Bradykinin receptor antagonists type 2 attenuate the inflammatory changes in peptidoglycan-induced acute arthritis in the Lewis rat.
OBJECTIVE
We studied the ability of bradykinin (BK) receptor antagonists type 1 and 2 (B1-RA, B2-RA) to prevent acute inflammation.


METHODS
A peptidoglycan-polysaccharide (PG-APS)-induced model of arthritis in the Lewis rat was analyzed.


METHODS
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-Dlgl-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-beta 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-1beta 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.
Uknis
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AB
Sol Sherry Thrombosis Research Center, Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
DeLa Cadena
R A
RA
Janardham
R
R
Sartor
R B
RB
Whalley
E T
ET
Colman
R W
RW
D000208:Acute Disease; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000502:physiology / Q000627:therapeutic use; D065168:Bradykinin Receptor Antagonists; D005260:Female; D007249:Inflammation / Q000517:prevention & control*; D007375:Interleukin-1 / Q000097:blood; D007610:Kallikreins / Q000097:blood; D009504:Neutrophils / Q000502:physiology; D009842:Oligopeptides / Q000627:therapeutic use*; D010457:Peptidoglycan / Q000633:toxicity*; D051381:Rats; D011917:Rats, Inbred Lew; D043782:Receptor, Bradykinin B2
C121351:B 9430; D065168:Bradykinin Receptor Antagonists; C107323:CP 0597; D007375:Interleukin-1; D009842:Oligopeptides; D010457:Peptidoglycan; D043782:Receptor, Bradykinin B2; D007610:Kallikreins; D001920:Bradykinin