The anti‐emetic effects of CP‐99,994 in the ferret and the dog: role of the NK1 receptor
The anti‐emetic effects of CP‐99,994 in the ferret and the dog: role of the NK1 receptor
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CP-99,994 对雪貂和狗的止吐作用：NK1 受体的作用
DOI：
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发表时间：
1995
影响因子：
7.3
通讯作者：
Paul L.R. Andrews
中科院分区：
文献类型：
--
作者：
J. W. Watson;S. F. Gonsalves;A. A. Fossa;Stafford McLean;T. Seeger;S. Obach;Paul L.R. Andrews
1选择性NK 1受体拮抗剂CP-99，994产生剂量相关（0.1 - 1.0 mg kg−1，s.c.）用中枢（洛哌丁胺和阿扑吗啡）、外周（CuSO 4）和混合中枢和外周（吐根、顺铂）催吐刺激物刺激雪貂，抑制呕吐和干呕。2对映体CP-100，263（1 mg kg −1，s.c.）的平行研究表明，其作为NK 1拮抗剂的效力低1 000倍以上，对CuSO 4、洛哌丁胺、顺铂和阿扑吗啡诱导的呕吐无显著影响。对吐根，它抑制干呕和呕吐，表达约1/10的CP-99，994的效力。3 5-HT 3受体拮抗剂托烷司琼（lmgkg−1，s.c.）对顺铂和吐根有抑制作用，但对硫酸铜和洛哌丁胺无抑制作用。4 CP-99，994（lmgkg-1，静脉注射）阻断腹侧迷走神经电刺激引起的干呕，而不影响心血管反应、对中枢迷走神经刺激的呼吸暂停反应或对内脏大神经刺激的保护和高血压反应。CP-99，994（1 mg kg−1，i.v.）未改变基线心血管和呼吸参数，且未能阻断静脉注射2-甲基-5-HT激发（von Bezold-Jorsch反射）后的特征性心率、血压和呼吸频率/深度变化。[5]使用体外放射自显影，[3 H]-P物质被证明与雪貂脑干的几个区域结合，孤束核中的结合密度远大于最后区。这种结合被CP-99，994以浓度相关的方式取代。6在犬中，CP-99，994（40 μg kg−1推注和300 μg kg−1 h−1，i. v.）对CuSO 4和阿扑吗啡的呕吐以及对CuSO 4的干呕产生了统计学上显著的减少。7总之，这些研究支持CP-99，994的NK 1受体拮抗剂特性是其广谱止吐作用的原因的假设。他们还表明CP-99，994在脑干内起作用，最有可能在孤束核内，尽管不能排除最后区的参与。
1 The selective NK1 receptor antagonist, CP‐99,994, produced dose‐related (0.1‐1.0 mg kg−1, s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (CuSO4) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli. 2 Parallel studies with the enantiomer, CP‐100,263 (1 mgkg−1, s.c), which is > 1 000 fold less potent as a NK1 antagonist, indicated that it was without significant effect against CuSO4, loperamide, cisplatin and apomorphine‐induced emesis. Against ipecac, it inhibited both retching and vomiting, expressing approximately l/10th the potency of CP‐99,994. 3 The 5‐HT3 receptor antagonist, tropisetron (lmgkg−1, s.c.) inhibited retching and vomiting to cisplatin and ipecac, but not CuSO4 or loperamide. 4 CP‐99,994 (lmgkg−1, i.v.) blocked retching induced by electrical stimulation of the ventral abdominal vagus without affecting the cardiovascular response, the apnoeic response to central vagal stimulation or the guarding and hypertensive response to stimulation of the greater splanchnic nerves. CP‐99,994 (1 mg kg−1, i.v.) did not alter baseline cardiovascular and respiratory parameters and it failed to block the characteristic heart rate, blood pressure and respiratory rate/depth changes in response to i.v. 2‐methyl‐5‐HT challenge (von Bezold‐Jarisch reflex). 5 Using in vitro autoradiography, [3H]‐substance P was shown to bind to several regions of the ferret brainstem with the density of binding in the nucleus tractus solitarius being much greater than in the area postrema. This binding was displaced by CP‐99,994 in a concentration‐related manner. 6 In dogs, CP‐99,994 (40 μg kg−1 bolus and 300 μg kg−1 h−1, i.v.) produced statistically significant reductions in vomiting to CuSO4 and apomorphine as well as retching to CuSO4. 7 Together, these studies support the hypothesis that the NK1 receptor antagonist properties of CP‐99,994 are responsible for its broad spectrum anti‐emetic effects. They also suggest that CP‐99,994 acts within the brainstem, most probably within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded.
DOI：
10.1152/ajpregu.1993.265.2.r269
发表时间：
1993
期刊：
The American journal of physiology
影响因子：
--
作者：
Mifflin,SW
通讯作者：
Mifflin,SW
培养的人 IM-9 淋巴母细胞上 P 物质的立体特异性受体。
DOI：
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发表时间：
1984
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Payan,DG;Brewster,DR;Goetzl,EJ
通讯作者：
Goetzl,EJ