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

Abstract

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 ϩ/ϩ and COX-1 Ϫ/Ϫ (131Ϯ2 versus 126Ϯ3 mm Hg; NS Key Words: hypertension Ⅲ nitric oxide Ⅲ prostaglandins Ⅲ renal circulation Ⅲ sympathetic nervous activity C yclooxygenase (COX) converts arachidonate to prostaglandin (PG) H 2 (PGH 2 ), 1,2 which can activate thromboxane-PGH 2 receptors. However, in vivo, PGH 2 is promptly metabolized to several biological active PGs and thromboxane A 2 (TxA 2 ). COX produces both vasoconstrictor and vasodilatator metabolites. Therefore, its role in the regulation of BP and hemodynamics is difficult to predict and may explain the positive and negative studies regarding the effect of nonselective COX inhibitors (nonsteroidal antiinflammatory drugs [NSAIDs]) on blood pressure (BP) in human. However, a metaanalysis showed a 5.0-mm Hg increase in the BP in NSAID users. 3 COX-2 is inducible, 4 -6 but in the kidney it is expressed constitutively in vascular endothelial cells, afferent arterioles, cortical thick ascending limbs, macula densa cells, and glomeruli. 7,8 COX-2 regulates renin secretion. 7 COX-1 is expressed in the extraglomerular and intraglomerular mesangium, the terminal distal convoluted tubule, collecting duct, and vascular endothelial cells. 9,10 Previous studies by Athirakul et al 11 have shown that COX-1 genedeficient (COX-1 Ϫ/Ϫ ) mice fail to conserve salt, leading to an exaggerated decline in the mean arterial pressure (MAP) during salt restriction. They also have diminished pressor and renal vasoconstrictor responses during an acute infusion of angiotensin II. 12 These studies suggest that COX-1 may be required to maintain BP during states of high angiotensin II. However, less is known concerning the role of COX-1 during states of normal or low angiotensin II. This study was conducted in mice consuming a normal salt diet.A loss of the normal reduction in BP during sleep ("nondipping" status) increases the risk for cardiovascular disease, 13-16 but the mechanism is not clear. The decline in nocturnal BP is associated with a reduced sympathetic nervous system tone. 17 Loss of the nocturnal decline in BP is accompanied by reduced physical activity, 18 increased

Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure

“…In support of the observation made with chronic infusion of SC-560, COX-1 KO mice developed hypertension during highsalt intake associated with a remarkable inhibition of high-saltinduced urinary PGE 2 excretion in wild-type mice. This phenomenon appears to agree with the observations of Kawada et al (16) that, under general anesthesia with modest salt loading, BP was increased in COX-1 KO mice compared with wild-type controls. However, inconsistencies between the two studies exist in the differences in urinary PGE 2 excretion.…”

Angiotensin-II Type 1 Receptor–Mediated Hypertension in D 4 Dopamine Receptor–Deficient Mice

“…In the second set of studies, TA-PAC20 transmitters (DSI) were implanted into 1 carotid artery, and blood pressures were measured by telemetry 1 week after the surgery. 22 …”

Targeted Cyclooxygenase Gene (Ptgs) Exchange Reveals Discriminant Isoform Functionality

“…This may explain partially why biosynthesis of PGs (PGI 2 and PGE 2 ) was not fully compensated by knocked-in COX-1 in COX-1 Ͼ COX-2 mice. Two additional points are worthy of general consideration: (i) COX-1, expressed in most tissues, is responsible for the majority of urinary PGEM synthesis in vivo (21,37); and (ii) PGI 2 is dominantly generated from COX-2 in healthy individuals and in WT mice (21,26,38). The altered PG biosynthesis in COX-1 Ͼ COX-2 mice (with COX-2 deletion) might allow a relative rediversion of knocked-in COX-1-derived PGH 2 toward PGE 2 formation if coupling to PGI 2 synthase (PGIS) is affected.…”

“…Although there has been no direct interaction reported between COX isozymes and the downstream PG synthases, accumulating evidence suggests PGIS coupling with COX-2, including physical co-localization (1,40) and physiological metabolism (21,37,40,41). We did not observe any obvious kidney developmental abnormalities in young COX-1 Ͼ COX-2 mice, suggesting that the COX-1 gene at the COX-2 locus is regulated in postnatal COX-1 Ͼ COX-2 pups in a manner analogous to the endogenous COX-2 gene in WT mice (42).…”