Deletion of cyclooxygenase-2 in the mouse increases arterial blood pressure with no impairment in renal NO production in response to chronic high salt intake

Abstract

Staehr M, Hansen PB, Madsen K, Vanhoutte PM, Nüsing RM, Jensen BL. Deletion of cyclooxygenase-2 in the mouse increases arterial blood pressure with no impairment in renal NO production in response to chronic high salt intake. Am J Physiol Regul Integr Comp Physiol 304: R899 -R907, 2013. First published March 27, 2013 doi:10.1152/ajpregu.00103.2012.-Experiments were designed to test the hypothesis that cyclooxygenase-2 (COX-2) activity attenuates the blood pressure increase during high NaCl intake by stimulation of endothelial nitric oxide synthase (eNOS)-mediated NO synthesis in the kidney medulla. COX-2 Ϫ/Ϫ (C57BL6) an COX-2 ϩ/ϩ mice were fed a diet with 0.004% (low salt, LS) or 4% (high salt, HS) NaCl for 18 days. Arterial blood pressure was recorded continuously using indwelling catheters. Food and water intake and diuresis were measured in metabolic cages. Urine osmolality and excretion of electrolytes, cGMP, cAMP, and NOx were determined, as well as plasma NOx and cGMP. There was a significant dependence of blood pressure on salt intake and genotype: COX-2 Ϫ/Ϫ exhibited higher blood pressure than COX-2 ϩ/ϩ both on HS and LS intake. COX-2 ϩ/ϩ littermates displayed an increase in blood pressure on HS versus LS (102.3 Ϯ 1.1 mmHg vs. 91.9 Ϯ 0.9 mmHg) day and night. The mice exhibited significant blood pressure increases during the awake phase (night) that were larger in COX-2 Ϫ/Ϫ on HS diet compared with COX-2 ϩ/ϩ . Water intake, diuresis, Na ϩ , and osmolyte excretions and NOx and cGMP excretions were significantly and similarly elevated with HS in COX-2 Ϫ/Ϫ and COX-2 ϩ/ϩ . In summary, C57BL6 mice exhibit a salt intake-dependent increase in arterial blood pressure with increased renal NO production. COX-2 activity has a general lowering effect on arterial blood pressure. COX-2 dampens NaCl-induced increases in arterial blood pressure in the awake phase. In conclusion, COX-2 activity attenuates the changes in nocturnal blood pressure during high salt intake, and COX-2 activity is not necessary for increased renal nitric oxide formation during elevated NaCl intake. kidney; eNOS; NaCl; hypertension; PGE2; prostacyclin PROSTAGLANDINS contribute to the regulation of blood pressure partly because they promote renal sodium excretion by their effects on the tubular epithelium and on medullary blood flow (9). A critical step in the production is the transformation of arachidonic acid to short-lived PGG 2 /PGH 2 , catalyzed by cyclooxygenase (COX). Two isoforms of this enzyme have been identified: COX-1 and COX-2 (3, 36), initially thought to be constitutive and inducible, respectively. But in the wake of the severe side effects (hypertension, thrombosis, and stroke) associated with the clinical use of specific COX-2 inhibitors, a more constitutive role for COX-2 in vascular homeostasis and kidney function has become apparent (4, 10). COX-2, microsomal PGE synthase (mPGES-1), and tissue/urine PGE 2 levels are increased by high salt intake in the medulla (12,13,16,39,40). Local inhibition of COX-2 only in the medulla l...

Lack of Suppression of Aldosterone Production Leads to Salt-Sensitive Hypertension in Female but Not Male Balb/C Mice

“…A previous study has observed that female FVB/N mice also develop a greater increase in BP in response to a HS diet compared to male counterparts 26 , indicating that the BP elevation in Balb/C mice may not be an anomaly, but rather, a representation of a genetic predisposition for salt sensitivity in these strains of female mice that parallels the human population. Notably, data in the C57BL/6 mouse indicates that no such salt-sensitive hypertension persists in females of that genetic background 11 . Therefore, strain and genetic specificity is particularly important for salt-sensitivity studies in females.…”

“…Despite this discrepancy in the human population, the majority of studies of salt-sensitivity in animal models have been restricted to male animals. Background strains such as the C57BL6 mouse and Sprague-Dawley rat have not been reported to develop salt-sensitive hypertension spontaneously in males or females 10, 11 . Therefore, transgenic models have traditionally been utilized to examine mechanisms of salt-sensitivity.…”

Regulation and function of renal medullary cyclooxygenase-2 during high salt loading

“…Staehr’s results also confirmed the increased BP in COX-2 knockout mice with no impairment in renal NO production in response to chronic high salt intake. (55, 56, 58) COX-2 inhibitors or the genetic absence of COX-2 markedly augments the constrictor actions of angiotensin II (59). …”

Angiotensin II receptor blockade alleviates calcineurin inhibitor nephrotoxicity by restoring cyclooxygenase 2 expression in kidney cortex

“…31 The impact of COX-2 in renal sodium handling has been demonstrated using COX-2-deficient mice, which developed marked hypertension in response to high salt diet. 62 A previous study showed that diuretic effects of furosemide and hydrochlorothiazide are partially mediated by COX-2 activation. 20 Therefore, intact COX-2 function is critical to the renal sodium handling and its normalization by candesartan observed in the present study may have significantly contributed the improvement of the sodium balance in our rat model.…”