Abstract
Because delayed gastric emptying and impaired gastric accommodation are regarded as pathophysiological mechanisms underlying functional dyspepsia (FD), prokinetics and fundic relaxants have been suggested as a new treatment for FD. We isolated tetrahydroberberine (THB), an isoquinoline alkaloid (5,8,13,13a-tetrahydro-9,10-dimethoxy-6H-benzo[g]-1,3-benzodioxolo[5,6-a]quinolizine) from Corydalis tuber, and found that it has micromolar affinity for dopamine D2 (pKi = 6.08) and 5-HT1A (pKi = 5.38) receptors but moderate to no affinity for other relevant serotonin receptors (i.e., 5-HT1B, 5-HT1D, 5-HT3, and 5-HT4; pKi < 5.00). Oral administration of THB not only resulted in significantly accelerated gastric emptying of normal rats in a bell-shaped relationship, with a maximal efficacy at a dose of 30 μg/kg, but also restored the delayed gastric emptying caused by apomorphine, which might be mediated by an antidopaminergic effect. Data from electromyography indicated enhanced motor function of the upper gastrointestinal tract by THB, which occurred through strengthening contractility and shortening the contraction interval. Furthermore, in rats stressed by repeated restraint, a significantly higher shift in the pressure-volume curve by THB (10 μg/kg, p < 0.05), which was inhibited by [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635), a 5-HT1A antagonist, and Nω-nitro-l-arginine methyl ester, a nitric-oxide synthase inhibitor but not a vasoactive intestinal peptide antagonist, was observed. Oral administration of THB resulted in a drastic increase of gastric accommodation in Beagle dogs. Area under the volume versus time curve was increased significantly by THB (30 μg/kg, p < 0.01) and comparable with that of sumatriptan (3 mg/kg), a potent fundic relaxant. Taken together, our data suggested that THB, with D2 receptor antagonist and 5-HT1A receptor agonist properties, has significant potential as a therapeutic for treatment of FD.
Footnotes
This study was supported by grants from the Plant Diverse Research Center of 21C Frontier R&D Programs, Ministry of Science and Technology [Grants PF06205-01, PF06205-02, PF06205-03]; National Research Foundation of Korea funded by the Government of Korea [Grants 2011-0003580, 2011-0004984]; and Technology Development Program for Agriculture and Forestry, Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.182048.
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ABBREVIATIONS:
- FD
- functional dyspepsia
- NO
- nitric oxide
- THB
- tetrahydroberberine
- l-NAME
- Nω-nitro-l-arginine methyl ester
- WAY-100635
- [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride
- VIP
- vasoactive intestinal peptide
- CHO
- Chinese hamster ovary
- 8-OH-DPAT
- 8-hydroxy-2-dipropylaminotetralin
- NAN-190
- 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl) piperazine hydrobromide
- GR65630
- 3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone
- MDL-72222
- 3-tropanyl-3,5-dichlorobenzoate
- EMG
- electromyography
- GR127935
- N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-1,1′-biphenyl-4-carboxamide
- GR11380
- 1-methyl-1H-indole-3-carboxylic acid, [1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl ester
- MMC
- migrating motor complex
- ANOVA
- analysis of variance
- 5-HT
- serotonin.
- Received March 22, 2011.
- Accepted June 8, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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