在mRen2.Lewis高血压大鼠中通过直接抑制肾素和阻断血管紧张素II受体恢复血压昼夜节律。
Restoration of the blood pressure circadian rhythm by direct renin inhibition and blockade of angiotensin II receptors in mRen2.Lewis hypertensive rats.
作者信息
Moniwa Norihito, Varagic Jasmina, Ahmad Sarfaraz, VonCannon Jessica L, Ferrario Carlos M
机构信息
Division of Surgical Sciences, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA.
出版信息
Ther Adv Cardiovasc Dis. 2012 Feb;6(1):15-29. doi: 10.1177/1753944711434039. Epub 2012 Jan 5.
BACKGROUND
Alterations in the circadian arterial pressure rhythm predict cardiovascular mortality. We examined the circadian arterial pressure rhythm and the effect of renin-angiotensin system blockade in congenic mRen2.Lewis hypertensive rats, a renin-dependent model of hypertension derived from the backcross of transgenic hypertensive [mRen-2]27 rats with Lewis normotensive ones.
METHODS
Twenty-nine mRen2.Lewis hypertensive rats were randomly assigned to drink tap water (vehicle; n = 9), valsartan (30 mg/kg/day; n = 10), or valsartan (30 mg/kg/day) combined with aliskiren given subcutaneously (50 mg/kg/day; n = 10) for 2 weeks. Arterial pressure, heart rate, and locomotive activity were recorded with chronically implanted radiotelemetry probes. The awake/asleep ratio was calculated as [awake mean arterial pressure (MAP) mean - asleep MAP mean)] / (awake MAP mean) x 100. Plasma renin activity (PRA) and concentration (PRC), and plasma and kidney angiotensin II (Ang II) were measured by radioimmunoassay (RIAs).
RESULTS
Untreated hypertensive rats showed an inverse arterial pressure rhythm, higher at day and lower at night, accompanied by normal rhythms of heart rate and locomotive activity. Treatment with valsartan or aliskiren and valsartan normalized the elevated arterial pressure and the arterial pressure rhythm, with the combination therapy being more effective in reducing MAP and in restoring the awake/asleep ratio. While PRA and PRC increased with the treatments, the addition of aliskiren to valsartan partially reversed the increases in plasma Ang II levels. Valsartan and the aliskiren and valsartan combination markedly reduced the renal cortical content of Ang II.
CONCLUSION
The altered circadian arterial pressure rhythm in this renin-dependent hypertension model uncovers a significant role of Ang II in the desynchronization of the circadian rhythm of arterial pressure, heart rate, and locomotive activity.
背景
昼夜动脉压节律的改变可预测心血管死亡率。我们研究了同源mRen2.Lewis高血压大鼠的昼夜动脉压节律以及肾素-血管紧张素系统阻断的作用，mRen2.Lewis高血压大鼠是一种肾素依赖性高血压模型，由转基因高血压[mRen-2]27大鼠与Lewis正常血压大鼠回交产生。
方法
将29只mRen2.Lewis高血压大鼠随机分为三组，分别饮用自来水（对照组；n = 9）、缬沙坦（30 mg/kg/天；n = 10）或缬沙坦（30 mg/kg/天）联合皮下注射阿利吉仑（50 mg/kg/天；n = 10），持续2周。通过长期植入的无线电遥测探头记录动脉压、心率和活动量。清醒/睡眠比值计算为[清醒平均动脉压（MAP）均值 - 睡眠MAP均值)] /（清醒MAP均值）×100。采用放射免疫分析法（RIAs）测定血浆肾素活性（PRA）和浓度（PRC），以及血浆和肾脏血管紧张素II（Ang II）。
结果
未经治疗的高血压大鼠呈现反向动脉压节律，白天较高而夜间较低，同时伴有正常的心率和活动量节律。缬沙坦或阿利吉仑与缬沙坦联合治疗可使升高的动脉压和动脉压节律恢复正常，联合治疗在降低MAP和恢复清醒/睡眠比值方面更有效。虽然治疗后PRA和PRC升高，但在缬沙坦中添加阿利吉仑可部分逆转血浆Ang II水平的升高。缬沙坦以及阿利吉仑与缬沙坦联合用药均显著降低了肾脏皮质中Ang II的含量。
结论
在这种肾素依赖性高血压模型中，昼夜动脉压节律的改变揭示了Ang II在动脉压、心率和活动量昼夜节律失调中起重要作用。
Zotero 插件