Cyclooxygenase-2 renoprotective effects during chronically augmented and attenuated endogenous AngII activity

Cyclooxygenase (COX) isoforms, COX1 and COX2, generate renal prostaglandin E2, prostaglandin I2 and thromboxane A2. Nonselective COX inhibitors decrease prostaglandin vasodilatory influence on total renal and vasa recta blood flow, especially in resistance vessels preconstricted with angiotensin II (AngII). While this signifies prostaglandin regulation of renal blood flow, each COX isoform's regulatory contribution remains unresolved. The significance of each enzyme can potentially be discriminated during conditions that selective regulate isoform expression. Angiotensin converting enzyme (ACE) inhibition selectively increases cortical COX2 and dietary salt restriction differentially increases cortical COX2 while decreasing cortical COX-1.;Interestingly, sodium-restricted animals show normal or only slightly lowered renal hemodynamic parameters despite high plasma renin activity. It remains unresolved whether the concurrently augmented COX-2 expression in sodium restricted animals yield vasodilatory influence to maintain renal hemodynamic parameters by opposing or modifying AngII effects. Hence, we tested the hypothesis that COX-2 inhibitor effects on renal hemodynamic and excretory function are increased in proportion to AngII activity.;Renal clearance experiments were conducted in four groups of anesthetized Sprague-Dawley rats: those characterized by attenuated AngII activity established by acute captopril either (1) alone (aACEi) or (2) in combination with chronic captopril pretreatment (cACEi); in contrast to rats fed (3) normal (NS) or (4) low (LS) sodium diet, respectively. Acute COX-2 inhibition with nimesulide (NMSLD) was thereafter used to investigate the activity of basal or augmented cortical COX-2 expression. NMSLD did not alter mean arterial blood pressure in any group but decreased renal plasma flow(RPF), cortical blood flow (CBF) and glomerular filtration rate (GFR) in the LS and cACEi groups. In contrast, medullary blood flow (MBF) was significantly decreased by COX-2 inhibition in all groups. Absolute (UNalpha) and fractional (FENalpha) sodium excretion rates were unchanged by NMSLD except in the LS group. These results demonstrate an augmented COX-2-mediated vasodilatation that is AngII-independent in contrast to an augmented COX-2-mediated sodium excretion where AngII activity is requisite. Further, COX-2 effects on MBF are neither AngII-dependent nor dependent on changes in cortical microvascular responses. Therefore, COX-2 continually regulates MBF and responsively limits AngII prohypertensinogenic effects on RPF, CBF, GFR, UNalpha and FENalpha.