Najafipour Hamid, Soltani Hekmat Ava, Nekooian Ali Akbar, Esmaeili-Mahani Saeed
Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran.
Regul Pept. 2012 Oct 10;178(1-3):43-50. doi: 10.1016/j.regpep.2012.06.006. Epub 2012 Jul 14.
Chronic kidney diseases lead to severe cardiovascular consequences such as hypertension and cardiac failure. Apelin, along with its receptor APJ have been shown to involve in cardiovascular functions including blood pressure (BP) lowering effect and also a positive inotropic effect on failing hearts. Therefore we investigated the effect of apelin on BP and cardiac contractility in chronic two-kidney-one-clip (2K1C) hypertension, a kidney disease hypertension model. The changes in the level of apelin and some other hemodynamically effective hormones in serum and apelin receptor gene expression in nonischemic and ischemic kidneys were also assessed.
2K1C was produced by placing a Plexiglas clip around the left renal artery. 16 weeks later, BP and cardiac indices of contractility were measured by power lab system. The mRNA and protein level of APJ were determined by RT-PCR and Western blot methods respectively.
2K1C increased BP from 115/75 mmHg in sham to 180/120 mmHg in test group. Hypertensive rats had about ten times higher basal left ventricular end-diastolic pressure (LVEDP) (P<0.001) and higher basal LV systolic pressure (LVSP) (P<0.01). Apelin-13 (20 μg/kg, iv) significantly decreased LVEDP and LVSP (P<0.001). Furthermore, apelin in 20 μg/kg dose significantly decreased systolic (SBP) and diastolic (DBP) blood pressures in hypertensive rats. This reduction was persistent and prominent in 40 μg/kg dose. 20 μg/kg apelin increased +LVdp/dt max and -LV dp/dt max. However in the dose of 40 μg/kg SBP, DBP, +LVdp/dt max and -LV dp/dt max greatly decreased. All of these effects were completely blocked by apelin antagonist F13A. 2K1C decreased serum apelin (P<0.05), did not change ang II and arginine-vasopressin levels, and slightly increased serum aldosterone. Apelin receptor mRNA and protein expression significantly decreased in both ischemic and non-ischemic kidneys.
Overall, chronic 2K1C rats showed hypertension and signs of cardiac failure. Apelin in medium doses induced antihypertensive and positive myocardial inotropic effects. Reduction of serum apelin and down regulation of apelin receptors in kidneys of hypertensive rats may play a role in pathophysiology of cardiovascular complications.
慢性肾脏病会导致严重的心血管后果，如高血压和心力衰竭。已证实阿片肽及其受体APJ参与心血管功能，包括降血压作用以及对衰竭心脏的正性肌力作用。因此，我们研究了阿片肽对慢性二肾一夹（2K1C）高血压（一种肾脏疾病高血压模型）的血压和心脏收缩力的影响。还评估了血清中阿片肽和其他一些血流动力学活性激素水平的变化以及非缺血和缺血肾脏中阿片肽受体基因的表达。
通过在左肾动脉周围放置有机玻璃夹制作2K1C模型。16周后，用Powerlab系统测量血压和心脏收缩指数。分别用RT-PCR和蛋白质印迹法测定APJ的mRNA和蛋白质水平。
2K1C使血压从假手术组的115/75 mmHg升高到试验组的180/120 mmHg。高血压大鼠的基础左心室舒张末期压力（LVEDP）高约10倍（P<0.001），基础左心室收缩压（LVSP）也更高（P<0.01）。阿片肽-13（20μg/kg，静脉注射）显著降低LVEDP和LVSP（P<0.001）。此外，20μg/kg剂量的阿片肽显著降低高血压大鼠的收缩压（SBP）和舒张压（DBP）。这种降低在40μg/kg剂量时持续且显著。20μg/kg阿片肽增加了+LVdp/dt max和-LV dp/dt max。然而，在40μg/kg剂量时，SBP、DBP、+LVdp/dt max和-LV dp/dt max大幅下降。所有这些作用均被阿片肽拮抗剂F13A完全阻断。2K1C降低了血清阿片肽（P<0.05），未改变血管紧张素II和精氨酸加压素水平，并使血清醛固酮略有升高。缺血和非缺血肾脏中阿片肽受体的mRNA和蛋白质表达均显著降低。
总体而言，慢性2K1C大鼠表现出高血压和心力衰竭迹象。中等剂量的阿片肽具有降压和正性心肌肌力作用。高血压大鼠血清阿片肽的降低和肾脏中阿片肽受体的下调可能在心血管并发症的病理生理过程中起作用。
