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

Abstract

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 = 13) or in combination with chronic captopril [chronic ACEi (cACEi)] pretreatment (n = 19). In another series of experiments, rats were fed a normal-sodium [0.4% (NS), n = 12] or a low-sodium [0.03% (LS), n = 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 ± 0.33 to 2.85 ± 0.26 and from 4.30 ± 0.19 to 3.22 ± 0.21 ml·min(-1)·g(-1)), cortical blood flow (-12 ± 8% and -13 ± 4%), and glomerular filtration rate (from 0.88 ± 0.04 to 0.65 ± 0.05 and from 0.95 ± 0.07 to 0.70 ± 0.05 ml·min(-1)·g(-1)). In contrast, medullary blood flow (MBF) was significantly decreased by COX-2 inhibition in NS (-24 ± 5%), LS (-27 ± 8%), aACEi (-16 ± 3.8%), and cACEi (-24 ± 4.2%) groups. Absolute and fractional sodium excretion rates were unchanged by NMSLD, except in the LS group (0.75 ± 0.05 μeq/min and 0.43 ± 0.15% and 0.51 ± 0.06 μeq/min and 0.26 ± 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.