β-抑制蛋白偏向性血管紧张素 II 激动剂TRV027可产生新生儿特异性的持续正性肌力作用而不增加心率。
β-Arrestin-Biased AT Agonist TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect Without Increasing Heart Rate.
作者信息
Kashihara Toshihide, Kawagishi Hiroyuki, Nakada Tsutomu, Numaga-Tomita Takuro, Kadota Shin, Wolf Elena E, Du Cheng-Kun, Shiba Yuji, Morimoto Sachio, Yamada Mitsuhiko
机构信息
Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.
Department of Biotechnology, Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan.
出版信息
JACC Basic Transl Sci. 2020 Nov 11;5(11):1057-1069. doi: 10.1016/j.jacbts.2020.08.011. eCollection 2020 Nov.
The treatment of pediatric heart failure is a long-standing unmet medical need. Angiotensin II supports mammalian perinatal circulation by activating cardiac L-type Ca channels through angiotensin type 1 receptor (ATR) and β-arrestin. TRV027, a β-arrestin-biased ATR agonist, that has been reported to be safe but not effective for adult patients with heart failure, activates the ATR/β-arrestin pathway. We found that TRV027 evokes a long-acting positive inotropic effect specifically on immature cardiac myocytes through the ATR/β-arrestin/L-type Ca channel pathway with minimum effect on heart rate, oxygen consumption, reactive oxygen species production, and aldosterone secretion. Thus, TRV027 could be utilized as a valuable drug specific for pediatric heart failure.
小儿心力衰竭的治疗是一个长期未得到满足的医疗需求。血管紧张素II通过血管紧张素1型受体（ATR）和β-抑制蛋白激活心脏L型钙通道，从而支持哺乳动物围产期循环。TRV027是一种偏向β-抑制蛋白的ATR激动剂，据报道对成年心力衰竭患者安全但无效，它可激活ATR/β-抑制蛋白途径。我们发现，TRV027通过ATR/β-抑制蛋白/L型钙通道途径，对未成熟心肌细胞产生长效正性肌力作用，对心率、耗氧量、活性氧生成和醛固酮分泌的影响最小。因此，TRV027可作为一种针对小儿心力衰竭的有价值药物。
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