Characterization of intracavernous pressure increase induced by Ym348, a novel 5-HT2C receptor agonist, in anesthetized rats.
OBJECTIVE
We investigated the effects of the novel 5-HT2C receptor agonist YM348 [(S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine] on ICP in anesthetized rats and clarified whether behavioral changes such as hypolocomotion induced at a high dose are a cause of the inverted U-shaped PE dose-response curves in conscious rats.


METHODS
Male Wistar rats (Japan SLC, Shizuoka, Japan) weighing 250 to 315 gm were used. The pro-erectile effect of YM348 (2.03 to 67.7 microg/kg subcutaneously) was examined in conscious rats. ICP was also monitored after YM348 treatment (0.677 to 67.7 mug/kg subcutaneously) in anesthetized rats. Response number, latency, duration, peak pressure and area under the curve were measured. The selective 5-HT2C receptor antagonist SB242084 [(6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline)] (0.03 to 1 mg/kg intraperitoneally) was administered 30 minutes before YM348 treatment.


RESULTS
YM348 induced PE and ICP increases, and was significantly inhibited by SB242084. Dose-response curves for the number of PEs and ICP increases were an inverted U shape. YM348 decreased the latency of but did not affect the quality of ICP (duration, peak pressure and area under the curve) even at the highest dose.


CONCLUSIONS
Activation of 5-HT2C receptor increased ICP and, as a result, induced PE. Since the dose-response curve for the number of ICP increases under anesthetized, behavior independent conditions still showed an inverted U shape, behavioral changes were not likely to have contributed to the inverted U-shaped dose-response curves for the number of PEs in conscious rats. Furthermore, the certain magnitude of ICP increases was likely to have occurred despite the stimulus intensity after the level of 5-HT2C receptor activation crossed the threshold.
Kimura
Yasuharu
Y
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan. yasuharu.kimura@jp.astellas.com
Naitou
Yuki
Y
Wanibuchi
Fumikazu
F
Yamaguchi
Tokio
T
D000758:Anesthesia; D000818:Animals; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D010413:Penis / Q000187:drug effects* / Q000502:physiology*; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D058826:Serotonin 5-HT2 Receptor Agonists
D007191:Indazoles; D058826:Serotonin 5-HT2 Receptor Agonists; C488691:YM348