Heikal Lamia, Starr Anna, Martin Gary P, Nandi Manasi, Dailey Lea Ann
Institute of Pharmaceutical Sciences, Faculty of Life Science & Medicine, King's College London, 150 Stamford Street, London, SE1 9NH, UK.
Institute of Pharmaceutical Sciences, Faculty of Life Science & Medicine, King's College London, 150 Stamford Street, London, SE1 9NH, UK.
Nitric Oxide. 2016 Sep 30;59:1-9. doi: 10.1016/j.niox.2016.06.006. Epub 2016 Jun 24.
S-nitrosophytochelatins (SNOPCs) are novel analogues of S-nitrosoglutathione (GSNO) with the advantage of carrying varying ratios of S-nitrosothiol (SNO) moieties per molecule. Our aim was to investigate the in vivo pharmacological potency and biodistribution of these new GSNO analogues after intravenous (i.v.) and intranasal (i.n.) administration in mice. SNOPCs with either two or six SNO groups and GSNO were synthesized and characterized for purity. Compounds were administered i.v. or i.n. at 1 μmol NO/kg body weight to CD-1 mice. Blood pressure was measured and biodistribution studies of total nitrate and nitrite species (NOx) and phytochelatins were performed after i.v. administration. At equivalent doses of NO, it was observed that SNOPC-6 generated a rapid and significantly greater reduction in blood pressure (∼60% reduction compared to saline) whereas GSNO and SNOPC-2 only achieved a 30-35% decrease. The reduction in blood pressure was transient and recovered to baseline levels within ∼2 min for all compounds. NOx species were transiently elevated (over 5 min) in the plasma, lung, heart and liver. Interestingly, a size-dependent phytochelatin accumulation was observed in several tissues including the heart, lungs, kidney, brain and liver. Biodistribution profiles of NOx were also obtained after i.n. administration, showing significant lung retention of NOx over 15 min with minor systemic increases observed from 5 to 15 min. In summary, this study has revealed interesting in vivo pharmacological properties of SNOPCs, with regard to their dramatic hypotensive effects and differing biodistribution patterns following two different routes of administration.
S-亚硝基植物螯合肽（SNOPC）是S-亚硝基谷胱甘肽（GSNO）的新型类似物，其优点是每个分子携带不同比例的S-亚硝基硫醇（SNO）基团。我们的目的是研究这些新型GSNO类似物在小鼠静脉内（i.v.）和鼻内（i.n.）给药后的体内药理活性和生物分布。合成了具有两个或六个SNO基团的SNOPC以及GSNO，并对其纯度进行了表征。以1 μmol NO/千克体重的剂量对CD-1小鼠进行静脉内或鼻内给药。测量血压，并在静脉内给药后进行总硝酸盐和亚硝酸盐（NOx）以及植物螯合肽的生物分布研究。在等效剂量的NO下，观察到SNOPC-6能迅速且显著地降低血压（与生理盐水相比降低约60%），而GSNO和SNOPC-2仅使血压降低30 - 35%。所有化合物引起的血压降低都是短暂的，在约2分钟内恢复到基线水平。血浆、肺、心脏和肝脏中的NOx种类短暂升高（超过5分钟）。有趣的是，在包括心脏、肺、肾脏、大脑和肝脏在内的多个组织中观察到了植物螯合肽的大小依赖性积累。鼻内给药后也获得了NOx的生物分布图谱，显示在15分钟内NOx在肺部有显著滞留，在5至15分钟内观察到轻微的全身增加。总之，本研究揭示了SNOPC有趣的体内药理特性，包括其显著的降压作用以及两种不同给药途径后的不同生物分布模式。
