Absence of effect of chronic angiotensin II type 1 receptor blockade on endogenous kinin concentrations in the carrageenan-induced paw edema model inthe rat

The effects of chronic treatment with losartan, an AT(1) receptor antagonis t, on the tissue content of bradykinin (BK) and des-Arg(9)-BK and on their pharmacological effects were examined in the carrageenan-induced paw edema model (0.5% solution, 50 mu l/paw) in the rat. These effects were compared with those of angiotensin-converting enzyme inhibitors (ACEi). For this pur pose, rats were chronically treated with losartan (3, 10 and 30 mg/kg/day) and enalapril or quinapril (1 mg/kg/day). Endogenous BK and des-Arg(9)-BK t issue contents at the site of local inflammation were measured by highly se nsitive and specific enzyme immunoassays. Losartan 3 mg/kg/day for 7, 14 an d 28 days had no significant effect on carrageenan-induced paw edema, but b oth losartan 10 and 30 mg/kg/day for 14 days significantly increased the hi ndpaw volume by 50% at 3 h and by 59% at 5 h. These effects, similar to tho se measured for ACEi, were inhibited by icatibant, a B-2 kinin receptor ant agonist (32.5 nmol/paw), that reduced carrageenan-induced paw edema to the level seen in vehicle-treated rats. In the same model, and contrary to ACEi , losartan 3, 10 and 30 mg/kg/day for 14 days had no significant effect on endogenous BK and des-Arg(9)-BK levels in the local inflammatory site or on circulating and tissue ACE activities. These results show, at least in tha t model, that the potentiating effects of losartan on carrageenan-induced p aw edema are independent of the concentrations of endogenous kinins. (C) 19 99 Elsevier Science Inc. All rights reserved.