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(Hypertension. 2005;45:1131.)
© 2005 American Heart Association, Inc.

Original Articles

Cyclooxygenase-1–Deficient Mice Have High Sleep-to-Wake Blood Pressure Ratios and Renal Vasoconstriction

Noritaka Kawada; Glenn Solis; Nathan Ivey; Stephanie Connors; Kathryn Dennehy; Paul Modlinger; Rebecca Hamel; Julie T. Kawada; Enyu Imai; Robert Langenbach; William J. Welch; Christopher S. Wilcox

From the Cardiovascular Kidney Institute and Division of Nephrology and Hypertension (N.K., G.S., N.I., S.C., K.D., P.M., R.H., J.T.K., W.J.W., C.S.W.), Georgetown University, Washington, DC; the Division of Nephrology (E.I.), Osaka University Graduate School of Medicine, Osaka, Japan; and the Comparative Medicine Branch (R.L.), National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Correspondence to Dr Christopher S. Wilcox, Division of Nephrology and Hypertension, Georgetown University Medical Center, 3800 Reservoir Road, NW, PHCF6003, Washington, DC 20007-2197. E-mail wilcoxch{at}georgetown.edu

We used cyclooxygenase-1 (COX-1)–deficient mice to test the hypothesis that COX-1 regulates blood pressure (BP) and renal hemodynamics. The awake time (AT) mean arterial pressures (MAPs) measured by telemetry were not different between COX-1^+/+ and COX-1^–/– (131±2 versus 126±3 mm Hg; NS). However, COX-1^–/– had higher sleep time (ST) MAP (93±1 versus 97±2 mm Hg; P<0.05) and sleep-to-awake BP ratio (+8.6%; P<0.05). Under anesthesia with moderate sodium loading, COX-1^–/– had higher MAP (109±5 versus 124±4 mm Hg; P<0.05), renal vascular resistance (23.5±1.6 versus 30.7±1.7 mm Hg · mL^–1 · min^–1 · g^–1; P<0.05) and filtration fraction (33.7±2.1 versus 40.2±2.0%; P<0.05). COX-1^–/– had a 89% reduction (P<0.0001) in the excretion of TxB₂, a 76% reduction (P<0.01) in PGE₂, a 40% reduction (P<0.0002) in 6-ketoPGF₁ (6keto), a 27% reduction (P<0.02) in 11-ßPGF₂ (11ß), a 35% reduction (P<0.01) in nitrate plus nitrite (NOx), and a 52% increase in metanephrine (P<0.02). The excretion of normetanephrine, a marker for sympathetic nervous activity, was reduced during ST in COX-1^+/+ (6.9±0.9 versus 3.2±0.6 g · g^–1 creatinine · 10^–3; P<0.01). This was blunted in COX-1^–/– (5.1±0.9 versus 4.9±0.7 g · g^–1 creatinine · 10^–3; NS). Urine collection during ST showed lower excretion of 6keto, 11ß, NOx, aldosterone, sodium, and potassium than during AT in both COX-1^+/+ and COX-1^–/–, and there were positive correlations among these parameters (6keto versus NOx; P<0.005; 11ß versus NOx; P<0.005; and NOx versus sodium; P<0.005). In conclusion, COX-1 mediates a suppressed sympathetic nervous activity and enhanced NO, which may contribute to renal vasodilatation and a reduced MAP while asleep or under anesthesia. COX-1 contributes to the normal nocturnal BP dipping phenomenon.

Key Words: hypertension • nitric oxide • prostaglandins • renal circulation • sympathetic nervous activity

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