Abstract
Renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure and brain function. Therefore, we studied the dynamic changes in the RAAS in the blood, cerebral cortex, and hippocampus and the effects of RAAS inhibitors on spatial learning and memory and hippocampal apoptosis in a rat model of chronic cerebral ischemia (CCI) established by bilateral ligation of the common carotid arteries of rats. The levels of renin, angiotensin II (Ang II), and aldosterone (ALD) in the plasma, and the homogenates of the left side of cerebral cortex and whole hippocampus of rats were detected on day 1, 3, 7, 14, 21, and 30 by radioimmunoassay. Spatial learning and memory and hippocampal apoptosis were evaluated on day 30 by Morris water maze test (navigation and space exploration tests) and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, respectively, after rats were orally administered with distilled water (DW), renin inhibitor aliskiren (30 mg/kg), Ang converting enzyme inhibitor enalapril (4 mg/kg), or Ang II receptor antagonist candesartan (2 mg/kg) daily for 30 days. The results showed that the levels of renin and Ang II were significantly higher but ALD fluctuated in the blood, cerebral cortex, and hippocampus in CCI rats compared to normal rats. However, aliskiren and enalapril could significantly decrease (p < 0.05) the levels of renin, Ang II and ALD in the blood, cerebral cortex, and hippocampus compared to DW treatment; while candesartan had similar effect on renin and ALD but no effect on Ang II in CCI rats. Furthermore, spatial learning and memory were significantly decreased but apoptosis in the hippocampus was obviously increased in CCI rats compared to normal rats (p < 0.05). However, aliskiren, enalapril, and candesartan were equally effective to improve spatial learning and memory and decrease apoptosis in the hippocampus. Therefore, RAAS plays an important role in the development of cerebral ischemia and RAAS inhibitors aliskiren, enalapril, and candesartan improve spatial learning and memory and protect brain injury by inhibiting hippocampal apoptosis in CCI rats.
Highlights
The renin-angiotensin aldosterone system (RAAS) plays an important role in the regulation of plasma sodium concentration, extracellular volume, tissue perfusion, and blood pressure (Atlas, 2007)
To investigate the dynamic changes in the RAAS in cerebral ischemia (CCI) rats, we first measured the levels of renin, angiotensin II (Ang II), and ALD in the plasma and tissue homogenates of left side of cerebral cortex and whole hippocampus of normal rats and CCI rats established by surgical ligation of bilateral common carotid arteries at various times
We studied the dynamic changes in renin, Ang II, and ALD and the effects of RAAS inhibitors aliskiren, enalapril, and candesartan on the RAAS in the blood, cerebral cortex and hippocampus, spatial learning and memory and hippocampal apoptosis in a rat model of CCI
Summary
The renin-angiotensin aldosterone system (RAAS) plays an important role in the regulation of plasma sodium concentration, extracellular volume, tissue perfusion, and blood pressure (Atlas, 2007). Ang II induces the release of aldosterone (ALD) from the zona glomerulosa in the adrenal cortex and is largely responsible for the long-term regulation of blood pressure (András and Hunyady, 2004; Hu et al, 2012; Bollag, 2014; Pacurari et al, 2014). Studies have shown that the RAAS regulates the physiological and pathological activities in the brain (Hajjar et al, 2009). A study by Kumaran and colleagues suggested that Ang II played a key role in nerve cell death and memory loss during brain hypoperfusion (Kumaran et al, 2008). The alterations of RAAS induced by chronic cerebral ischemia (CCI) and the correlation between it and brain dysfunction need to be further studied
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