Involvement of substance P in neutral endopeptidase modulation of carotid body sensory responses to hypoxia.
Involvement of substance P in neutral endopeptidase modulation of carotid body sensory responses to hypoxia.
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P 物质参与中性肽链内切酶调节颈动脉体对缺氧的感觉反应。
DOI：
10.1152/jappl.2000.88.1.195
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Prabhakar,NR
中科院分区：
文献类型：
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作者：
Kumar,GK;Kou,YR;Overholt,JL;Prabhakar,NR
以前，我们表明，颈动脉体表达中性内肽酶（NEP）样酶的活性和phosphoramidon，一种有效的抑制剂NEP，增强化学敏感反应的颈动脉体缺氧在体内。NEP可水解神经元组织中的甲硫氨酸脑啡肽（Met-Enk）和P物质（SP）。本研究的目的是确定NEP是否水解Met-Enk和SP在颈动脉体，如果是这样，这些肽是否有助于磷酰胺诱导的增强缺氧的感觉反应。在从麻醉的成年猫（n= 72个颈动脉体）切除的颈动脉体上进行实验。采用HPLC法分析Met-Enk和SP的水解情况。结果表明，SP和Met-Enk均能被颈动脉体水解，但Met-Enk的水解速率约为SP的4倍。Phosphoramidon（400 μM）可显著抑制SP水解（抑制率约为90%），但对Met-Enk水解的抑制率仅为15%。缺氧（68 ± 6 Torr）和外源性SP（10和20 nmol）均可增加离体颈动脉体的感觉放电。磷酰胺对缺氧和SP（10 nmol）的感觉反应分别增强80%和275%（P< 0.01）。SP-受体拮抗剂Spantide（肽基）和CP-96345（nonpeptidyl）要么取消或显着减弱磷酰胺诱导的增强的感觉反应的颈动脉体缺氧，以及SP。这些结果表明，SP是一个优选的基板NEP在颈动脉体和SP参与增强的缺氧反应的颈动脉体磷酰胺。
Previously, we showed that carotid bodies express neutral endopeptidase (NEP)-like enzyme activity and that phosphoramidon, a potent inhibitor of NEP, potentiates the chemosensory response of the carotid body to hypoxia in vivo. NEP has been shown to hydrolyze methionine enkephalin (Met-Enk) and substance P (SP) in neuronal tissues. The purpose of the present study is to determine whether NEP hydrolyzes Met-Enk and SP in the carotid body and if so whether these peptides contribute to phosphoramidon-induced potentiation of the sensory response to hypoxia. Experiments were performed on carotid bodies excised from anesthetized adult cats (n= 72 carotid bodies). The hydrolysis of Met-Enk and SP was analyzed by HPLC. The results showed that both SP and Met-Enk were hydrolyzed by the carotid body, but the rate of Met-Enk hydrolysis was approximately fourfold higher than that of SP. Phosphoramidon (400 μM) markedly inhibited SP hydrolysis (∼90%) but had only a marginal effect on Met-Enk hydrolysis (∼15% inhibition). Hypoxia (Po2, 68 ± 6 Torr) as well as exogenous administration of SP (10 and 20 nmol) increased the sensory discharge of the carotid body in vitro. Sensory responses to hypoxia and SP (10 nmol) were potentiated by ∼80 and ∼275%, respectively (P< 0.01), in the presence of phosphoramidon. SP-receptor antagonists Spantide (peptidyl) and CP-96345 (nonpeptidyl) either abolished or markedly attenuated the phosphoramidon-induced potentiation of the sensory response of the carotid body to hypoxia as well as to SP. These results demonstrate that SP is a preferred substrate for NEP in the carotid body and that SP is involved in the potentiation of the hypoxic response of the carotid body by phosphoramidon.