PPAR-gamma agonist rosiglitazone reverses increased cerebral venous hydraulic conductivity during hypertension.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists have been shown to protect the cerebral vasculature, including the blood-brain barrier. In the present study, we investigated the effect of the PPAR-gamma agonist rosiglitazone on changes in venous permeability during chronic hypertension induced by nitric oxide synthase inhibition. Female Sprague-Dawley rats were either treated with N(G)-nitro-L-arginine methyl ester (L-NAME; 0.5 g/l in drinking water) for 5 wk (HTN; n = 8), L-NAME for 5 wk plus the PPAR-gamma agonist rosiglitazone (20 mg/kg in food) for the last 3 wk (HTN + Rosi; n = 5), L-NAME for 5 wk plus the superoxide dismutase mimetic Tempol (1 mmol/l in drinking water) for the last 3 wk (HTN + Tempol; n = 8), or were untreated controls (n = 9). Fluid filtration (J(v)/S) and hydraulic conductivity (L(p)) of cerebral veins were compared in vitro between groups after a step increase in pressure from 10 to 25 mmHg to mimic the change in hydrostatic pressure during acute hypertension. Hypertension increased J(v)/S by 2.2-fold and L(p) by 3.2-fold. Rosiglitazone treatment after 2 wk of hypertension completely reversed the increased J(v)/S and L(p) that occurred during hypertension, whereas Tempol had no effect. These results demonstrate that rosiglitazone was effective at reversing changes in venous permeability that occurred during chronic hypertension, an effect that does not appear to be related to its antioxidant properties. Our findings suggest that PPAR-gamma may be a key regulator of blood-brain barrier permeability and a potential therapeutic target during hypertension.
Roberts
Tim J M
TJ
1Departments of Neurology, Obstetrics, Gynecology and Reproductive Sciences, and Pharmacology, University of Vermont, Burlington, Vermont 05405, USA.
Chapman
Abbie C
AC
Cipolla
Marilyn J
MJ
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001929:Brain Edema / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D002199:Capillary Permeability / Q000187:drug effects*; D002550:Cerebral Veins / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002908:Chronic Disease; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006874:Hydrostatic Pressure; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D013113:Spin Labels; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors
D000959:Antihypertensive Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D047495:PPAR gamma; D013113:Spin Labels; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester