In the current experiments we determined the response of plasma renin concentration (PRC) to acute i.p. administration of furosemide (40 mg/kg), hydralazine (2 mg/kg), isoproterenol (10 mg/kg), candesartan (50 µg), or quinaprilate (50 µg ) in conscious wild type (WT) and COX-2-/- mice on 3 different genetic backgrounds (mixed, C57BL/6, 129J). PRC was measured in plasma obtained by tail vein puncture. Basal PRC was significantly lower in COX-2-/- than WT mice independent of genetic background (51%, 10%, and 17% of WT in mixed, 129J, and C57BL/6). All five acute interventions caused significant increases of PRC in both COX-2+/+ and -/- mice, but the response was consistently less in COX-2-deficient mice (e.g. PRC in ng Ang I/ml hr caused by furosemide, isoproterenol, hydralazine, quinaprilate, or candesartan 4699±544, 3534±957, 2522±369, 9453±1705, 66455±21938 in 129J WT, and 201±78, 869±275,140±71, 902±304, 2660±954 in 129J COX-2-/-). A low NaCl diet and enalapril for one week caused a 14fold elevation of PRC in COX-2-/- mice, and was associated with a greatly increased PRC response to acute furosemide (PRC 201±78 before and 15984±2397 after lo Na/enalapril). As measured by radiotelemetry, blood pressure and heart rate responses to furosemide, hydralazine, isoproterenol, candesartan, or quinaprilate were not different between COX-2 genotypes. In conclusion, chronic absence of COX-2 reduces renin expression, release, and PRC, and is associated with a reduced ability to alter PRC during acute stimulation regardless of the nature of the stimulus. COX-2 activity does not appear to be a mandatory and specific requirement for furosemide-stimulated renin secretion.