As delayed gastric emptying and impaired gastric accommodation are regarded as the pathophysiological mechanisms underlying functional dyspepsia (FD), prokinetic and fundic relaxants have been suggested as a new treatment for FD. We isolated tetrahydroberberine (THB), an isoquinoline alkaloid, (5,8,13,13 a-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 significantly accelerated gastric emptying of normal rats in a bell-shaped relationship with a maximal efficacy at the dose of 30 μg/kg, but also restored the delayed gastric emptying caused by apomorphine, which might be mediated by an anti-dopaminergic effect. Data from electromyography indicated that THB enhanced gastro motor function of the upper GI tract by strengthening contractility and shortening the contraction interval. Furthermore, in rats stressed by repeated restraint, a significantly higher shift in pressure-volume curve by THB (10 μg/kg, P<0.05), which was inhibited by WAY100635, a 5- HT1A antagonist and L-NAME, a NOS inhibitor, but not VIP 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 significantly increased by THB (30 μg/kg, p<0.01), comparable to that of sumatriptan (3 mg/kg), a potent fundic relaxant. Taken together, our data suggested that THB, with D2 antagonist and 5-HT1A agonist properties, has great potential as a therapeutic for treatment of FD.
- Received March 22, 2011.
- Revision received June 7, 2011.
- Accepted June 8, 2011.
- The American Society for Pharmacology and Experimental Therapeutics