Renal safety of combined cyclooxygenase 2 (COX-2) inhibitor and angiotensin II receptor blocker administration in mild volume depletion.

Principles: Drugs that either inhibit prostaglandin synthesis or antagonise angiotensin II effects are likely to impair renal function, especially in patients with an activated renin-angiotensin-aldosterone system. Of the former, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, and newer agents with cyclooxygenase 2 (COX-2) specific inhibition may have fewer renal side effects compared to non-selective NSAIDs. We therefore investigated whether combination of a COX-2 inhibitor with an angiotensin II subtype 1 (AT1) receptor blocker is safe with regard to preservation of normal renal function in a state of slight volume contraction. Methods: Mild volume depletion was induced by a salt-restricted diet in 5 healthy volunteers who were then given a single dose of 400 mg celecoxib, a COX-2 inhibitor, alone or in combination with 150 mg irbesartan, an AT1 receptor blocker. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by measuring inulin and PAH clearance respectively, along with plasma renin activity (PRA) and urinary electrolyte excretion before and over 100 minutes after drug administration. Results: PRA was high prior to drug administration, indicating slight salt depletion, and dropped by 65% after intake of celecoxib alone (p = 0.008) but only by 25% after combined intake with irbesartan (p = n.s.). GFR was not affected either by celecoxib alone or by combined administration with irbesartan. In contrast, ERPF increased by 28% 80 minutes after simultaneous drug intake (p = 0.029), but not after celecoxib alone. Renal sodium and potassium excretion did not significantly change under celecoxib alone or in combination with irbesartan. Conclusion: Selective COX-2 inhibition by celecoxib in combination with an AT1 receptor blocker (irbesartan) has no acute adverse effects on renal haemodynamics and renal salt handling in slightly volume-depleted subjects with normal renal function. Moreover, our data obtained in humans appear to confirm the co-regulatory interaction of COX-2 and angiotensin II in the control of renin release, as suggested by animal studies.