Aldosterone and the mineralocorticoid receptor in the cerebral circulation and stroke

Elevated plasma aldosterone level is an independent cardiovascular risk factor [1,2]. The mineralocorticoid receptor (MR) is known to be expressed in brain [3], blood vessels [4-6] and heart [7,8] as well as its classical site of expression in epithelial tissues such as the distal nephron. The MR is a member of the nuclear receptor superfamily and comprises an N-terminal domain, a central DNA-binding domain and a hinge region linked to a C-terminal ligand-binding domain. The MR has two physiological ligands, aldosterone and cortisol (corticosterone in rodents). It is established that in epithelial tissues aldosterone requires the enzyme 11β-hydroxysteroid dehydrogenase (11-βHSD2) to activate the MR, since 11-βHSD2 metabolises cortisol to cortisone [9]. Cortisol and corticosterone circulate at 100-1000 times the concentration of aldosterone, thus in the absence of 11-βHSD2 and under conditions of normal cortisol levels, the MR would be occupied by cortisol [10]. Co-localisation of 11-βHSD2 and the MR has been demonstrated in the vasculature (i.e. in endothelial and smooth muscle cells) [11-13], suggesting that aldosterone interacts with the MR in the vasculature.Patients with primary aldosteronism (characterized by an overproduction of aldosterone) suffer stroke and cardiovascular events more frequently [14] than essential hypertensive patients despite having lower blood pressure, suggesting that elevated plasma aldosterone increases the risk of these events in a blood pressure-independent manner. Ischemic stroke is caused by interruption of blood flow to the brain, and deleterious stimuli which alter cerebral vascular structure and function will ultimately adversely influence cerebral blood flow [15]. Therefore, in humans with underlying cardiovascular risk factors, detrimental vascular actions of aldosterone, perhaps acting via the MR, may contribute to the pathophysiology of hypertension and stroke. The purpose of this article is to review evidence for a contribut