Bartosiewicz Jacek, Kaminski Tomasz, Pawlak Krystyna, Karbowska Malgorzata, Tankiewicz-Kwedlo Anna, Pawlak Dariusz
1 Department of Pharmacodynamics, Medical University of Bialystok, 15-222 Bialystok, Poland.
2 Department of Monitored Pharmacotherapy, Medical University of Bialystok, 15-222 Bialystok, Poland.
Exp Biol Med (Maywood). 2017 Apr;242(7):750-761. doi: 10.1177/1535370217693114. Epub 2017 Jan 1.
Hypertension is a serious condition that can lead to many health problems. The mechanisms underlying this process are still not fully understood. The kynurenine pathway may be involved in the occurrence and progression of hypertension. The purpose of this study was to examine the activity of peripheral kynurenine pathway in rats with renovascular hypertension in Goldblatt 2K1C model. Hypertension was induced in the experimental groups by constricting the renal artery of the left kidney of the rats. Determination of tryptophan (Trp) and kynurenine pathway metabolites was assessed by high-performance liquid chromatography in plasma and tissues obtained at 4, 8, and 16 weeks after the surgical intervention or sham surgery. Levels of Ang II were evaluated using commercial immuno-enzymatic ELISA kits. Surgical treatment led to increased values of mean blood pressure and systolic blood pressure, whereas Trp concentrations were decreased in experimental animals compared to appropriate controls. Simultaneously, the considerable increment of kynurenine pathway components and a significant increase in the activity of tryptophan 2,3-dioxygenase were observed in rats with developed hypertension in comparison with controls. There were no differences between Ang II levels in controls and experimental groups. The inverse relationship was between plasma Trp and both SBP and Ang II values, and Trp independently affected Ang II concentrations in hypertensive rats. In contrast, tryptophan 2,3-dioxygenase activity and plasma kynurenine metabolites positively correlated with blood pressure values as well as with Ang II levels in these animals. Moreover, kynurenine was independently connected with MBP. Renovascular hypertension influences kynurenine pathway and leads to an imbalance in Trp and its metabolite levels. Tryptophan 2,3-dioxygenase and part of the kynurenine metabolites in plasma and tissues positively correlated with blood pressure values and Ang II levels. Although the mechanisms underlying this phenomenon are unclear, our experiment showed a link between renovascular hypertension and activation of kynurenine pathway. Impact statement As hypertension is a major health problem, our research has focused on the connection between the kynurenine pathway and hypertension. We assessed the levels of the main metabolites of dietary tryptophan and analyzed its levels in terms of high blood pressure. The results of our work indicated that in the renovascular rat's model of hypertension, an alteration of the kynurenine pathway occurred. According to our knowledge, this is the first study that has investigated in a comprehensive manner the alteration of the kynurenine pathway under the condition of elevated blood pressure. On the one hand, the work supports a better understanding of pathophysiological basics of the occurrence of hypertension, and on the other hand it provides potential opportunities to treat this disease.
高血压是一种严重的病症，可导致许多健康问题。这一过程背后的机制仍未完全明晰。犬尿氨酸途径可能参与高血压的发生和发展。本研究的目的是检测采用戈德布拉特2K1C模型的肾血管性高血压大鼠外周犬尿氨酸途径的活性。通过结扎大鼠左肾动脉在实验组诱导高血压。采用高效液相色谱法对手术干预或假手术后4周、8周和16周获取的血浆和组织中的色氨酸（Trp）及犬尿氨酸途径代谢产物进行测定。使用商业免疫酶联ELISA试剂盒评估血管紧张素II（Ang II）的水平。手术治疗导致平均血压和收缩压值升高，而与相应对照组相比，实验动物的Trp浓度降低。同时，与对照组相比，在已患高血压的大鼠中观察到犬尿氨酸途径成分显著增加以及色氨酸2,3-双加氧酶活性显著升高。对照组和实验组之间的Ang II水平无差异。血浆Trp与收缩压和Ang II值均呈负相关，且Trp独立影响高血压大鼠的Ang II浓度。相反，色氨酸2,3-双加氧酶活性及血浆犬尿氨酸代谢产物与这些动物的血压值以及Ang II水平呈正相关。此外，犬尿氨酸与平均血压独立相关。肾血管性高血压影响犬尿氨酸途径并导致Trp及其代谢产物水平失衡。血浆和组织中的色氨酸2,3-双加氧酶及部分犬尿氨酸代谢产物与血压值和Ang II水平呈正相关。尽管这一现象背后的机制尚不清楚，但我们的实验表明肾血管性高血压与犬尿氨酸途径的激活之间存在联系。影响声明 由于高血压是一个主要的健康问题，我们的研究聚焦于犬尿氨酸途径与高血压之间的关联。我们评估了膳食色氨酸主要代谢产物的水平，并就高血压方面分析了其水平。我们的研究结果表明，在肾血管性高血压大鼠模型中，犬尿氨酸途径发生了改变。据我们所知，这是第一项全面研究血压升高情况下犬尿氨酸途径改变的研究。一方面，该研究有助于更好地理解高血压发生的病理生理基础，另一方面，它为治疗这种疾病提供了潜在机会。
