Department of Cardiac Surgery, Laboratory of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
J Cardiovasc Pharmacol Ther. 2013 Jan;18(1):70-7. doi: 10.1177/1074248412455696. Epub 2012 Aug 22.
Oxidative stress interferes with nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signalling pathway through reduction of endogenous NO and formation of the strong intermediate oxidant peroxynitrite and leads to vascular dysfunction. We evaluated the effects of oral treatment with NO- and heme-independent sGC activator cinaciguat on peroxynitrite-induced vascular dysfunction in rat aorta. Sprague-Dawley rats were treated orally 2 times at an interval of 17 hours with vehicle or with cinaciguat (10 mg/kg). One hour after the last treatment, the animals were anesthetized, the thoracic aorta was removed, and the aortic segment preparations were incubated with and without the reactive oxidant peroxynitrite (200 µmol/L, 30 minutes). Endothelium-dependent (acetylcholine), -independent (sodium nitroprusside) vasorelaxations were investigated, and histopathological examination was performed. Incubation of aortic rings with peroxynitrite significantly attenuated the maximal endothelium-dependent relaxation (R (max)) to acetylcholine (peroxynitrite, 44.5% ± 5.9% vs control, 93.2% ± 2.0%, P < .05) and decreased pD(2) values (-logEC(50), EC(50) being the concentration of acetylcholine that elicited 50% of the maximal response) for the concentration-response curves as compared to control segments. Treatment of rats with cinaciguat significantly improved the decreased acetylcholine-induced vasorelaxation after exposure of aortic rings to peroxynitrite (cinaciguat + peroxynitrite, 67.1% ± 3.5% vs peroxynitrite, 44.5% ± 5.9%, P < .05). Incubation of aortic segments with peroxynitrite caused a significant shift of the sodium nitroprusside concentration-response curves to the right without any alterations in the R (max). Moreover, exposure of aortic rings to peroxynitrite resulted in increased nitro-oxidative stress and DNA breakage which were improved by cinaciguat. Treatment of rats with cinaciguat significantly increased intracellular cGMP levels in the aortic wall. Our results show under conditions of nitro-oxidative stress when signalling in the NO/sGC/cGMP pathway is impaired, acute activation of sGC by cinaciguat might be advantageous in the treatment of endothelial dysfunction in cardiovascular disease.
氧化应激通过还原内源性一氧化氮和形成强中间氧化剂过氧亚硝酸盐干扰一氧化氮（NO）/可溶性鸟苷酸环化酶（sGC）/环鸟苷单磷酸（cGMP）信号通路，导致血管功能障碍。我们评估了口服给予非一氧化氮和血红素依赖性 sGC 激活剂西那卡吉（cinaciguat）对大鼠主动脉中过氧亚硝酸盐诱导的血管功能障碍的影响。Sprague-Dawley 大鼠经口给予 vehicle 或 cinaciguat（10mg/kg），两次间隔 17 小时。最后一次治疗后 1 小时，麻醉动物，取出胸主动脉，孵育含有和不含有反应性氧化剂过氧亚硝酸盐（200µmol/L，30 分钟）的主动脉节段制剂。研究了内皮依赖性（乙酰胆碱）、非依赖性（硝普钠）血管舒张作用，并进行了组织病理学检查。孵育过氧亚硝酸盐可显著减弱乙酰胆碱诱导的最大内皮依赖性舒张（R（max））（过氧亚硝酸盐，44.5%±5.9%vs 对照，93.2%±2.0%，P<.05），并降低浓度-反应曲线的 pD（2）值（-logEC（50），EC（50）为产生最大反应的 50%的乙酰胆碱浓度）与对照节段相比。与暴露于过氧亚硝酸盐的主动脉环相比，给予 cinaciguat 的大鼠的乙酰胆碱诱导的血管舒张明显改善（cinaciguat+过氧亚硝酸盐，67.1%±3.5%vs 过氧亚硝酸盐，44.5%±5.9%，P<.05）。孵育过氧亚硝酸盐引起硝普钠浓度-反应曲线明显右移，而最大反应（R（max））无任何改变。此外，过氧亚硝酸盐暴露导致主动脉环中硝基氧化应激和 DNA 断裂增加，cinaciguat 可改善这些变化。给予 cinaciguat 的大鼠主动脉壁细胞内 cGMP 水平显著升高。我们的结果表明，在硝基氧化应激条件下，当 NO/sGC/cGMP 信号通路中的信号转导受损时，急性激活 sGC 可能有利于治疗心血管疾病中的内皮功能障碍。
