Department and Graduate Institute of Pharmacology, Kaohsiung Medical University, Taiwan.
Br J Pharmacol. 2010 Mar;159(5):1151-60. doi: 10.1111/j.1476-5381.2009.00587.x. Epub 2010 Feb 2.
To determine whether KMUP-1, a novel xanthine-based derivative, attenuates isoprenaline (ISO)-induced cardiac hypertrophy in rats, and if so, whether the anti-hypertrophic effect is mediated by the nitric oxide (NO) pathway.
In vivo, cardiac hypertrophy was induced by injection of ISO (5 mg.kg(-1).day(-1), s.c.) for 10 days in Wistar rats. In the treatment group, KMUP-1 was administered 1 h before ISO. After 10 days, effects of KMUP-1 on survival, cardiac hypertrophy and fibrosis, the NO/guanosine 3'5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) and hypertrophy signalling pathways [calcineurin A and extracellular signal-regulated kinase (ERK)1/2] were examined. To investigate the role of nitric oxide synthase (NOS) in the effects of KMUP-1, a NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA) was co-administered with KMUP-1. In vitro, anti-hypertrophic effects of KMUP-1 were studied in ISO-induced hypertrophic neonatal rat cardiomyocytes.
In vivo, KMUP-1 pretreatment attenuated the cardiac hypertrophy and fibrosis and improved the survival of ISO-treated rats. Plasma NOx (nitrite and nitrate) and cardiac endothelial NOS, cGMP and PKG were all increased by KMUP-1. The activation of hypertrophic signalling by calcineurin A and ERK1/2 in ISO-treated rats was also attenuated by KMUP-1. All these effects of KMUP-1 were inhibited by simultaneous administration of L-NNA. Similarly, in vitro, KMUP-1 attenuated hypertrophic responses and signalling induced by ISO in neonatal rat cardiomyocytes.
KMUP-1 attenuates the cardiac hypertrophy in rats induced by administration of ISO. These effects are mediated, at least in part, by NOS activation. This novel agent, which targets the NO/cGMP pathway, has a potential role in the prevention of cardiac hypertrophy.
为了确定新型黄嘌呤衍生物 KMUP-1 是否能减轻异丙肾上腺素（ISO）诱导的大鼠心肌肥厚，如果是，抗肥厚作用是否通过一氧化氮（NO）途径介导。
在体内，通过皮下注射 ISO（5mg/kg/天）10 天诱导 Wistar 大鼠心肌肥厚。在治疗组，KMUP-1 在 ISO 前 1 小时给药。10 天后，观察 KMUP-1 对生存、心肌肥厚和纤维化的影响，以及 NO/鸟苷 3'5'-环单磷酸（cGMP）/蛋白激酶 G（PKG）和肥厚信号通路[钙调神经磷酸酶 A 和细胞外信号调节激酶（ERK）1/2]的影响。为了研究一氧化氮合酶（NOS）在 KMUP-1 作用中的作用，给予 NOS 抑制剂 N（ω）-硝基-L-精氨酸（L-NNA）与 KMUP-1 共同给药。在体外，研究了 KMUP-1 在 ISO 诱导的肥厚新生大鼠心肌细胞中的抗肥厚作用。
体内，KMUP-1 预处理可减轻 ISO 处理大鼠的心肌肥厚和纤维化，提高生存率。KMUP-1 增加了血浆 NOx（硝酸盐和亚硝酸盐）和心脏内皮 NOS、cGMP 和 PKG。ISO 处理大鼠的钙调神经磷酸酶 A 和 ERK1/2 激活的肥厚信号也被 KMUP-1 减弱。L-NNA 的同时给药抑制了 KMUP-1 的所有这些作用。同样，在体外，KMUP-1 减轻了 ISO 诱导的新生大鼠心肌细胞的肥厚反应和信号。
KMUP-1 减轻 ISO 诱导的大鼠心肌肥厚。这些作用至少部分通过 NOS 激活介导。这种靶向 NO/cGMP 途径的新型药物可能在预防心肌肥厚方面具有作用。
