Zou Jun, Ren Jiang-hua, Feng Dan, Wang Hong, Xu Jiang
Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Chin Med J (Engl). 2008 Jul 5;121(13):1220-5.
Bradykinin (BK) acts mainly on two receptor subtypes: B(1) and B(2), and activation of B(2) receptor mediates the most well-known cardioprotective effects of angiotensin converting enzyme inhibitors (ACEi), however, the role that B(1) receptor plays in ACEi has not been fully defined. We examined the role of B(1) receptor in the inhibitory effect of ACE inhibitor captopril on rat cardiomyocyte hypertrophy and cardiac fibroblast proliferation induced by angiotensin II (Ang II) and explored its possible mechanism.
Neonatal cardiomyocytes and cardiac fibroblasts (CFs) were randomly treated with Ang II, captopril, B(2) receptor antagonist (HOE-140) and B(1) receptor antagonist (des-Arg(10), Leu(9)-kallidin) alone or in combination. Flow cytometry was used to evaluate cell cycle, size and protein content. Nitric oxide (NO) and intracellular cyclic guanosine monophosphate (cGMP) level were measured by colorimetry and radioimmunoassay.
After the CFs and cardiomyocytes were incubated with 0.1 micromol/L Ang II for 48 hours, the percentage of CFs in the S stage, cardiomyocytes size and protein content significantly increased (both P < 0.01 vs control), and these increases were inhibited by 10 micromol/L captopril. However, NO and cGMP levels were significantly higher than that with Ang II alone (both P < 0.01). 1 micromol/L HOE-140 or 0.1 micromol/L des-Arg(10), Leu(9)-kallidin attenuated the effects of captopril, which was blunted further by blockade of both B(1) and B(2) receptors.
Acting via B(2) receptor, BK contributes to the antihypertrophic and antiproliferative effects of captopril on cardiomyocytes and CFs. In the absence of B(2) receptor, B(1) receptor may act a compensatory mechanism for the B(2) receptor and contribute to the inhibition of cardiomyocyte hypertrophy and CFs proliferation by captopril. NO and cGMP play an important role in the effect of B(1) receptor.
缓激肽（BK）主要作用于两种受体亚型：B(1)和B(2)，B(2)受体的激活介导了血管紧张素转换酶抑制剂（ACEi）最著名的心脏保护作用，然而，B(1)受体在ACEi中的作用尚未完全明确。我们研究了B(1)受体在ACE抑制剂卡托普利对血管紧张素II（Ang II）诱导的大鼠心肌细胞肥大和心脏成纤维细胞增殖的抑制作用中的作用，并探讨了其可能机制。
新生大鼠心肌细胞和心脏成纤维细胞（CFs）分别单独或联合用Ang II、卡托普利、B(2)受体拮抗剂（HOE-140）和B(1)受体拮抗剂（des-Arg(10)，Leu(9)-缓激肽）处理。采用流式细胞术评估细胞周期、细胞大小和蛋白质含量。用比色法和放射免疫分析法测定一氧化氮（NO）和细胞内环磷酸鸟苷（cGMP）水平。
CFs和心肌细胞与0.1 μmol/L Ang II孵育48小时后，CFs处于S期的百分比、心肌细胞大小和蛋白质含量显著增加（与对照组相比，P均<0.01），而10 μmol/L卡托普利可抑制这些增加。然而，NO和cGMP水平显著高于单独使用Ang II时（P均<0.01）。1 μmol/L HOE-140或0.1 μmol/L des-Arg(10)，Leu(9)-缓激肽减弱了卡托普利的作用，而同时阻断B(1)和B(2)受体可进一步削弱该作用。
BK通过B(2)受体发挥作用，有助于卡托普利对心肌细胞和CFs的抗肥大和抗增殖作用。在缺乏B(2)受体时，B(1)受体可能作为B(2)受体的一种代偿机制，有助于卡托普利抑制心肌细胞肥大和CFs增殖。NO和cGMP在B(1)受体的作用中起重要作用。
