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), gran isetron and ondansetron were examined in the vagus nerve and cerebral cortex of rats. 5-HT and 2-methyl-5-HT induced dose-dependent depolari zations of rat isolated vagus nerve with EC(50) values of 2.53 (1.93-3 .33) x 10(-6) and 4.03 (2.87-5.66) x 10(-6) M, respectively. YM060, YM 114 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 pA(2) values for t hese antagonists were 10.27 +/- 0.09, 10.12 +/- 0.16 and 9.44 +/- 0.40 , respectively. Ondansetron produced a clear rightward shift of the co ncentration-response curve to 5-HT. The pA(2) value was 8.63 (8.23-9.6 8). YM060 and YM114 at up to 10(-5) M produced no significant depressi on of the depolarizing responses to DMPP and GABA. YM060, YM114, grani setron and ondansetron displaced specific binding of [H-3]GR65630 to r at cortical membranes with pKi values of 10.48 (10.41-10.57), 10.24 (1 0.18-10.28), 9.15 (9.02-9.28) and 8.70 (8.64-8.77), respectively. An e xcellent correlation (r = 0.97) was obtained between pA(2) values in t he vagus nerve and pKi values in the cerebral cortex. YM060, YM114, gr anisetron and ondansetron showed low affinities for 5-HT1A, 5-HT2 rece ptor, adrenergic alpha(1), alpha(2), dopamine D-2, muscarinic M(2), mu -opioid, benzodiazepine and histamine H-1 receptors. These results sup port the possibility that the same type of 5-HT3 receptor occurs in ra t vagus nerve and cerebral cortex.