Hidenobu Yuki

Mechanisms of cisplatin- and m-chlorophenylbiguinide-induced emesis in ferrets

We investigated the involvement of peripheral and central serotonin (5-HT)3 receptors in cisplatin- and 5-HT3 receptor agonist-induced emesis in ferrets. Cisplatin (10 mg/kg i.v.)-induced emesis was inhibited by intravenous YM060 (0.003-0.1 microgram/kg). A highly selective and potent 5-HT3 receptor agonist, m-chlorophenylbiguanide (1-10 mg/kg i.p.), dose dependently elicited emesis an effect which was inhibited by YM060 (0.003-0.3 microgram/kg i.v.). Vagotomy markedly reduced this emesis, and the combination of abdominal vagotomy and greater splanchnicectomy abolished emesis. Lesion of greater splanchnic nerves alone did not markedly inhibit emesis. Intracerebroventricularly (4th ventricle) administered YM060 inhibited cisplatin- and m-chlorophenylbiguanide-induced emesis only at higher doses (0.01-0.1 and 0.01-0.03 microgram, respectively). Intracerebroventricularly (4th ventricle) administered m-chlorophenylbiguanide (30-100 micrograms) produced only a weak retching response. These results indicate that stimulation of abdominal vagal afferent nerves via peripheral 5-HT3 receptors is important for triggering cisplatin- and m-chlorophenylbiguanide-induced emesis in ferrets.

Grey-scale contrast enhancement in rabbit liver with DMP115 at different acoustic power levels.

The contrast enhancement effect of ultrasound (US) contrast agent DMP-115 (YM454, Definity) in rabbit liver at two acoustic transmit power levels was studied. A total of 12 rabbits with healthy livers and 7 rabbits with VX-2 tumors were used. Grey-scale ultrasonograms in both fundamental (3.75 MHz) and harmonic (2.5/5.0 MHz) imaging modes were performed at a frame rate of 26 Hz under baseline acoustic power (MI = 0.6) or lower acoustic power (MI = 0.2). The contrast enhancement depended on the contrast agent dose and the acoustic power. The video intensity change was higher in the portal vein under the baseline acoustic power and higher in the liver parenchyma under the lower acoustic power. The contrast-enhanced US observation of the VX-2 tumor in the arterial phase correlated well with the angiographic and histopathological appearance of the tumor. In the parenchymal phase, the borderline of the tumor could be clearly delineated from the surrounding liver parenchyma. Continuous fundamental and harmonic grey-scale imaging with DMP115 has the capability of making peripheral circulation images of liver parenchyma and tumors.

Pharmacological profile of YM-31636, a novel 5-HT3 receptor agonist, in vitro.

We investigated the in vitro pharmacological profile of YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate). In cloned human 5-HT3A receptors, YM-31636 had a pKi value of 9.67 vs. ramosetron and pKi values for other 5-HT3 receptor agonists were less than 7. YM-31636 showed very low affinities for other receptors. YM-31636 induced contraction of isolated guinea pig distal colon. The intrinsic activity was approximately 0.90 compared with 5-hydroxytryptamines (5-HT) 1.0, and the potency was 26 times greater than that of 5-HT. YM-31636 increased short-circuit current (Isc) in the isolated guinea pig distal colon. In this case, the relative intrinsic activity was approximately 0.19. In isolated guinea pig right atrium, YM-31636 induced tachycardia with the relative intrinsic activity of approximately 0.23. All these effects of YM-31636 were antagonized by ramosetron, a selective 5-HT3 receptor antagonist. These results suggest that YM-31636 is a potent and selective 5-HT3 receptor agonist, preferentially acting on the contraction of the colon.

Comparison of the effects of trimebutine and YM114 (KAE-393), a novel 5-HT3 receptor antagonist, on stress-induced defecation

YM114 (KAE-393), (R)-5-[(2,3-dihydro-1-indolyl)carbonyl]-4,5,6,7- tetrahydro-1H-benzimidazole hydrochloride, is a derivative of YM060, a potent 5-HT3 receptor antagonist. We investigated the effects of YM114 on 5-HT3 receptors, both in vitro and in vivo, and on bowel dysfunction induced by restraint stress, 5-HT and thyrotropin-releasing hormone (TRH), and compared them with the effect of trimebutine. YM114 dose dependently inhibited the reduction in heart rate induced by 5-HT (30 micrograms/kg i.v.) in rats (ED50 = 0.31 micrograms/kg i.v.), and the potency of YM114 was almost the same as that of the racemate. The S-form of YM114 also inhibited 5-HT-induced bradycardia, but 1350 times less potent than the R-form. YM114 and its S-form inhibited [3H]GR65630 binding to N1E-115 cell membranes in a concentration-dependent manner with Ki values of 0.341 and 616 nM, respectively, showing the isomeric activity ratio (R-/S-form) of YM114 to be much greater (1800). YM114 antagonized 5-HT-induced depolarization of the nodose ganglion (EC50 = 1.39 nM). Trimebutine (1 mg/kg i.v.) failed to inhibit 5-HT-induced bradycardia, implying that it does not possess 5-HT3 receptor antagonistic activity. YM114 significantly and dose dependently prevented restraint stress-, 5-HT- and TRH-induced increases in fecal pellet output, and restraint stress- and 5-HT-induced diarrhea in rats and mice (ED50 = 6.9, 72.5, 154.6, 9.7 and 52.4 micrograms/kg p.o., respectively). Trimebutine significantly prevented stress- and 5-HT-induced diarrhea (ED50 = 29.4 and 87.3 mg/kg p.o., respectively), but only partially affected stress-, 5-HT- and TRH-induced increases in fecal pellet output. Thus, YM114 is a potent and stereoselective 5-HT3 receptor antagonist with much greater protective effects against stress-induced defecation than trimebutine.

Extra-Low Acoustic Power Harmonic Images of the Liver With Perflutren Novel Imaging for Real-Time Observation of Liver Perfusion

Objective. The features of images below the extra‐low mechanical index level were studied to elucidate a suitable mechanical index level for observing real‐time and continuous harmonic images of rabbit livers with VX‐2 tumors with the use of perflutren. Methods. Eight New Zealand White rabbits, 2 with healthy livers and 6 with VX‐2 tumors, were examined by harmonic imaging (1.85 and 3.7 MHz) at a frame rate of 17 Hz under various mechanical index levels. Results. Real‐time enhanced images of the liver were observed continuously in all rabbits. Vascular images were more clearly visualized at the low mechanical index level (mechanical index, 0.18) than at any other level. However, predominant enhanced images of the whole liver were observed only at the extra‐low mechanical index level (mechanical index, 0.06). In VX‐2 tumors, tumor vessels were shown more clearly at a low acoustic power level than at an extra‐low level. The histologically proved area of viable tumor was enhanced as a stain in the tumor nodule at an extra‐low mechanical index level. Conclusions. Harmonic imaging under extra‐low mechanical index levels with perflutren could provide real‐time and continuous enhanced images of the liver, which would contribute to improvement of the diagnostic ability of contrast‐enhanced sonography in liver diseases.

Investigation of the effects of YM-31636, a novel 5-HT3 receptor agonist, on defecation in normal and constipated ferrets

We examined the effects of YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate), a newly synthesized 5-HT(3) receptor agonist, on defecation in normal and constipated ferrets, and evaluated it as an agent against constipation. YM-31636 facilitated defecation without inducing diarrhea or emetic episodes. This effect occurred within 1 h after oral administration, mostly within 30 min, whereas sodium picosulfate, a widely used laxative, tended to increase the frequency of defecation for several hours with much lower peak incidence than that of YM-31636, and induced diarrhea. UK14304 (brimonidine), an alpha2 receptor agonist, and morphine reduced the frequency of defecation and YM-31636 restored it. These effects of YM-31636 were antagonized by ramosetron, a 5-HT(3) receptor antagonist. These results suggest that YM-31636 could be promising in the treatment of constipation. Because of an early and reliable onset of action compared with sodium picosulfate, YM-31636 could make it easier to control the time of defecation.

YM022, A Potent and Selective Gastrin/CCK-B Receptor Antagonist, Inhibits Peptone Meal-Induced Gastric Acid Secretion in Heidenhain Pouch Dogs

We examined the affinity of YM022, a potent andselective gastrin/CCK-B receptor antagonist, for caninegastrin/CCK-B and CCK-A receptors and the effects ofYM022 on secretagogue- and peptone meal-induced acid secretion in the denervated, surgicallyseparated (Heidenhain) canine gastric pouch model incomparison with those of famotidine, an H-receptorantagonist, and atropine. YM022 inhibited the binding of [125I]CCK-8 and[3H]devazepide to canine gastrin/CCK-B andCCK-A receptors, with IC50 values of 0.73 and136 nM, respectively. Intravenous YM022 dose-dependentlyinhibited pentagastrin- and peptone meal-induced acid secretion with ED50 values of0.0261 and 0.0654 mumol/kg, respectively, withoutaffecting histamine- or methacholine-induced acidsecretion. Famotidine inhibited acid secretion inducedby all stimulants, while atropine inhibited the acid secretioninduced by every stimulant except histamine. Theseresults indicated that YM022 is a highly potent andselective antagonist for the canine gastrin/CCK-Breceptor and suppressed pentagastrin- and peptonemeal-induced gastric acid secretion without affectinghistamine- or methacholine-induced acid secretion inHeidenhain pouch dogs.