Pretreatment with candesartan (0.3 mg/kg/d) for 28 days completely reversed inward eutrophic remodeling and normalized eNOS and iNOS expression in cerebrovascular circulation of hypertensive rats.
Does candesartan improve cerebrovascular morphology and normalize eNOS/iNOS expression in spontaneously hypertensive rats?
AT1 receptor blockade with candesartan reverses cerebrovascular remodeling and normalizes eNOS/iNOS expression in spontaneously hypertensive rats, potentially explaining its protective effect against stroke.
Inhibition of angiotensin II AT1 receptors protects against stroke, reducing the cerebral blood flow decrease in the periphery of the ischemic lesion. To clarify the mechanism, spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were pretreated with the AT1 receptor antagonist candesartan (0.3 mg. kg.(-1) d(-1)) for 28 days, a treatment identical to that which protected SHR from brain ischemia, and the authors studied middle cerebral artery (MCA) and common carotid morphology, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), and protein expression in cerebral microvessels, principal arteries of the Willis polygon, and common carotid artery. The MCA and common carotid artery of SHR exhibited inward eutrophic remodeling, with decreased lumen diameter and increased media thickness when compared with WKY rats. In addition, there was decreased eNOS and increased iNOS protein and mRNA in common carotid artery, circle of Willis, and brain microvessels of SHR when compared with WKY rats. Both remodeling and alterations in eNOS and iNOS expression in SHR were completely reversed by long-term AT1 receptor inhibition. The hemodynamic, morphologic, and biochemical alterations in hypertension associated with increased vulnerability to brain ischemia are fully reversed by AT1 receptor blockade, indicating that AT1 receptor activation is crucial for the maintenance of the pathologic alterations in cerebrovascular circulation during hypertension, and that their blockade may be of therapeutic advantage.
Yamakawa et al. (2003) studied Hypertension. Candesartan vs. Normotensive WKY rats / untreated SHR was evaluated on Middle cerebral artery and common carotid morphology, eNOS and iNOS mRNA and protein expression. Pretreatment with candesartan (0.3 mg/kg/d) for 28 days completely reversed inward eutrophic remodeling and normalized eNOS and iNOS expression in cerebrovascular circulation of hypertensive rats.