Mineralocorticoid Receptor Activation Causes Cerebral Vessel Remodeling and Exacerbates the Damage Caused by Cerebral Ischemia

Abstract

Abstract-Mineralocorticoid receptor antagonists protect against ischemic cerebrovascular disease; this appears to be caused by changes in cerebral vessel structure that would promote blood flow. Therefore, we hypothesized that mineralocorticoid receptor activation with deoxycorticosterone acetate would cause deleterious remodeling of the cerebral vasculature and exacerbate the damage caused by cerebral ischemia. Six-week-old male Wistar rats were treated with deoxycorticosterone acetate (200 mg/kg) for 6 weeks. At 12 weeks of age, the deoxycorticosterone acetate-treated rats had elevated systolic blood pressure compared with age-matched controls (157Ϯ5.9 versus 124Ϯ3.1 mm Hg deoxycorticosterone acetate versus control; PϽ0.05). The area of ischemic damage resulting from middle cerebral artery occlusion was greater in the deoxycorticosterone acetate-treated rats than control (63.5Ϯ3.72 versus 46.6Ϯ5.52% of the hemisphere infarcted, deoxycorticosterone acetate versus control; PϽ0.05). Middle cerebral artery structure was assessed using a pressurized arteriograph under calcium-free conditions. Over a range of intralumenal pressures, the lumen and ODs of the middle cerebral arteries were smaller in the deoxycorticosterone acetate-treated rats than the control rats (PϽ0.05). There was also an increase in the wall thickness and wall:lumen ratio in the vessels from deoxycorticosterone acetate-treated rats (PϽ0.05). The vessels from the deoxycorticosterone acetate-treated rats were stiffer than those from control rats as evidenced by a leftward shift in the stress/strain curve. These novel data suggest that mineralocorticoid receptor activation without salt loading and nephrectomy is sufficient to elicit deleterious effects on the cerebral vasculature that lead to inward hypertrophic remodeling and an increase in the ischemic damage in the event of a stroke. Key Words: mineralocorticoids Ⅲ cerebral ischemia Ⅲ remodeling Ⅲ cerebral arteries Ⅲ aldosterone S troke, in particular, ischemic stroke, is a leading cause of death and disability in the Western world. Yet, the factors that increase an individual's risk of having a stroke or exacerbate the damage caused by a stroke are still not completely understood. Studies using stroke-prone spontaneously hypertensive rats (SHRSPs) suggest that cerebral vascular structure plays an important role in the pathogenesis of cerebral ischemia. SHRSPs have larger cerebral infarcts when ischemia is induced by middle cerebral artery (MCA) occlusion than their normotensive counterparts, the Wistar Kyoto rats. 1,2 This difference appears to be because of remodeling of the cerebral vessels that results in the vessels having a smaller lumen diameter and an impaired ability to dilate in response to ischemia. [3][4][5] It is becoming increasingly clear that aldosterone is involved in the pathophysiology of cardiovascular disease. 6 We have shown previously that chronic treatment of SHRSPs with spironolactone, the aldosterone antagonist, reduces the ischemic cerebral infarct size after MCA occlus...

Spironolactone improves structure and increases tone in the cerebral vasculature of male spontaneously hypertensive stroke-prone rats

“…Similar to the studies by Rocha, et al (Rocha et al, 1998), these changes occurred without a reduction in blood pressure. The opposite effect has also recently been shown by our laboratory; whereby, intact, male Wistar rats that were treated with the mineralocorticoid, deoxycorticosterone acetate (DOCA), had increased ischemic cerebral infarct sizes compared to non-treated rats (Dorrance et al, 2006b). …”

“…Alternatively, activation of the mineralocorticoid receptor, using DOCA, has been shown by our laboratory to cause hypertrophic remodeling of the MCA (middle cerebral artery) and increased ischemic infarct size in intact male Wistar rats on a normal salt diet (Dorrance et al, 2006b). Similarly, when cerebral ischemia is induced experimentally, using MCA occlusion (Longa et al, 1989), the resultant ischemic infarct is greater in SHRSP compared to normotensive rats (Coyle and Jokelainen, 1983).…”

Role of Mineralocorticoid Receptor on Experimental Cerebral Aneurysms in Rats

“…Rigsby et al 38 and Dorrance et al 39 indicated that MR blockade by spironolactone reduced the cerebral infarction size in male stroke-prone spontaneously hypertensive rats, and MR activation with DOCA increased the size of cerebral infarcts; they suggested that MR activation results in inward hypertrophic remodeling of the cerebral vasculature and an increase in infarct size. However, cerebral aneurysms involve outward remodeling, and the vascular aneurysmal wall tends to be thin rather than thick.…”

Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats

“…13,14,38,42). Remodeling of the resistance vasculature encompasses structural changes that lead to a reduction in the lumen diameter and an increase in the wall thickness and wall-to-lumen ratio (2,17,23,36).…”