Hypertension and Atherosclerosis Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Am J Hypertens. 2010 May;23(5):562-8. doi: 10.1038/ajh.2010.20. Epub 2010 Feb 25.
The cardioprotective benefits of bradykinin are attributable to activation of its B(2) receptor (B(2)R)-mediated actions and abolished by B(2)R antagonists. The current experiments evaluated the cardioprotective potential of a potent, long-acting B(2)R-selective agonist peptide analogue of bradykinin, the compound NG291.
We compared the extent of cardiac tissue damage and remodeling and expression pattern of selected genes in mice submitted to acute myocardial infarct (MI) and treated for 1 week with either NG291 [Hyp(3),Thi(5),(N)Chg(7),Thi(8)]-bradykinin or with saline delivered via osmotic minipump.
Active treatment resulted in better ejection fraction (EF) 69 +/- 1% vs. 61 +/- 3.1% (P = 0.01), (vs. 85 +/- 1.3% in sham-operated controls), fractional shortening (FS) 38 +/- 4% vs. 32 +/- 8% (NS) (vs. 53 +/- 1.2 in sham-operated controls), and fewer markers of myocyte apoptosis (TUNEL-positive nuclei 4.9 +/- 1.1% vs. 9.7 +/- 0.03%, P = 0.03). Systolic blood pressure (SBP) at end point was normal at 110 +/- 4.2 in actively treated mice, but tended to be lower at 104 +/- 4.7 mm Hg in saline controls with decreased cardiac systolic capacity. Expression patterns of selected genes to factors related to tissue injury, inflammation, and metabolism (i.e., the B(1)R, B(2)R, endothelial nitric oxide synthase (eNOS), TNF-alpha, cardiomyopathy-associated 3 (Cmya3), and pyruvate dehydrogenase kinase isoenzyme 4 (PDK4)) showed that acute MI induced significant upregulation of these genes, and active treatment prevented or attenuated this upregulation, whereas the B(2)R agonist itself produced no difference in the myocardium of sham-operated mice.
Treatment with a selective B(2)R agonist initiated at the time of induction of acute MI in mice had a beneficial effect on cardiac function, tissue remodeling, and inflammation-related tissue gene expression, which may explain its structural and functional benefits.
缓激肽的心脏保护作用归因于其 B(2) 受体（B(2)R）介导的作用的激活，并被 B(2)R 拮抗剂所阻断。本实验评估了一种强效、长效的缓激肽 B(2)R 选择性激动肽类似物 NG291 的心脏保护潜力。
我们比较了在急性心肌梗死（MI）后接受 1 周 NG291[Hyp(3),Thi(5),(N)Chg(7),Thi(8)]-缓激肽或盐水通过渗透微泵治疗的小鼠的心脏组织损伤和重构程度以及选定基因的表达模式。
积极治疗导致射血分数（EF）更好（69 +/- 1%对 61 +/- 3.1%，P = 0.01）（与假手术对照组的 85 +/- 1.3%相比），短轴缩短率（FS）更高（38 +/- 4%对 32 +/- 8%，无统计学意义）（与假手术对照组的 53 +/- 1.2%相比），并且心肌细胞凋亡的标志物（TUNEL 阳性核 4.9 +/- 1.1%对 9.7 +/- 0.03%，P = 0.03）较少。终点时的收缩压（SBP）在积极治疗的小鼠中正常为 110 +/- 4.2mmHg，但在接受盐水治疗的对照组中倾向于较低，为 104 +/- 4.7mmHg，这与心脏收缩能力降低有关。选定与组织损伤、炎症和代谢相关的因素的基因（即 B(1)R、B(2)R、内皮型一氧化氮合酶（eNOS）、肿瘤坏死因子-α（TNF-α）、心肌病相关蛋白 3（Cmya3）和丙酮酸脱氢酶激酶同工酶 4（PDK4））的表达模式表明，急性 MI 诱导这些基因的显著上调，而积极治疗可防止或减弱这种上调，而 B(2)R 激动剂本身在假手术小鼠的心肌中没有差异。
在诱导急性 MI 后立即给予选择性 B(2)R 激动剂治疗，对心脏功能、组织重构和与炎症相关的组织基因表达有有益的影响，这可能解释了其结构和功能的益处。
