Wang Youping, Novotny Martin, Quaiserová-Mocko Veronika, Swain Greg M, Wang Donna H
Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.
Am J Physiol Regul Integr Comp Physiol. 2008 May;294(5):R1517-23. doi: 10.1152/ajpregu.00005.2008. Epub 2008 Mar 12.
This study was designed to test the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channel, expressed primarily in sensory nerves, and substance P (SP), released by sensory nerves, play a protective role against lipopolysaccharide (LPS)-induced hypotension. LPS (10 mg/kg iv) elicited tachycardia and hypotension in anesthetized male Wistar rats, which peaked at 10 min and gradually recovered 1 h after the injection. Blockade of TRPV1 with its selective antagonist capsazepine (CAPZ, 3 mg/kg iv) impaired recovery given that the fall in mean arterial pressure (MAP) was greater 1 h after CAPZ plus LPS injections compared with LPS injection alone (45 +/- 5 vs. 25 +/- 4 mmHg, P < 0.05). Blockade of the neurokinin 1 (NK1) receptor with its selective antagonists RP-67580 (5 mg/kg iv) or L-733,060 (4 mg/kg iv) prevented recovery, considering that falls in MAP were not different 1 h after injections of NK1 antagonists plus LPS from their peak decreases (66 +/- 9 vs. 74 +/- 5 mmHg or 60 +/- 7 vs. 69 +/- 3 mmHg, respectively, P > 0.05). LPS increased plasma SP, norepinephrine (NE), and epinephrine (Epi) levels compared with vehicles, and the increases in plasma SP, NE, and Epi were significantly inhibited by CAPZ or RP-67580. The survival rate at 24 or 48 h after LPS injection (20 mg/kg ip) was lower in conscious rats pretreated with CAPZ or RP-67580 compared with rats treated with LPS alone (P < 0.05). Thus our results show that the TRPV1, possibly via triggering release of SP which activates the NK1 and stimulates the sympathetic axis, plays a protective role against endotoxin-induced hypotension and mortality, suggesting that TRPV1 receptors are essential in protecting vital organ perfusion and survival during the endotoxic condition.
主要在感觉神经中表达的瞬时受体电位香草酸亚型1（TRPV1）通道以及感觉神经释放的P物质（SP），对脂多糖（LPS）诱导的低血压具有保护作用。LPS（10mg/kg静脉注射）可使麻醉的雄性Wistar大鼠出现心动过速和低血压，在注射后10分钟达到峰值，并在1小时后逐渐恢复。用其选择性拮抗剂辣椒素（CAPZ，3mg/kg静脉注射）阻断TRPV1会损害恢复，因为与单独注射LPS相比，在CAPZ加LPS注射后1小时平均动脉压（MAP）的下降幅度更大（45±5 vs. 25±4mmHg，P<0.05）。用其选择性拮抗剂RP-67580（5mg/kg静脉注射）或L-733,060（4mg/kg静脉注射）阻断神经激肽1（NK1）受体可阻止恢复，因为在注射NK1拮抗剂加LPS后1小时MAP的下降幅度与其峰值下降幅度无差异（分别为66±9 vs. 74±5mmHg或60±7 vs. 69±3mmHg，P>0.05）。与溶剂相比，LPS可增加血浆SP、去甲肾上腺素（NE）和肾上腺素（Epi）水平，并且血浆SP、NE和Epi的增加被CAPZ或RP-67580显著抑制。与单独用LPS处理的大鼠相比，用CAPZ或RP-67580预处理的清醒大鼠在LPS注射（20mg/kg腹腔注射）后24或48小时的存活率较低（P<0.05）。因此，我们的结果表明，TRPV1可能通过触发SP的释放来激活NK1并刺激交感神经轴，从而对内毒素诱导的低血压和死亡率发挥保护作用，这表明TRPV1受体在内毒素状态下保护重要器官灌注和存活中至关重要。
