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

Rigsby, Christine S.; Pollock, David M.; Dorrance, Anne M.

doi:10.1016/j.mvr.2006.12.001

Cited by 76 publications

(103 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With very few available options for the treatment of stroke, to reduce stroke risk it seems prudent to identify therapies aimed at primary prevention. We have shown previously that improving MCA structure reduces the damage caused by cerebral ischemia (13,41,42). In the present report, we show that chronic DOX treatment attenuates the hypertensive vascular remodeling observed in SHRSP.…”

Section: Discussionsupporting

confidence: 75%

“…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).…”

mentioning

confidence: 99%

“…MCA structure was assessed using pressure myography as described previously (42). MCAs were isolated and placed in cold physiological salt solution (PSS; in mmol/l: 141.9 NaCl, 4.7 KCl, 1.7 MgSO 4, 0.5 EDTA, 2.8 CaCl2, 10.0 HEPES, 1.2 KH2PO4, and 5.0 glucose).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Pires

Rogers

McClain

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

Pires PW, Rogers CT, McClain JL, Garver HS, Fink GD, Dorrance AM. Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 301: H87-H97, 2011. First published May 6, 2011 doi:10.1152/ajpheart.01206.2010 are a family of zinc peptidases involved in extracellular matrix turnover. There is evidence that increased MMP activity is involved in remodeling of resistance vessels in chronic hypertension. Thus we hypothesized that inhibition of MMP activity with doxycycline (DOX) would attenuate vascular remodeling. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with DOX (50 mg·kg Ϫ1 ·day Ϫ1 in the drinking water) for 6 wk. Untreated SHRSP were controls. Blood pressure was measured by telemetry during the last week. Middle cerebral artery (MCA) and mesenteric resistance artery (MRA) passive structures were assessed by pressure myography. MMP-2 expression in aortas was measured by Western blot. All results are means Ϯ SE. DOX caused a small increase in mean arterial pressure (SHRSP, 154 Ϯ 1; SHRSP ϩ DOX, 159 Ϯ 3 mmHg; P Ͻ 0.001). Active MMP-2 expression was reduced in aorta from SHRSP ϩ DOX (0.21 Ϯ 0.06 vs. 0.49 Ϯ 0.13 arbitrary units; P Ͻ 0.05). In the MCA, at 80 mmHg, DOX treatment increased the lumen (273.2 Ϯ 4.7 vs. 238.3 Ϯ 6.3 m; P Ͻ 0.05) and the outer diameter (321 Ϯ 5.3 vs. 290 Ϯ 7.6 m; P Ͻ 0.05) and reduced the wall-to-lumen ratio (0.09 Ϯ 0.002 vs. 0.11 Ϯ 0.003; P Ͻ 0.05). Damage after transient cerebral ischemia (transient MCA occlusion) was reduced in SHRSP ϩ DOX (20.7 Ϯ 4 vs. 45.5 Ϯ 5% of hemisphere infarcted; P Ͻ 0.05). In the MRA, at 90 mmHg DOX, reduced wall thickness (29 Ϯ 1 vs. 22 Ϯ 1 m; P Ͻ 0.001) and wall-to-lumen ratio (0.08 Ϯ 0.004 vs. 0.11 Ϯ 0.008; P Ͻ 0.05) without changing lumen diameter. These results suggest that MMPs are involved in hypertensive vascular remodeling in both the peripheral and cerebral vasculature and that DOX reduced brain damage after cerebral ischemia. vascular remodeling; middle cerebral artery; hypertension PRIMARY PREVENTION OF ISCHEMIC stroke is increasing in importance as a strategy for management of individuals at high risk. Recently published clinical trials (18), such as ONTARGET and TRANSCEND, show that therapies aimed at reducing cardiovascular incidents are a valuable tool for prevention of the first occurrence of myocardial infarction, heart failure, and stroke. In the ONTARGET trial, the beneficial effects observed were not preceded by a reduction in systemic blood pressure. Therefore, it is possible that a major component of the risk for ischemic stroke is not blood pressure itself. The consequences of vascular adaptation to increased intralumenal pressure might provide an additional risk. Hence, prevention of hypertensive vascular remodeling might be a candidate for primary prevention of stroke.Damage caused by cerebral ischemia is related to the extent of hypertensive remodeling of the middle c...

show abstract

Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Pires

Rogers

McClain

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, Titze et al 37 showed that DOCA-salt led to a total-body sodium excess. Our and other findings suggest that MR activation increases sodium retention and that high sodium retention may have additive harmful effects on the formation of cerebral aneurysms.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.…”

mentioning

confidence: 99%

Role of Mineralocorticoid Receptor on Experimental Cerebral Aneurysms in Rats

et al. 2009

View full text Add to dashboard Cite

Abstract-Activation of the renin-angiotensin (Ang)-aldosterone system is involved in the pathology of vascular diseases.Although the blockade of the mineralocorticoid receptor protects against vascular diseases, its role in cerebral aneurysms remains to be elucidated. We treated female rats subjected to renal hypertension, increased hemodynamic stress, and estrogen deficiency for 3 months with the mineralocorticoid receptor blocker eplerenone (30 or 100 mg/kg per day) or vehicle (vehicle control). Eplerenone reduced the incidence of cerebral aneurysms and saline intake without lowering of the blood pressure. In the aneurysmal wall, the production of Ang II and nitrotyrosine was increased. The mRNA levels of Ang-converting enzyme 1 and NADPH oxidase subunits NOX4, Rac1, monocyte chemoattractant protein 1, and matrix metalloproteinase 9 were increased. Eplerenone brought about a reduction in these molecules, suggesting that mineralocorticoid receptor blockade suppresses cerebral aneurysm formation by inhibiting oxidative stress, inflammatory factors, local renin-Ang system activation, and saline intake. Other female rats implanted with pellets of the mineralocorticoid receptor agonist deoxycorticosterone acetate manifested a high incidence of cerebral aneurysm formation and the upregulation of molecules related to oxidative stress, inflammatory factors, and the local renin-Ang system; their saline intake was increased. We demonstrate that mineralocorticoid receptor activation at least partly contributes to the pathogenesis of cerebral aneurysms. (Hypertension. 2009;54:552-557.)Key Words: cerebral Ⅲ aneurysm Ⅲ inflammation Ⅲ mineralocorticoid receptor Ⅲ oxidative stress R upture of cerebral artery aneurysms results in catastrophic subarachnoid hemorrhage and a high risk for morbidity and mortality. 1 On the basis of epidemiological data showing a high incidence of cerebral aneurysms in postmenopausal women, we subjected female rats to increased hemodynamic stress, hypertension, and estrogen deficiency (by oophorectomy); in these animals, the incidence of cerebral aneurysms was high. 2 Treatment with 17␤-estradiol or an angiotensin (Ang) II type 1 receptor blocker reduced this incidence. 2 Elsewhere we suggested that endothelial injury is an initial event in the pathogenesis of cerebral aneurysms and that an increase in Ang II and NADPH oxidase subunits is involved. 2 Also, inflammation and degradation of the extracellular matrix in the vascular wall play a role in the development of cerebral aneurysms. [3][4][5] The renin-Ang-aldosterone system is involved in the pathophysiology of cardiovascular and kidney diseases, activation of the mineralocorticoid receptor (MR) is especially highlighted in recent studies. 6 -10 The identification of a new site of MR expression in nonepithelial tissues, such as the heart, 11 vasculature, 12 and brain, 13 suggested the presence in these tissues of potential new MR target genes with unexpected biological functions. In aortic endothelial cells, aldosterone increased the express...

show abstract

The Effects of Hypertension on Cerebral Artery Structure and Function, and Cerebral Blood Flow

Pires

Dorrance

2016

Hypertension and the Brain as an End-Organ Target

View full text Add to dashboard Cite

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

Cited by 76 publications

References 35 publications

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

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

Role of Mineralocorticoid Receptor on Experimental Cerebral Aneurysms in Rats

The Effects of Hypertension on Cerebral Artery Structure and Function, and Cerebral Blood Flow

Contact Info

Product

Resources

About