Renal Changes Induced by a Cyclooxygenase-2 Inhibitor During Normal and Low Sodium Intake

Abstract

Cyclooxygenase-2 (COX-2) has been identified in renal tissues under normal conditions, with its expression enhanced during sodium restriction. To evaluate the role of COX-2-derived metabolites in the regulation of renal function, we infused a selective inhibitor (nimesulide) in anesthetized dogs with normal or low sodium intake. The renal effects elicited by nimesulide and a non-isozyme-specific inhibitor (meclofenamate) were compared during normal sodium intake. In ex vivo assays, meclofenamate, but not nimesulide, prevented the platelet aggregation elicited by arachidonic acid. During normal sodium intake, nimesulide infusion (n=6) had no effects on arterial pressure or renal hemodynamics but did reduce urinary sodium excretion, urine flow rate, and fractional lithium excretion. In contrast, nimesulide administration increased arterial pressure and decreased renal blood flow, urine flow rate, and fractional lithium excretion during low sodium intake (n=6). COX-2 inhibition reduced urinary prostaglandin E(2) excretion in both groups but did not modify plasma renin activity in dogs with low (8.1+/-1.1 ng angiotensin I. mL(-1). h(-1)) or normal (1.8+/-0.4 ng angiotensin I. mL(-1). h(-1)) sodium intake. Meclofenamate infusion in dogs with normal sodium intake (n=8) induced a greater renal hemodynamic effect than nimesulide infusion. These results suggest that COX-2-derived metabolites (1) are involved in the regulation of sodium excretion in dogs with normal sodium intake, (2) play an important role in the regulation of renal hemodynamic and excretory function in dogs with low sodium intake, and (3) are not involved in the maintenance of the high renin levels during a long-term decrease in sodium intake.

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

“…We observed that COX-2 inhibition does not elicit significant alterations of RPF and GFR under NS conditions. This finding is consistent with previous in vivo studies under NS conditions that have not demonstrated a discernible consequence of acutely attenuated prostaglandin biosynthesis on renal hemodynamics (11,26,30). Furthermore, afferent arteriolar diameters of juxtamedullary nephrons in NS rats were not changed by COX-2 inhibition with NS-398 (16).…”

“…Similar to our present findings in rats, sodium-restricted dogs exhibited decreases in GFR and RPF with acute or chronic nimesulide treatment (30,31). In addition, we present the novel finding that nimesulide decreases GFR and RPF in chronically ACE-inhibited rats.…”

“…Next, injection of a bolus of the selective COX-2 inhibitor nimesulide (3 mg/kg body wt) or a 50 mM sodium carbonate vehicle (1 ml/kg body wt) was followed by a 15-min delay. Nimesulide has been previously shown to be selective for COX-2 (4,34) and to elicit alterations in renal function (26,30,31). The third and fourth 30-min urine samples were collected during COX-2 inhibition.…”

“…When studies involving nonselective inhibition of renal COX are reconsidered in view of more recent isoform-distinct experiments, COX-2 appears to mediate the dynamic hemodynamic and excretory effects previously attributed to COX-1 or both isoforms. For example, nonselective COX inhibition-mediated reductions of glomerular filtration rate (GFR), RBF, sodium excretion, and urine flow in sodium-restricted animals are similar to those precipitated by acute or chronic COX-2 inhibition in similar models (30,31). The effects of dietary sodium restriction to augment macula densa COX-2 expression help explain the increased COX-2 influence on renal hemodynamics (13,42).…”

Cyclosporine A Suppresses Cyclooxygenase-2 Expression in the Rat Kidney

“…This concept has been supported by data obtained from experiments with certain COX-2 blockers (7,45,46) and with COX-2 knockout mice (47,48). However, conflicting data have also been recently reported, raising some doubts on this concept, because commonly available COX-2 blockers do not consistently influence the control of renin synthesis and secretion (31,44,49).…”