Comparative study of the affinities of the 5-HT3 receptor antagonists, YM060, YM114 (KAE-393), granisetron and ondansetron in rat vagus nerve and cerebral cortex.
The 5-HT3 receptor blocking properties of YM060, YM114 (KAE-393), granisetron and ondansetron were examined in the vagus nerve and cerebral cortex of rats. 5-HT and 2-methyl-5-HT induced dose-dependent depolarizations of rat isolated vagus nerve with EC50 values of 2.53 (1.93-3.33) x 10(-6) and 4.03 (2.87-5.66) x 10(-6) M, respectively. YM060, YM114 and granisetron dose-dependently antagonized the depolarization of the rat vagus nerve induced by 5-HT, with decreases in the slope and maximal response at higher concentrations. Apparent pA2 values for these antagonists were 10.27 +/- 0.09, 10.12 +/- 0.16 and 9.44 +/- 0.40, respectively. Ondansetron produced a clear rightward shift of the concentration-response curve to 5-HT. The pA2 value was 8.63 (8.23-9.68). YM060 and YM114 at up to 10(-5) M produced no significant depression of the depolarizing responses to DMPP and GABA. YM060, YM114, granisetron and ondansetron displaced specific binding of [3H]GR65630 to rat cortical membranes with pKi values of 10.48 (10.41-10.57), 10.24 (10.18-10.28), 9.15 (9.02-9.28) and 8.70 (8.64-8.77), respectively. An excellent correlation (r = 0.97) was obtained between pA2 values in the vagus nerve and pKi values in the cerebral cortex. YM060, YM114, granisetron and ondansetron showed low affinities for 5-HT1A, 5-HT2 receptor, adrenergic alpha 1, alpha 2, dopamine D2, muscarinic M2, mu-opioid, benzodiazepine and histamine H1 receptors. These results support the possibility that the same type of 5-HT3 receptor occurs in rat vagus nerve and cerebral cortex.
Ito
H
H
Neuroscience and Gastrointestinal Research Laboratory, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.
Akuzawa
S
S
Tsutsumi
R
R
Kiso
T
T
Kamato
T
T
Nishida
A
A
Yamano
M
M
Miyata
K
K
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D017829:Granisetron / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D017294:Ondansetron / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014630:Vagus Nerve / Q000187:drug effects*
D001562:Benzimidazoles; D017829:Granisetron; D017294:Ondansetron; D012701:Serotonin; D012702:Serotonin Antagonists; C085986:YM 114; C071315:ramosetron