Published Online
on May 9, 2005

A more recent version of this article appeared on June 1, 2005

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Submitted on November 22, 2004
Revised on December 16, 2004

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; and 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.

^* To whom correspondence should be addressed. E-mail: wilcoxch{at}georgetown.edu.

Abstract--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-PGF₂ (11), 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, 11, 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; 11 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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