11beta-hydroxysteroid dehydrogenase type II inhibition causes cerebrovascular remodeling and increases infarct size after cerebral ischemia.
Direct mineralocorticoid receptor (MR) activation with deoxycorticosterone acetate has deleterious effects on the cerebral vasculature. Inhibition of 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2) mimics the detrimental effects of elevated mineralocorticoids in the heart, but the effect of enzyme inactivation on the cerebral vasculature is unknown. Therefore, we hypothesized that systemic 11betaHSD2 inhibition with carbenoxolone (CBX) would cause remodeling of the middle cerebral artery (MCA) and increase the damage caused by cerebral ischemia. Six-week-old male Sprague Dawley rats were divided into control and CBX (2.5 mg/d) + 0.9% NaCl treated. After 4 wk treatment, rats were used to assess either structure and reactivity of the MCA or the response to cerebral ischemia using the MCA occlusion technique. Cerebral damage was assessed by 2,3,5-triphenyltetrazolium chloride staining and expressed as a percentage of the hemisphere infarcted. CBX treatment increased systolic blood pressure (153.2 +/- 7.3 vs. 122.1 +/- 4.4 mm Hg; P < 0.05) compared with control rats. MCAs from CBX treated rats were smaller and stiffer than control MCAs over a range of intralumenal pressures, indicating inward remodeling of the vessel. CBX treatment significantly increased ischemic cerebral infarct size compared with control rats (27.1 +/- 5.4% vs. 14.8 +/- 4.2%; P < 0.05). These data indicate that inhibition of 11betaHSD2, and, thus, disproportionate glucocorticoid activation of the MR, results in remodeling of the MCA and worsens the outcome of cerebral ischemia, further underscoring the importance of understanding the mechanism by which MR activation leads to cerebrovascular disease.
Osmond
Jessica M
JM
Department of Physiology, Medical College of Georgia, Augusta, GA 30912, USA.
Dorrance
Anne M
AM
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors*; D000818:Animals; D002545:Brain Ischemia / Q000150:complications* / Q000473:pathology; D002229:Carbenoxolone / Q000494:pharmacology*; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000473:pathology; D024510:Muscle Development / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D004791:Enzyme Inhibitors; D012701:Serotonin; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D002229:Carbenoxolone