Angiotensin AT2 Receptor-Mediated Neuroprotection and Nitric Oxide–Bioavailability in Stroke
To the Editor:
We read with great interest the article by Dr McCarthy and colleagues1 dealing with the relationship between the angiotensin II type 2 receptors (AT2R) and neuroprotection in stroke. The results of their study demonstrated that, using a model of stroke in conscious spontaneously hypertensive rats, the pretreatment with the AT2R agonist CGP42112 significantly prevented cortical and striatal infarction and preserved brain function, all of which was independent of changes in blood pressure. In addition, it was shown that the effect of CGP42112 was abolished by the coadministration of the AT2R antagonist PD123319. The authors suggest that AT2R stimulation might be neuroprotective against stroke, and further propose that AT2R might be a potential therapeutic target in the treatment of stroke.
Evidence indicates that nitric oxide (NO) may actively participate in neuroprotection in cerebral ischemia. In a study we presented previously, a relationship between membrane fluidity (a reciprocal value of membrane microviscosity) of red blood cells and NO was investigated by means of an electron paramagnetic resonance method.2 The decreased membrane fluidity of red blood cells might cause a disturbance in the blood rheological behavior and the microcirculation, which could contribute, at least in part, to the pathophysiology of circulatory disorders. We demonstrated that NO increased the membrane fluidity of red blood cells and improved the rigidity of cell membranes in humans.2 In the separate series of the study, we showed that the lower membrane fluidity of red blood cells was associated with decreased levels of plasma NO-metabolites and increased levels of asymmetrical dimethylarginine (an endogenous NO synthase inhibitor).3 One hypothesis is that NO would be a defense against vascular complications in circulatory disorders. Recently, it has been shown that AT2R stimulation might cause an increase in endothelial nitric oxide synthase phosphorylation and enhance the vascular NO-production in hypertensive rat models.4 It was also demonstrated that CGP42112 induced vasodilation of porcine pial arteries that was blocked by the NO synthase inhibitor.5 In this context, we speculate that improved NO-bioavailability might partially explain the neuroprotective effect of CGP42112 in the stroke model. Therefore, we would like to know whether NO-related pathways might be involved in the mechanisms of the beneficial effect of CGP42112 in the study of Dr McCarthy and colleagues. Further studies should be performed to assess more precisely the functional interactions between AT2R stimulation and NO-metabolism, and their contribution to the prevention of stroke.
McCarthy CA, Vinh A, Callaway JK, Widdop RE. Angiotensin AT2 receptor stimulation causes neuroprotection in a conscious rat model of stroke. Stroke. 2009; 40: 1482–1489.
Hiyoshi H, Yayama K, Takano M, Okamoto H. Angiotensin type 2 receptor-mediated phosphorylation of eNOS in the aortas of mice with 2-kidney, 1-clip hypertension. Hypertension. 2005; 45: 967–973.