Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China; Department of Internal Medicine, Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston Salem, NC, United States.
Department of Internal Medicine, Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston Salem, NC, United States; Department of Cardiology, the Second Affiliated Hospital of Nantong University, Nantong, China.
Int J Cardiol. 2018 Aug 1;264:137-144. doi: 10.1016/j.ijcard.2018.03.066. Epub 2018 Apr 21.
Angiotensin-(1-12) [Ang-(1-12)] is a chymase-dependent source for angiotensin II (Ang II) cardiac activity. The direct contractile effects of Ang-(1-12) in normal and heart failure (HF) remain to be demonstrated. We assessed the hypothesis that Ang-(1-12) may modulate [Ca] regulation and alter cardiomyocyte contractility in normal and HF rats.
We compared left ventricle (LV) myocyte contractile and calcium transient ([Ca]) responses to angiotensin peptides in 16 SD rats with isoproterenol-induced HF and 16 age-matched controls. In normal myocytes, versus baseline, Ang II (10 M) superfusion significantly increased myocyte contractility (dL/dt: 40%) and [Ca] (29%). Ang-(1-12) (4 × 10 M) caused similar increases in dL/dt (34%) and [Ca] (25%). Compared with normal myocytes, superfusion of Ang II and Ang-(1-12) in myocytes obtained from rats with isoproterenol-induced HF caused similar but significantly attenuated positive inotropic actions with about 42% to 50% less increases in dL/dt and [Ca]. Chymostatin abolished Ang-(1-12)-mediated effects in normal and HF myocytes. The presence of an inhibitory cAMP analog, Rp-cAMPS prevented Ang-(1-12)-induced inotropic effects in both normal and HF myocytes. Incubation of HF myocytes with pertussis toxin (PTX) further augmented Ang II-mediated contractility.
Ang-(1-12) stimulates cardiomyocyte contractile function and [Ca] in both normal and HF rats through a chymase mediated action. Altered inotropic responses to Ang-(1-12) and Ang II in HF myocytes are mediated through a cAMP-dependent mechanism that is coupled to both stimulatory G and inhibitory PTX-sensitive G proteins.
血管紧张素-(1-12)[Ang-(1-12)]是糜酶依赖性血管紧张素 II(Ang II)心脏活性的来源。Ang-(1-12)在正常和心力衰竭 (HF) 中的直接收缩作用仍有待证明。我们评估了这样一个假设，即 Ang-(1-12)可能调节[Ca]调节并改变正常和 HF 大鼠的心肌细胞收缩性。
我们比较了 16 只 SD 大鼠和 16 只年龄匹配的对照组的左心室 (LV) 心肌细胞收缩和钙瞬变 ([Ca]) 对血管紧张肽的反应，这些大鼠用异丙肾上腺素诱导 HF。在正常心肌细胞中，与基线相比，Ang II(10 µM)灌注显著增加心肌细胞收缩力(dL/dt：40%)和Ca。Ang-(1-12)(4×10 M)引起的 dL/dt(34%)和Ca增加相似。与正常心肌细胞相比，异丙肾上腺素诱导的 HF 大鼠心肌细胞中 Ang II 和 Ang-(1-12)的灌注引起类似但明显减弱的正性变力作用，dL/dt 和[Ca]增加分别减少约 42%至 50%。糜酶抑制剂可消除正常和 HF 心肌细胞中 Ang-(1-12)介导的作用。抑制 cAMP 类似物 Rp-cAMPS 的存在可防止正常和 HF 心肌细胞中 Ang-(1-12)诱导的变力作用。HF 心肌细胞孵育百日咳毒素 (PTX) 进一步增强 Ang II 介导的收缩性。
Ang-(1-12)通过糜酶介导的作用刺激正常和 HF 大鼠的心肌细胞收缩功能和[Ca]。HF 心肌细胞对 Ang-(1-12)和 Ang II 的变力反应的改变是通过一种 cAMP 依赖性机制介导的，该机制与刺激型 G 和抑制型 PTX 敏感型 G 蛋白都有关联。
