Many previous studies have demonstrated that cyclooxygenase-2 (COX-2) is constitutively expressed in the kidney (macula densa, thick ascending limb of Henle, medullary interstitial cells, …) and that COX-2-derived metabolites are involved in the acute and long-term regulation of renal function (Harris & Breyer, 2001; Roig et al. 2002). The objective of this study was to evaluate whether COX-2 is involved in producing the prostaglandins that protect the renal vasculature from the prolonged haemodynamic effects secondary to a reduction in nitric oxide (NO) synthesis.

The study was performed in conscious dogs instrumented as previously described (Gonzalez et al. 1998) and with normal sodium intake (70 mEq day^-1). Surgery was performed under anaesthesia induced with pentobarbital (30 mg kg^-1) and maintained with a 1.5-2 % halothane-O₂ mixture. Experiments were designed according to the national guidelines and the Guiding Principles of the American Physiological Society. We examined the renal haemodynamic and excretory response to the oral administration of a selective COX-2 inhibitor (nimesulide, 5 mg kg^-1 day^-1) during eight consecutive days, with and without the simultaneous intravenous infusion of a NO synthesis inhibitor (L-NAME, 5 µg kg^-1 min^-1). Mean arterial pressure (MAP) and renal blood flow (RBF) were continuously measured with Transonic equipment. Data are given as means ± S.E.M.

The nimesulide administration (n = 7) did not modify MAP and glomerular filtration rate (GFR) but induced a significant and continuous reduction in RBF (17 ± 3 %, P < 0.05) and a transitory decrease in urinary sodium excretion (U_NaV). The prolonged NO synthesis inhibition in the second group of dogs (n = 6) elicited a 25 ± 4 % (P < 0.05) elevation in MAP, a transitory decrease in RBF (15 ± 2 %, P < 0.05) and no changes in GFR and U_NaV. In the third experimental group (n = 7), the continuous NO synthesis inhibition elicited similar changes to those described for group 2. The prolonged administration of the COX-2 inhibitor to these dogs with a reduced NO production elicited a continuous decrease in GFR (41 ± 4 %, P < 0.05) and RBF (37 ± 4 %, P < 0.05) and a transitory sodium retention that was similar to that found in the dogs only treated with the COX-2 inhibitor.

The results of this study suggest that COX-2-derived metabolites protect the renal vasculature from the prolonged vasoconstriction secondary to a reduction in NO, and that COX-2 is only acutely involved in regulating the renal excretory function when NO synthesis is reduced.

This study was supported by grants from the Fondo de Investigación Sanitaria of Spain (2001/719) and Fundación Séneca (PI-73/890//FS/01) of Murcia (Spain).