title: Atorvastatin enhanced nitric oxide release and reduced blood pressure, nitroxidative stress and rantes levels in hypertensive rats with diabetes.
abstract: Clinical trials have shown that atorvastatin benefits patients with diabetes even with normal baseline LDL levels. We hypothesized that atorvastatin improves endothelial cell (EC) function and reduces inflammation in hypertensive rats with diabetes. Non-diabetic and streptozotocin-induced type 2 diabetic male spontaneously hypertensive rats (SHR) were treated with atorvastatin at 20 mg/kg/day. After five weeks, nitric oxide (NO) and peroxynitrite (ONOO(-)) were measured in aortic and glomerular endothelial cells. A tandem of nanosensors was used to simultaneously measure NO and ONOO(-) concentration and their ratio [NO]/[ONOO(-)] was monitored with a time resolution better than 10 μs and detection limit 1 nM. [NO]/[ONOO(-)] was applied as a marker of endothelial NO synthase (eNOS) uncoupling, endothelial dysfunction and nitroxidative stress. Glucose, cholesterol, blood pressure (BP), and the cytokine RANTES were also measured. Diabetic SHR rats had elevated glucose (355 ± 38 mg/dL), mean BP (172 ± 15 mmHg), and plasma RANTES (38.4 ± 2.7 ng/mL), low endothelial NO bioavailability and high ONOO(-). Maximal NO release measured 267 ± 29 nM in aortic endothelium of SHR rats and 214 ± 20 nM for diabetic SHR rats; [NO]/[ONOO(-)] was 0.88 ± 12 and 0.61 ± 0.08, respectively. [NO]/[ONOO(-)] ratios below one indicate a high uncoupling of eNOS, endothelial dysfunction and high nitroxidative stress. Atorvastatin treatment partially restored endothelial function by increasing NO level by 98%, reducing ONOO(-) by 40% and favorably elevating [NO]/[ONOO(-)] to 1.1 ± 0.2 for diabetic SHR rats and 1.6 ± 0.3 for SHR rats. The effects of atorvastatin were similar in glomerular endothelial cells and were partially reproduced by modulators of eNOS or NADPH oxidase. Atorvastatin had no significant effect on fasting glucose or total cholesterol levels but reduced mean BP by 21% and 11% in diabetic and non-diabetic animals, respectively. Atorvastatin also reduced RANTES levels by 50%. Atorvastatin favorably increased the [NO]/[ONOO(-)] balance, enhanced endothelial cytoprotective NO, decreased cytotoxic ONOO(-) and reduced BP, inflammation and RANTES levels in diabetic, hypertensive rats without altering cholesterol levels. These findings provide insights into mechanisms of restoration of endothelial function and vascular protection by atorvastatin in diabetes and hypertension.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. malinski@ohio.edu.
authors.forename: R P
authors.initials: RP
authors.lastname: Mason
authors.forename: J J
authors.initials: JJ
authors.lastname: Corbalan
authors.forename: R F
authors.initials: RF
authors.lastname: Jacob
authors.forename: H
authors.initials: H
authors.lastname: Dawoud
authors.forename: T
authors.initials: T
authors.lastname: Malinski
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000069059:Atorvastatin / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D018946:Chemokine CCL5 / Q000097:blood*; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D011918:Rats, Inbred SHR
chemical_list: D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D015415:Biomarkers; D001786:Blood Glucose; D018946:Chemokine CCL5; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D002784:Cholesterol; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat