Absence of effect of chronic angiotensin II type 1 receptor blockade on endogenous kinin concentrations-induced paw edema model in the rat.
The effects of chronic treatment with losartan. an AT1 receptor antagonist, on the tissue content of bradykinin (BK) and des-Arg9-BK and on their pharmacological effects were examined in the carrageenan-induced paw edema model (0.5% solution, 50 microl/paw) in the rat. These effects were compared with those of angiotensin-converting enzyme inhibitors (ACEi). For this purpose, 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-Arg9-BK tissue contents at the site of local inflammation were measured by highly sensitive and specific enzyme immunoassays. Losartan 3 mg/kg/day for 7, 14 and 28 days had no significant effect on carrageenan-induced paw edema, but both losartan 10 and 30 mg/kg/day for 14 days significantly increased the hindpaw volume by 50% at 3 h and by 59% at 5 h. These effects, similar to those measured for ACEi, were inhibited by icatibant, a B2 kinin receptor antagonist (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-Arg9-BK levels in the local inflammatory site or on circulating and tissue ACE activities. These results show, at least in that model, that the potentiating effects of losartan on carrageenan-induced paw edema are independent of the concentrations of endogenous kinins.
Blais
C
C
Faculté de pharmacie, Université de Montréal, Québec, Canada.
Leclair
P
P
Molinaro
G
G
Adam
A
A
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002351:Carrageenan / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000378:metabolism; D005079:Excipients / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007705:Kinins / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000378:metabolism*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D005079:Excipients; D007705:Kinins; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D002351:Carrageenan; D019808:Losartan