Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II

Abstract

Green T, Rodriguez J, Navar LG. Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II. Am J Physiol Renal Physiol 299: F954 -F962, 2010. First published July 28, 2010 doi:10.1152/ajprenal.00609.2009.-Nonsteroidal anti-inflammatory drug usage has long revealed renoprotective prostaglandin actions on the renal microvasculature during increased pressor hormone influence, but whether increased cyclooxygenase (COX)-2 expression supports prostaglandin vasodilatory influence by interfering with the actions of ANG II remains unresolved. Therefore, we tested the hypothesis that COX-2 inhibition causes hemodynamic and excretory effects that are increased in proportion to ANG II activity. In anesthetized Sprague-Dawley rats having augmented cortical COX-2 expression but different ANG II activity, we conducted renal clearance experiments during acute inhibition of COX-2 with nimesulide (NMSLD) and inhibition of COX-1 with SC-560. In one series of experiments, acute captopril [acute angiotensin-converting enzyme (ACE) inhibitor (aACEi)] was administered alone (n ϭ 13) or in combination with chronic captopril [chronic ACEi (cACEi)] pretreatment (n ϭ 19). In another series of experiments, rats were fed a normal-sodium [0.4% (NS), n ϭ 12] or a low-sodium [0.03% (LS), n ϭ 18] diet. NMSLD did not alter mean arterial blood pressure in any group but, in the LS and cACEi groups, decreased renal plasma flow (from 3.99 Ϯ 0.33 to 2.85 Ϯ 0.26 and from 4.30 Ϯ 0.19 to 3.22 Ϯ 0.21 ml·min Ϫ1 ·g Ϫ1 ), cortical blood flow (Ϫ12 Ϯ 8% and Ϫ13 Ϯ 4%), and glomerular filtration rate (from 0.88 Ϯ 0.04 to 0.65 Ϯ 0.05 and from 0.95 Ϯ 0.07 to 0.70 Ϯ 0.05 ml·min Ϫ1 ·g Ϫ1 ). In contrast, medullary blood flow (MBF) was significantly decreased by COX-2 inhibition in NS (Ϫ24 Ϯ 5%), LS (Ϫ27 Ϯ 8%), aACEi (Ϫ16 Ϯ 3.8%), and cACEi (Ϫ24 Ϯ 4.2%) groups. Absolute and fractional sodium excretion rates were unchanged by NMSLD, except in the LS group (0.75 Ϯ 0.05 eq/min and 0.43 Ϯ 0.15% and 0.51 Ϯ 0.06 eq/min and 0.26 Ϯ 0.10%). SC-560 did not augment the effects of NMSLD. These results demonstrate an augmented COX-2-mediated vasodilation that is not contingent on ANG II, in contrast to COX-2-mediated augmented sodium excretion, where ANG II activity is requisite. Furthermore, the COX-2 effects on MBF are not contingent on ANG II or changes in cortical microvascular responses. These results reflect COX-2 continual regulation of MBF and adaptive opposition to ANG II prohypertensinogenic effects on renal plasma flow, cortical blood flow, glomerular filtration rate, and absolute and fractional sodium excretion.angiotensin-converting enzyme inhibition; sodium restriction; medullary blood flow THE DYNAMIC PROSTAGLANDIN biosynthetic capacity in the kidney relies on the catalysis of the rate-limiting step by the cyclooxygenase (COX) isoforms COX-1 and COX-2 (25). Adaptive renal responses to reduced sodium intake involve augmented COX activity, along with activation of the renin-angiotensin system (RAS) (21,36,38,41). Interactions of th...

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“…Two twenty-minute basal clearance periods were followed by the iv administration of nimesulide at a dose (3 mg/kg) that is effective in the selective COX2 inhibition (9,16). Thirty minutes after nimesulide infusion was initiated, two 30-min clearances were obtained.…”

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“…In an experimental work of Torrance Green Sprague-Dawley anesthetized rats were treated with nimesulide, a selective COX-2 inhibitor [13]. To increase cortical COX-2 expression -tubuloglomerular feedback and renin release via PGE2-Sprague-Dawley anesthetized rats were kept in sodium restriction or under captopril treatment.…”

Interaction of the renin angiotensin and cox systems in the kidney

“…Two recently studied models of upregulated COX-2 indicated the effects of COX-2 inhibition on the intrarenal Ang II activity. The sodium restriction model has augmented Ang II level along with elevated COX-2 expression while the chronic ACE inhibition model has similar high levels of COX-2 activity but decreased Ang II levels (17). In rats fed with a low sodium diet, inhibition of COX-2 and ACE using captopril decreased glomerular filtration rate (GFR) and renal plasma flow, and points to the counter regulation between RAS and COX system (17).…”

“…The sodium restriction model has augmented Ang II level along with elevated COX-2 expression while the chronic ACE inhibition model has similar high levels of COX-2 activity but decreased Ang II levels (17). In rats fed with a low sodium diet, inhibition of COX-2 and ACE using captopril decreased glomerular filtration rate (GFR) and renal plasma flow, and points to the counter regulation between RAS and COX system (17). Similar results were obtained with COX-2 inhibition alone and demonstrated that cortical COX-2 expression promotes vasodilation in the renal vasculature (9).…”