OBJECTIVES: Ondansetron is an antagonist of 5-HT3 receptors mostly used as an antiemetic yet known to modulate metabolism and appetite. We tested the metabolic effects of ondansetron in newly derived congenic rat strain, carrying limited chromosome 8 regions of (PD) Brown Norway (BN) and polydactylous (PD) strain origins (including variant serotonin receptor Htr3b gene) within the genomic background of highly inbred model of metabolic syndrome, the spontaneously hypertensive rat (SHR). METHODS: Adult, standard diet-fed male rats of SHR and the congenic SHR.(PD/BN)8 strains received ondansetron (2mg/kg body weight/day) or vehicle (n=6/strain/treatment) via oral gavage for 14 days while we followed their metabolic and morphometric profiles including glucose tolerance and triacylgycerol and cholesterol concentrations in 20 lipoprotein fractions. RESULTS: We fine-mapped the chromosome 8 differential segment in the new SHR.(PD/BN)8 congenic strain: it comprises BN-derived region together with an adjacent 422kb stretch of PD origin. The SHR.(PD/BN)8 rats were heavier than SHR, the fasting glucose was significantly higher in ondansetron-treated congenic than in SHR (post-hoc Tukey's HSD p=0.02). Compared to SHR, ondansetron induced significantly more robust increases of cholesterol and triacylglycerol concentrations in total, chylomicron, VLDL and HDL particles in the SHR.(PD/BN)8 congenic strain. CONCLUSION: We established new congenic model with distinct pharmacogenetic profile related to metabolic effects of ondansetron, facilitating thus the search for responsible genetic variants within the limited genomic region demarcated by the differential segment.
- MeSH
- hypertenze farmakoterapie genetika metabolismus MeSH
- krysa rodu Rattus MeSH
- lipidy krev MeSH
- metabolický syndrom farmakoterapie genetika metabolismus MeSH
- modely nemocí na zvířatech * MeSH
- ondansetron farmakologie MeSH
- polydaktylie genetika MeSH
- porucha glukózové tolerance farmakoterapie genetika metabolismus MeSH
- potkani inbrední BN MeSH
- potkani inbrední SHR * MeSH
- receptory serotoninové 5-HT3 genetika metabolismus MeSH
- savčí chromozomy MeSH
- serotoninové receptory 5-HT3 - antagonisté farmakologie MeSH
- zvířata kongenní MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- lipidy MeSH
- ondansetron MeSH
- receptory serotoninové 5-HT3 MeSH
- serotoninové receptory 5-HT3 - antagonisté MeSH
The relaxations mediated by the activation of 5-HT receptors in the guinea pig proximal colon were investigated. Longitudinal strips were cut from the colon segment and placed into the bath. In the presence of atropine (0.2 microM), the relaxations were evoked by adding increasing concentrations of 5-HT (1-100 microM). Noncumulative concentration-response curves were established in the absence and presence of either 5-HT or nitric oxide synthase (NOS) antagonists. Selective 5-HT3 antagonists tropisetron (10 and 100 nM) and ondansetron (1 microM) inhibited the relaxations and shifted the concentration-response curves to the right. Similar effects were observed in the presence of the NOS inhibitor N(G)-nitro-L-arginine (3.2, 10, 32 microM) and partly reversed with L-arginine (100, 320 microM). N(G)-nitro-D-arginine, serving as a negative control, was ineffective. The relaxations were further inhibited in the presence of the soluble guanylate cyclase blocker methylene blue (10 microM) or NO scavenger hemoglobin (32 microM). These results suggest that the 5-HT3 receptor plays a role in neurogenic relaxations of guinea pig proximal colon, which are at least partly mediated via release of NO from nerve endings.
- MeSH
- antagonisté serotoninu farmakologie MeSH
- hemoglobiny farmakologie MeSH
- hladké svalstvo účinky léků inervace MeSH
- indoly farmakologie MeSH
- inhibitory enzymů farmakologie MeSH
- kolon účinky léků inervace MeSH
- methylenová modř farmakologie MeSH
- morčata MeSH
- nitroarginin farmakologie MeSH
- ondansetron farmakologie MeSH
- oxid dusnatý antagonisté a inhibitory fyziologie MeSH
- receptory serotoninové 5-HT3 MeSH
- receptory serotoninové aplikace a dávkování účinky léků fyziologie MeSH
- relaxace svalu účinky léků MeSH
- synthasa oxidu dusnatého, typ I MeSH
- synthasa oxidu dusnatého antagonisté a inhibitory MeSH
- techniky in vitro MeSH
- tropisetron MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- morčata MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antagonisté serotoninu MeSH
- hemoglobiny MeSH
- indoly MeSH
- inhibitory enzymů MeSH
- methylenová modř MeSH
- nitroarginin MeSH
- ondansetron MeSH
- oxid dusnatý MeSH
- receptory serotoninové 5-HT3 MeSH
- receptory serotoninové MeSH
- synthasa oxidu dusnatého, typ I MeSH
- synthasa oxidu dusnatého MeSH
- tropisetron MeSH
Concentration-dependent 5-hydroxytryptamine (5-HT) relaxations of guinea pig proximal colon were evoked in the presence of atropine (0.2 microM). 5-HT effect was neuronally mediated since it was blocked by tetrodotoxin (TTX) (0.5 microM). The type of 5-HT receptor mediating the relaxations was investigated using both 5-HT agonists and antagonists. Selective 5-HT3 antagonists tropisetron (10, 50, 500 nM) and ondansetron (1 microM) shifted the concentration-response curves for 5-HT to the right. Another 5-HT3 antagonist MDL 72222 (0.5 microM), 5-HT1/5-HT2 antagonists methiothepin (0.1 microM) and metergoline (0.1 microM), 5-HT(1A,B) antagonist propranolol (l microM) and 5-HT1B antagonist isamoltane (10 nM) were ineffective. Specific agonist of 5-HT3 receptors 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) and agonist of 5-HT1 receptors 5-carboxamidotryptamine (5-CT) also relaxed the preparation, although the relaxation was not 5-HT relaxation. Neither was it neurogenic because it persisted in the presence of TTX (0.5 microM). The concentration-response curve for 2-methyl-5-HT was not affected by ondansetron (1 microM) or tropisetron (0.5 microM), but it was shifted to the right in the presence of 5-HT1/5-HT2 receptor antagonists methiothepin (0.1 microM) and metergoline (0.1 microM) and in the presence of 5-HT(1Da)/5-HT2A receptor antagonist ketanserin (1 microM). Methiothepin (0.1 microM) also inhibited the relaxations evoked in the presence of 5-CT. Specific agonist of 5-HT4 receptors 5-methoxytryptamine did not exert any effect on the preparation. It is suggested that there are two different mechanisms of relaxation in the guinea pig proximal colon. One is neurogenic and involves the activation of 5-HT3 receptors located on inhibitory neurons to the muscle; the other is myogenic and might be mediated via yet unclassified 5-HT receptors located on the muscle.
- MeSH
- agonisté serotoninových receptorů farmakologie MeSH
- antagonisté serotoninu farmakologie MeSH
- hladké svalstvo * chemie účinky léků MeSH
- indoly farmakologie MeSH
- ketanserin farmakologie MeSH
- kolon chemie účinky léků MeSH
- metergolin farmakologie MeSH
- methiothepin farmakologie MeSH
- morčata MeSH
- ondansetron farmakologie MeSH
- receptory serotoninové fyziologie MeSH
- relaxace svalu * účinky léků MeSH
- serotonin analogy a deriváty farmakologie MeSH
- svalová kontrakce účinky léků MeSH
- techniky in vitro MeSH
- tetrodotoxin farmakologie MeSH
- tropisetron MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- morčata MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 2-methyl-5-HT MeSH Prohlížeč
- 5-carboxamidotryptamine MeSH Prohlížeč
- agonisté serotoninových receptorů MeSH
- antagonisté serotoninu MeSH
- indoly MeSH
- ketanserin MeSH
- metergolin MeSH
- methiothepin MeSH
- ondansetron MeSH
- receptory serotoninové MeSH
- serotonin MeSH
- tetrodotoxin MeSH
- tropisetron MeSH
