NK1-RECEPTOR AND NH3-RECEPTOR MEDIATED INHIBITION OF 5-HYDROXYTRYPTAMINE RELEASE FROM THE VASCULARLY PERFUSED SMALL-INTESTINE OF THE GUINEA-GIG

The effects of tachykinins on the spontaneous release of 5-hydroxytryp tamine (5-HT) from the enterochromaffin cells into the portal circulat ion was investigated in vitro using the vascularly perfused isolated g uinea-pig small intestine. 5-HT was determined by HPLC with electroche mical detection. Test substances were applied intraarterially. Substan ce P (SP) caused a concentration-dependent decrease in 5-HT outflow wi th an EC50 of 50 pmol/l. Similarly, the selective NK1 receptor agonist SP methyl ester (1 nmol/l) significantly inhibited 5-HT outflow (to 5 1+/-3%). When tetrodotoxin (1 mu mol/l) was added to the arterial perf usion medium, the inhibition by SP of 5-HT outflow was not affected. T he selective NK1 receptor antagonist CP 99994 S,3S)-3-(2-methoxybenzyl amino)-2-phenylpiperidine] (0.1 mu mol/l) prevented the inhibitory eff ect of SP (0.1 mu mol/l). Neither GR 94800 (PhCO-Ala-Ala-DTrp-Phe-DPro -Pro-NleNH(2)) (0.1 mu mol/l) nor SR 142801 propyl)-4-phenylpiperidin- 4-yl)-N-methylacetamide] (10 nmol/l), which are selective NK2 and NK3 receptor antagonists, changed the SP-mediated inhibition. The selektiv e NK3 receptor agonist senktide (10 nmol/l) also decreased the 5-HT ou tflow (to 57+/-5%). This inhibition was prevented by SR 142801 (10 nmo l/l) and by tetrodotoxin. CP 99994 (0.1 mu mol/l) significantly antago nized the senktide-mediated inhibition of 5-HT outflow. The outflow of 5-HT was unaffected when CP 99994, GR 94800 or SR 142801 alone were a dded to the perfusion medium. It is concluded that the release of 5-HT from enterochromaffin cells is directly inhibited by NK1 receptors, a nd indirectly by neuronal NK3 receptors whose stimulation leads to the release of SP.