserod, R149402 (4-amino-5-chloro-2,2-dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid [3-hy-droxy-1-(3-methoxy-propyl)-piperidin-4ylmethyl]-amide), and R199715 (4-amino-5-chloro-2,3-dihydro-benzofuran-7-car

Ketanserin: A selective antagonist of 5-HT2 serotoninergic receptors

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Porcine left atrial and sinoatrial 5-HT4 receptor-induced responses: fading of the response and influence of development

1. In this study, we aimed to characterize in vitro the effects of the benzofuran 5-HT(4) receptor agonists prucalopride, R149402 and R199715 and the indolic agents tegaserod and 5-HT in the atria of young pigs (10–11 weeks) and newborn piglets. 2. In the paced left atrium of young pigs, only 5-HT results in positive inotropic responses when administered cumulatively (maximal effect relative to isoprenaline=53%, pEC(50)=6.8); however, all agonists showed lusitropic effects. Noncumulative administration results in greater positive inotropic responses for 5-HT and induces moderate positive inotropic responses for the other agonists; these responses fade. 3. Phosphodiesterase (PDE) enzyme inhibition with 3-isobutyl-1-methylxanthine (IBMX; 20 μM) enhances the responses to cumulatively administered 5-HT (maximal effect=89%, pEC(50)=7.7) and reveals clear positive inotropic effects for prucalopride, tegaserod, R149402 and R199715; fading is abolished. The maximal effect of the benzofurans is less pronounced than that of the indoles. 4. In the spontaneously beating right atrium of young pigs, all agonists show chronotropic activity when administered cumulatively in the absence of IBMX, without fade. Benzofurans behaved as partial agonists compared to 5-HT (maximal effect=54%, pEC(50)=6.5). 5. In newborns, the inotropic activity of the agonists in the IBMX-treated left atrium was less pronounced than in the young pig; the same applied for the chronotropic response in the right atrium, except for 5-HT. 6. In conclusion, the atrial responses to 5-HT(4) receptor activation increase in the first months of life; the inotropic response is regulated by PDEs. Prucalopride, R149402 and R199715 are partial agonists compared to 5-HT