Selective inhibition of the carotid body sensory response to hypoxia by the substance P receptor antagonist CP-96,345.
Selective inhibition of the carotid body sensory response to hypoxia by the substance P receptor antagonist CP-96,345.
复制标题
P 物质受体拮抗剂 CP-96,345 选择性抑制颈动脉体对缺氧的感觉反应。
DOI：
10.1073/pnas.90.21.10041
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发表时间：
1993
影响因子：
11.1
通讯作者：
Snider,RM
中科院分区：
文献类型：
--
作者：
Prabhakar,NR;Cao,H;Lowe3rd,JA;Snider,RM
颈动脉体是监测动脉氧和CO2的感觉器官。以往的研究表明，化学感受器组织含有P物质（SP），外源性给予SP可增强化学感受性放电。在本研究中，我们使用选择性非肽SP [神经激肽（NK）1]受体拮抗剂CP-96，345研究了SP在颈动脉体化学感受中的生理重要性。在对麻醉猫进行的实验中，从颈动脉体原位记录感觉放电。为了控制血流的变化，对颈动脉体进行了体外研究。在体内研究中，近距离颈动脉体（动脉内）给予CP-96，345以剂量依赖性方式减弱了对缺氧的感觉反应，在0.3-0.6 mg/kg剂量下，73%的反应消失。相似剂量的（2 R，3R）-对映异构体对缺氧诱导的兴奋没有影响，表明CP-96，345的作用不是由于非特异性作用。相反，颈动脉体对高CO2的反应不受CP-96，345的影响，这意味着只有缺氧反应是由NK-1受体介导的，并证实SP拮抗剂的作用不是由于非特异性作用。在体外颈动脉体中也获得了对缺氧的感觉反应的显著衰减，这表明NK-1拮抗剂的作用不继发于心血管变化。这些结果表明，CP-96，345减弱或消除化学感觉反应，但不对CO2的缺氧，并表明，SP介导的缺氧诱导的感觉兴奋的猫颈动脉体通过NK-1受体激活。
Carotid bodies are sensory organs for monitoring arterial oxygen and CO2. Previous studies have shown that chemoreceptor tissue contains substance P (SP) and exogenously administered SP augments chemosensory discharge. In the present study, we examined the physiological importance of SP in carotid body chemoreception by using a selective nonpeptide SP [neurokinin (NK) 1] receptor antagonist CP-96,345. In experiments performed on anesthetized cats, sensory discharge was recorded from the carotid body in situ. To control for alterations in blood flow, additional studies were conducted on the carotid body in vitro. In in vivo studies, close carotid body (intraarterial) administration of CP-96,345 attenuated the sensory response to hypoxia in a dose-dependent manner with 73% of the response abolished at doses of 0.3-0.6 mg/kg. Comparable doses of the (2R,3R)-enantiomer had no effect on hypoxia-induced excitation, indicating that the effect of CP-96,345 was not due to nonspecific action. In contrast, the carotid body response to high CO2 was not affected by CP-96,345, implying that only the hypoxic response is mediated by NK-1 receptor and confirming that the effect of the SP antagonist was not due to nonspecific actions. Marked attenuation of the sensory response to hypoxia was also obtained in the carotid body in vitro, suggesting that the effects of the NK-1 antagonist were not secondary to cardiovascular changes. These results demonstrate that CP-96,345 attenuates or abolishes the chemosensory response to hypoxia but not to CO2 and suggest that SP mediates the hypoxia-induced sensory excitation in the cat carotid body via NK-1 receptor activation.