Pinacidil suppression on 5-HT3 receptor-mediated contraction of guinea pig ileum in vitro.
OBJECTIVE
To study the effects of the K+ channel opener pinacidil on 5-HT3 receptor-mediated contractions of the isolated guinea pig ileum (GPI) longitudinal muscle-myenteric plexus strip preparations.


METHODS
GPI contractions were recorded with a chart recorder through isometric transducers. The effect of pinacidil on binding properties of 5-HT3 receptors was assessed using [3H]GR65630 binding assay in membrane preparations of rat entorhinal cortex.


RESULTS
(1) A selective 5-HT3 receptor agonist 2-methyl-5-HT 0.1-300 mumol.L-1 and 5-HT 0.001-50 mumol.L-1 elicited GPI contractile responses in concentration-dependent manners, the EC50 values (and 95% confidence limits) for 2-methyl-5-HT and 5-HT were 10.0 (8.9-11.2) mumol.L-1 and 1.6 (1.3-1.9) mumol.L-1, respectively. Selective 5-HT3 receptor antagonist tropisetron 0.1 mumol.L-1 competitively inhibited the responses to 2-methyl-5-HT and 5-HT. (2) Pinacidil 0.5-5 mumol.L-1 inhibited 5-HT3 receptor-mediated contractions. (3) Pinacidil 1 mumol.L-1 enhanced the inhibitory effects of tropisetron 0.1 mumol.L-1 or another selective 5-HT3 receptor antagonist benesetron 1 mumol.L-1 on 5-HT-induced GPI contractile responses. (4) Pinacidil 1-5 mumol.L-1 did not affect GPI contractile responses evoked by a selective M-ACh receptor agonist carbachol 1 mumol.L-1. (5) Pinacidil 1-5 mumol.L-1 had no effect on binding properties of 5-HT3 receptors with selective 5-HT3 receptor radioligand [3H]GR65630 in the entorhinal cortex of rat brain.


CONCLUSIONS
The inhibition by pinacidil of 5-HT3 receptor-mediated GPI contractile responses may be mediated through activation of ATP-sensitive K+ channels located in prejunctional myenteric neurons.
Yuan
Y M
YM
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
Xu
D Y
DY
Hu
G Y
GY
D000818:Animals; D002217:Carbachol / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D009197:Myenteric Plexus / Q000187:drug effects; D020110:Pinacidil / Q000494:pharmacology*; D015221:Potassium Channels / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists
D015221:Potassium Channels; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C045918:2-methyl-5-HT; D020110:Pinacidil; D002217:Carbachol