Inhibition of cyclooxygenase-2 in the rat renal medulla leads to sodium-sensitive hypertension.

Cyclooxygenase-2 expression in the renal medulla is regulated by dietary salt intake. The present study was performed to determine the influence of chronic inhibition of medullary cyclooxygenase-2 on arterial blood pressure in conscious Sprague-Dawley rats maintained on a high-salt (4% NaCl) or a low-salt (0.4% NaCl) diet. Rats were uninephrectomized and instrumented with femoral arterial and femoral vein or renal medullary interstitial catheters. Each rat received a continuous medullary or intravenous infusion of saline (0.5 mL per hour) for 3 control days, followed by infusion of the cyclooxygenase-2 inhibitor NS-398 (10 mg/kg per day) for 5 days. Medullary interstitial infusion of NS-398 significantly increased mean arterial pressure in the 4% NaCl group from 126+/-2 to 146+/-2 mm Hg (n=6) but did not alter blood pressure in the 0.4% NaCl group (n=6). Intravenous infusion of NS-398 to rats on the 4.0% NaCl diet also failed to alter mean arterial pressure (n=5). To test the blood pressure effect of a mechanistically different inhibitor of cyclooxygenase-2, an antisense oligonucleotide against cyclooxygenase-2 (18-mer; 8 nmol per hour) was infused into the renal medulla of rats maintained on a high-salt diet. Administration of the antisense oligonucleotide reduced cyclooxygenase-2 immunoreactive protein by 36% and significantly increased mean arterial pressure from 127+/-2 to 147+/-2 mm Hg (n=6). Renal medullary interstitial infusion of a scrambled oligonucleotide did not alter arterial pressure (n=5). These results demonstrate the importance of cyclooxygenase-2 in the renal medulla in maintaining blood pressure during high-salt intake.