Handy R L, Wallace P, Moore P K
Biomedical Sciences Division, King's College, University of London, UK.
Pharmacol Biochem Behav. 1996 Oct;55(2):179-84. doi: 10.1016/s0091-3057(96)00051-2.
A range of substituted isothiourea compounds including S-isopropylisothiourea (IPTU), S-methylisothiourea (SMT), S-ethylisothiourea (ETU), N-pentylisothiourea (PTU), S-(2 aminoethyl)isothiourea (AETU), and S-acetamidoisothiourea (AATU) inhibit mouse spinal cord/cerebellar neuronal nitric oxide synthase (nNOS) and bovine aortic endothelial cell eNOS in vitro. IP administration of isothioureas increased mean arterial blood pressure of the urethane-anaesthetised mouse (rank order of effect: IPTU > ETU > SMT > AETU). PTU and AATU were without vasopressor activity. IPTU (50 mg/kg, IP) inhibited late phase formalin-induced hindpaw licking behaviour in the mouse while SMT (50 mg/kg, IP) was without effect. Neither compound influenced the formalin-induced increase in hindpaw weight reflecting a lack of significant peripheral antioedema effect in this model. IPTU (50 mg/kg, IP) but not SMT (50 mg/kg, IP) inhibited mouse spinal cord and cerebellar NOS activity measured ex vivo in animals killed 45 min after injection. The present study confirms the potent NOS inhibitory effect of selected substituted isothioureas in vitro. Little or no isoform selectivity (i.e., nNOS vs. eNOS) was apparent. The potent vasopressor effect of isothioureas indicates that these compounds may be of limited use as tools to study the role of nitric oxide in pain perception.
一系列取代异硫脲化合物，包括S - 异丙基异硫脲（IPTU）、S - 甲基异硫脲（SMT）、S - 乙基异硫脲（ETU）、N - 戊基异硫脲（PTU）、S - （2 - 氨基乙基）异硫脲（AETU）和S - 乙酰氨基异硫脲（AATU），在体外可抑制小鼠脊髓/小脑神经元型一氧化氮合酶（nNOS）和牛主动脉内皮细胞内皮型一氧化氮合酶（eNOS）。经腹腔注射异硫脲可使氨基甲酸乙酯麻醉的小鼠平均动脉血压升高（作用强度顺序为：IPTU > ETU > SMT > AETU）。PTU和AATU无升压活性。IPTU（50 mg/kg，腹腔注射）可抑制小鼠福尔马林诱导的后期后爪舔舐行为，而SMT（50 mg/kg，腹腔注射）则无此作用。两种化合物均未影响福尔马林诱导的后爪重量增加，表明在该模型中缺乏显著的外周抗水肿作用。IPTU（50 mg/kg，腹腔注射）而非SMT（50 mg/kg，腹腔注射）可抑制注射后45分钟处死的动物离体测定的小鼠脊髓和小脑NOS活性。本研究证实了所选取代异硫脲在体外具有强大的NOS抑制作用。几乎没有明显的同工型选择性（即nNOS与eNOS之间）。异硫脲强大的升压作用表明，这些化合物作为研究一氧化氮在疼痛感知中作用的工具，其用途可能有限。
