Takeuchi Fumihiko, Liang Yi-Qiang, Isono Masato, Ang Mia Yang, Mori Kotaro, Kato Norihiro
Department of Gene Diagnostics and Therapeutics (F.T., Y.-Q.L., M.I., M.Y.A., N.K.), Research Institute, National Center for Global Health and Medicine, Japan.
Medical Genomics Center (F.T., K.M., N.K.), Research Institute, National Center for Global Health and Medicine, Japan.
Hypertension. 2022 Feb;79(2):413-423. doi: 10.1161/HYPERTENSIONAHA.121.18026. Epub 2021 Dec 9.
Certain classes of antihypertensive drug may exert specific, blood pressure (BP)-independent protective effects on end-organ damages such as left ventricular hypertrophy, although the overall evidence has not been definitive in clinical trials. To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amelioration of end-organ damages, we performed in vivo phenotypic evaluation and transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred strains (ie, hypertensive and normotensive) of rats. We chose 6 antihypertensive classes: enalapril (angiotensin-converting enzyme inhibitor), candesartan (angiotensin receptor blocker), hydrochlorothiazide (diuretics), amlodipine (calcium-channel blocker), carvedilol (vasodilating β-blocker), and hydralazine. In the tested rat strains, 4 of 6 drugs, including 2 renin-angiotensin system inhibitors, were effective for BP lowering, whereas the remaining 2 drugs were not. Besides BP lowering, there appeared to be some interdrug heterogeneity in phenotypic changes, such as suppressed body weight gain and body weight-adjusted heart weight reduction. For the transcriptomic response, a considerable number of genes showed prominent mRNA expression changes either in a BP-dependent or BP-independent manner with substantial diversity between the target organs. Noticeable changes of mRNA expression were induced particularly by renin-angiotensin system blockade, for example, for genes in the natriuretic peptide system ( and ) in the heart and for those in the renin-angiotensin system/kallikrein-kinin system ( and rat paralogs) and those related to calcium ion binding ( and ) in the kidney. The research resources constructed here will help corroborate occasionally inconclusive evidence in clinical settings.
某些类别的抗高血压药物可能对诸如左心室肥厚等终末器官损害发挥特定的、不依赖于血压（BP）的保护作用，尽管在临床试验中总体证据尚未明确。为了揭示抗高血压药物诱导的、可能与终末器官损害改善相关的基因表达变化，我们对两种近交系（即高血压和正常血压）大鼠给予抗高血压药物后，对其心脏和肾脏进行了体内表型评估和转录组分析。我们选择了6类抗高血压药物：依那普利（血管紧张素转换酶抑制剂）、坎地沙坦（血管紧张素受体阻滞剂）、氢氯噻嗪（利尿剂）、氨氯地平（钙通道阻滞剂）、卡维地洛（血管舒张性β受体阻滞剂）和肼屈嗪。在受试大鼠品系中，6种药物中的4种，包括2种肾素 - 血管紧张素系统抑制剂，对降低血压有效，而其余2种药物则无效。除了降低血压外，在表型变化方面似乎存在一些药物间的异质性，如体重增加受抑制和体重调整后的心脏重量减轻。对于转录组反应，相当数量的基因以依赖于血压或不依赖于血压的方式显示出显著的mRNA表达变化，且靶器官之间存在很大差异。特别是肾素 - 血管紧张素系统阻断尤其诱导了明显的mRNA表达变化，例如，心脏中利钠肽系统（和）的基因，以及肾脏中肾素 - 血管紧张素系统/激肽释放酶 - 激肽系统（和大鼠同源物）的基因和与钙离子结合相关的基因（和）。这里构建的研究资源将有助于确证临床环境中偶尔不确定的证据。
