Chang A Y, Chan J Y, Kao F J, Huang C M, Chan S H
Center for Neuroscience, Department of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC.
J Biomed Sci. 2001 Nov-Dec;8(6):475-83. doi: 10.1007/BF02256610.
We evaluated the relationship between the toxicity induced by the organophosphate mevinphos (Mev) and inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic neurogenic vasomotor tone. Adult Sprague-Dawley rats that were anesthetized and maintained with propofol were used. Laser scanning confocal microscopic analysis revealed colocalization of the M2 subtype of muscarinic receptors (M(2)R) and iNOS immunoreactivity in RVLM neurons. Comicroinjection bilaterally of Mev (10 nmol) and artificial cerebrospinal fluid (aCSF) into the RVLM elicited a progressive decline in systemic arterial pressure (SAP) and heart rate. This was accompanied during phase 1 Mev intoxication by an increase in the power density of the very high-frequency (VHF; 5-9 Hz), high-frequency (HF; 0.8-2.4 Hz), low-frequency (LF; 0.25- 0.8 Hz) and very low-frequency (VLF; 0-0.25 Hz) components of SAP signals. Phase 2 exhibited a reversal of the VHF and VLF power to control levels and a further reduction in the power density of both HF and LF components to below baseline. Hypotension and bradycardia promoted by Mev were significantly blunted on coadministration into the RVLM of the selective iNOS inhibitors S-methylisothiourea (250 pmol) or aminoguanidine (250 pmol). Not only was the augmented power density of HF and LF components during phase 1 Mev intoxication further enhanced, the reduced power of these two spectral components during phase 2 was appreciably antagonized. On the other hand, the temporal changes in VHF and VLF power were essentially the same as with coadministration of Mev and aCSF. We conclude that, as a cholinesterase inhibitor, Mev may induce toxicity via nitric oxide produced by iNOS on activation of the M(2)R by the accumulated acetylcholine in the RVLM.
我们评估了有机磷酸酯类农药百治磷（Mev）诱导的毒性与延髓头端腹外侧区（RVLM）中诱导型一氧化氮合酶（iNOS）之间的关系，RVLM是交感神经源性血管运动张力的延髓起源部位。实验使用了用丙泊酚麻醉并维持麻醉状态的成年Sprague-Dawley大鼠。激光扫描共聚焦显微镜分析显示，RVLM神经元中M2型毒蕈碱受体（M(2)R）和iNOS免疫反应性共定位。双侧向RVLM微量注射Mev（10 nmol）和人工脑脊液（aCSF）可引起全身动脉压（SAP）和心率逐渐下降。在Mev中毒的第1阶段，这伴随着SAP信号的极高频（VHF；5 - 9 Hz）、高频（HF；0.8 - 2.4 Hz）、低频（LF；0.25 - 0.8 Hz）和极低频（VLF；0 - 0.25 Hz）成分的功率密度增加。第2阶段表现为VHF和VLF功率恢复到对照水平，且HF和LF成分的功率密度进一步降低至基线以下。在RVLM共同注射选择性iNOS抑制剂S - 甲基异硫脲（250 pmol）或氨基胍（250 pmol）时，Mev引起的低血压和心动过缓明显减弱。不仅Mev中毒第1阶段HF和LF成分增强的功率密度进一步增强，第2阶段这两个频谱成分降低的功率也明显受到拮抗。另一方面，VHF和VLF功率的时间变化与Mev和aCSF共同注射时基本相同。我们得出结论，作为一种胆碱酯酶抑制剂，Mev可能通过RVLM中积累的乙酰胆碱激活M(2)R后，由iNOS产生的一氧化氮诱导毒性。
