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

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 TxB 2 , a 76% reduction ( P <0.01) in PGE 2 , a 40% reduction ( P <0.0002) in 6-ketoPGF 1α (6keto), a 27% reduction ( P <0.02) in 11-βPGF 2α (11β), 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, 11β, 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; 11β 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.