Bradykinin receptor antagonists type 2 attenuate the inflammatory changes in peptidoglycan-induced acute arthritis in the Lewis rat

Abstract:

Objective and Design: We studied the ability of bradykinin (BK) receptor antagonists type 1 and 2 (B1-RA, B2-RA) to prevent acute inflammation.¶Material: A peptidoglycan-polysaccharide (PG-APS)-induced model of arthritis in the Lewis rat was analyzed.¶Treatment: Four groups of animals were studied for 5 days. Treatment was administered subcutaneously (s.c.) 1 mg/kg every 12 h. Group I received PG-APS and was treated with the B2-RA, CP-0597 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-NChg-Arg). Group II received PG-APS and was treated with a combined B1 and B2-RA, B9430 (DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg). Group III received PG-APS and albumin control. Group IV received albumin control.¶Methods: Joint diameter, liver weight, hematocrit, white blood count and plasma concentrations of prekallikrein, high molecular weight kininogen, HK and IL-1β were measured. Groups were compared by ANOVA.¶Results: Acute arthritis and hepatomegaly were attenuated in the B2-RA-treated animals (p<0.05). Weight loss was more pronounced in the B1/B2-RA-treated animals. Anemia induced by PG-APS was prevented by B2-RA and B1/B2-RA treatment (p<0.001). A marked decrease in plasma HK to 64% of normal was found in the disease-untreated animals, which was completely normalized by B2-RA treatment and partially attenuated by the B1/B2-RA (78%). The decrease in plasma prekallikrein levels was prevented by combined B1/B2-RA treatment (p<0.05). Finally, elevated plasma IL-1β levels were lowered by B1/B2-RA treatment and were below detection limits with the B2-RA treatment.¶Conclusions: These results indicate that the systemic inflammation is due in part to BK generation which can be blocked by B2-RA, while inhibiting the B1 receptor prevents an anti-inflammatory response.¶