Normalization of Endothelial and Inducible Nitric Oxide Synthase Expression in Brain Microvessels of Spontaneously Hypertensive Rats by Angiotensin II AT₁ Receptor Inhibition

Abstract

Summary:Inhibition of angiotensin II AT 1 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 AT 1 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 AT 1 receptor inhibition. The hemodynamic, morphologic, and biochemical alterations in hypertension associated with increased vulnerability to brain ischemia are fully reversed by AT 1 receptor blockade, indicating that AT 1 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.

Losartan improved respiratory function and coenzyme Q content in brain mitochondria of young spontaneously hypertensive rats

“…Thus, the beneficial effect of losartan administration on both BP and arterial wall mass may also have a preventive impact on cardiovascular risk factors in the brain. The findings are also in good consent with the literature data documenting beneficial effect of AT1R blockade on BP (Kawano et al 1994), antiproliferative impact on smooth muscle cells of conduit arteries (Koprdova et al, 2009), inflammation (Ando et al 2004b;Benicky et al 2009), and NOS expression in cerebral vessels and microvessels of SHR (Yamakawa et al 2003). In the experimental model of hypertension induced by long-term administration of L-NAME, losartan reduced the increased permeability of the blood-brain barrier (Kucuk et al 2002).…”

“…Increased ROS production was found in cerebral microvessels (Kazama et al 2004) as well as in neurons of SHR (Sun et al 2005). Additionally, the remodeling of the middle cerebral artery and significantly altered expression of endothelial and inducible forms of NOS in the artery and brain microvessels in SHR were demonstrated (Yamakawa et al 2003). The increased permeability of blood-brain barrier (Johansson 1999;Kucuk et al 2002) and inflammation in cerebral vasculature and brain tissue also occur in hypertension (Ando et al 2004b;Sun et al 2006).…”

Brain Angiotensin II: New Developments, Unanswered Questions and Therapeutic Opportunities

“…In all brain vessels studied, SHR expressed lower eNOS mRNA and protein and higher iNOS mRNA and protein than WKY (Fig. 17) (Yamakawa et al, 2003). AT 1 receptor blockade increased eNOS mRNA and protein, and decreased iNOS mRNA and protein, in all brain Lower figures-images of sections obtained after determination of blood flow by the 14 C-iodoantipyrine method, and analyzed with the use of the image processing system and computerized image analysis to reveal the area corresponding to a cerebral blood flow below the 0.50 mL/g/min thresholds.…”

“…15). Because adrenergic receptor blockade (Nishimura et al, 2000a) or calcium channel inhibition Ito et al, 2002;Yamakawa et al, 2003) did not protect from ischemia, it appears that inhibition of the Ang II system is essential to ensure tissue survival after MCA occlusion.…”

Current Therapeutic Strategies to Mitigate the eNOS Dysfunction in Ischaemic Stroke

“…ARBs, such as candesartan, have also been shown to provide vascular protection by concurrently normalising the decreases in eNOS and increases in iNOS mRNA and protein expressions in common carotid artery, circle of Willis and cerebral microvessels of SHR. However, the importance of AT1R blockade in overall ARB-mediated benefits is emphasised by comprehensive translational studies revealing better cardiovascular protection in SHR despite obtaining similar levels of BP reduction with other agents including the combination of diuretics and smooth muscle relaxant (Yamakawa et al 2003;Demirci et al 2005). A subgroup analysis of prevention regimen for effectively avoiding second strokes (PRoFESS) study has concluded that despite being safe and successful lowering the BP (6-7 mmHg) in patients with acute mild ischaemic stroke, telmisartan (80 mg/day) displayed no significant effects on functional dependency, death or ischaemic stroke recurrence (Bath et al 2009).…”