Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, 243122, India.
Division of Animal Biochemistry, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, 243122, India.
Pharmacol Rep. 2022 Oct;74(5):1054-1068. doi: 10.1007/s43440-022-00399-4. Epub 2022 Aug 8.
Luteolin, a naturally occurring flavonoid, is thought to have health-promoting properties as a part of human diet and has been reported to possess a wide range of pharmacological activities. Therefore, the present study was undertaken to evaluate the effect of luteolin pre-treatment on vascular dysfunctions in sepsis induced by caecal ligation and puncture (CLP) in the mouse model.
Mice were divided into four groups: sham, luteolin plus sham, CLP, and luteolin plus CLP. Luteolin was administered (0.2 mg/kg body weight) intraperitoneally one hour (h) before CLP surgery in mice. 20 ± 2 h post CLP surgery, the isolated thoracic aorta of mice was assessed for its vascular reactivity to noradrenaline (NA) and acetylcholine (ACh). To explore the underlying mechanism, aortic mRNA expressions of α adrenoceptors, eNOS and iNOS were investigated.
In mice with CLP-induced sepsis luteolin pre-treatment markedly increased the survival time and attenuated serum lactate level. The CLP group manifested the reduced vascular reactivity to NA and this deficit was restored by luteolin pre-treatment. However, luteolin pre-treatment did not improve α adrenoceptors down-regulation observed in septic mice aorta. In the presence of 1400 W, the NA contractile response was significantly restored in CLP mice aortic tissue in comparison with the respective control of septic mice and further enhanced in the presence of luteolin. Luteolin reduced the iNOS mRNA expression and iNOS-derived nitrite production. Pre-treatment with luteolin restored the endothelial dysfunction in septic mice aorta by improving eNOS mRNA expression and enhanced eNOS-derived nitric oxide (NO) production in septic mice aorta and aortic iNOS gene expression and inducible NO production.
The present study suggests that the vasoplegic state to NA in aorta was restored through the iNOS pathway and endothelial dysfunction was reversed via eNOS and NO production pathway.
木犀草素是一种天然存在的类黄酮，被认为具有促进健康的特性，是人类饮食的一部分，并且据报道具有广泛的药理活性。因此，本研究旨在评估木犀草素预处理对盲肠结扎和穿刺（CLP）诱导的脓毒症小鼠模型中血管功能障碍的影响。
将小鼠分为四组：假手术组、木犀草素加假手术组、CLP 组和木犀草素加 CLP 组。在 CLP 手术前 1 小时，通过腹腔内注射给予小鼠木犀草素（0.2mg/kg 体重）。CLP 手术后 20±2 小时，评估小鼠离体胸主动脉对去甲肾上腺素（NA）和乙酰胆碱（ACh）的血管反应性。为了探讨潜在机制，研究了主动脉α肾上腺素受体、eNOS 和 iNOS 的 mRNA 表达。
在 CLP 诱导的脓毒症小鼠中，木犀草素预处理显著增加了存活时间并降低了血清乳酸水平。CLP 组表现出对 NA 的血管反应性降低，而木犀草素预处理可恢复这种缺陷。然而，木犀草素预处理并没有改善脓毒症小鼠主动脉中观察到的α肾上腺素受体下调。在 1400W 的存在下，与脓毒症小鼠相应的对照相比，CLP 小鼠主动脉组织中 NA 收缩反应显著恢复，并且在木犀草素存在下进一步增强。木犀草素降低了 iNOS mRNA 表达和 iNOS 衍生的亚硝酸盐产生。木犀草素预处理通过改善 eNOS mRNA 表达和增强脓毒症小鼠主动脉中 eNOS 衍生的一氧化氮（NO）产生，恢复了脓毒症小鼠主动脉中的内皮功能障碍，并进一步增强了主动脉 iNOS 基因表达和诱导型 NO 产生。
本研究表明，主动脉对 NA 的血管扩张状态通过 iNOS 途径得到恢复，内皮功能障碍通过 eNOS 和 NO 产生途径得到逆转。
