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Acute and Chronic Regulation of Thick Ascending Limb Endothelial Nitric Oxide Synthase by Statins

Henry Ford Health System, Detroit, Michigan

Correspondence to Dr. Jeffrey L. Garvin, Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, 2799 W. Grand Boulevard, Detroit, MI 48202. Phone: 313-916-2048; Fax: 313-916-1479; E-mail: jgarvin1{at}hfhs.org

ABSTRACT. Statins, 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, acutely increase endothelial nitric oxide synthase (eNOS) activity and chronically increase eNOS expression in endothelial cells. NO decreases transport in thick ascending limbs (TAL). We hypothesized that statins inhibit TAL transport by acutely activating eNOS, thereby increasing NO production and chronically enhancing eNOS expression. Oxygen consumption (QO₂) by TAL suspensions from Sprague-Dawley rats was used as a measure of active NaCl reabsorption. Na/K ATPase activity was assessed by measuring ATP hydrolysis in the presence and absence of ouabain. eNOS expression was measured by Western blot. A total of 50 µM pravastatin decreased QO₂ by 18.6 ± 3.4% (P < 0.01). In the presence of 500 µM furosemide and 200 µM amiloride, transport blockers, QO₂ remained the same after pravastatin was added. Na/K ATPase activity was not different from controls and TAL treated with 50 µM pravastatin (0.33 ± 0.07 versus 0.29 ± 0.04 nmol P_i/µg protein/min, where P_i is inorganic phosphate). Nystatin stimulated QO₂ to 178 ± 13.7 in pravastatin-treated TAL and 195 ± 11.5 in furosemide-treated TAL. The inhibitory effect of pravastatin on QO₂ was blocked by L-nitroarginine methyl ester, an NOS inhibitor. In addition, pravastatin increased NO production as measured by the fluorescent dye DAF-2A. Pravastatin at a dose of 10 mg/kg per d had no effect on eNOS protein at 1 d (24.1 ± 2.7 versus 25.5 ± 1.1 arbitrary units [AU]) or 7 d (24.1 ± 2.7 versus 20.9 ± 1.3 AU). Similarly, at 1 d, 50 mg/kg per d had no effect on expression (24.1 ± 2.7 versus 21.2 ± 3.6 AU). At 7 d, this dose decreased eNOS protein from 24.1 ± 2.7 to 11.8 ± 4.4 AU. It is concluded that pravastatin acutely decreases NaCl entry into the TAL by releasing NO. Pravastatin does not chronically increase eNOS expression in TAL.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673