THE ROLE OF B-1 AND B-1 KININ RECEPTORS IN EDEMA FORMATION AFTER LONG-TERM TREATMENT WITH MYCOBACTERIUM-BOVIS BACILLUS-CALMETTE-GUERIN (BCG)

1 The present study was designed to investigate the influence of long- term systemic treatment with Mycobacterium bovis bacillus Calmette-Gue rin (BCG, 1 dose per animal. containing 6 x 10(4) colony-forming-units (CFu), 5 to 75 days beforehand) on oedema formation induced by intrad ermal injection of B-1 and B-2 selective agonists. The interaction bet ween the B-1 agonist des-Arg(9)-bradykinin and bradykinin was also inv estigated. 2 Intradermal injection (i.d.) of the B-2 selective agonist tyrosine(8)-bradykinin (1-10 nmol) in naive (saline pretreated) anima ls, or in animals that had received BCG (30 days beforehand, caused do se-related and very similar oedema formation (ED(50); 1.1 and 1.0 nmol /paw, respectively). I.d. injection of the selective B-1 agonists des- Arg(9)-bradykinin (100 nmol) or des-Arg(10)-kallidin in naive animals caused very little paw oedema (0.04 +/- 0.06 and 0.07 +/- 0.02 ml, res pectively, n = 5). However, i.d. injection of des-Arg(9)-bradykinin (1 0-300 nmol) or des-Arg(10)-kallidin (3-100 nmol) in animals pretreated with BCG, 30 days previously, resulted in dose-related and marked oed ema formation, with mean ED(50) values of 20.1 and 5.5 nmol/paw, respe ctively. 3 Oedema caused by i.d. injection of des-Arg(9)-bradykinin (1 00 nmol/paw) in rats pretreated with BCG was evident 5 days after trea tment, reaching the maximum 30 days later, remaining stable for up to 45 days. and reduced markedly at 75 days. 4 The i.d. co-injection of t he selective B-1 antagonists des-Arg(9)[Leu(8)]-bradykinin (200 nmol), des-Arg(10)[Leu(9)]-bradykinin (30 nmol) and des-Arg(9)-NPC 17731 (30 nmol) significantly (18 +/- 3, 34 +/- 2 and 56 +/- 4%, respectively) prevented the paw oedema caused by i.d. injection of des-Arg(9)-bradyk inin (100 nmol) in rats treated with BCG. These effects were selective , because the i.d. injection of the B-1 selective antagonist des-Arg(1 0)[Leu(9)]-kallidin (30 nmol), at the same dose that consistently anta gonized des-Arg(9)-bradykinin (100 nmol)-mediated paw oedema, had no s ignificant effect against tyrosine(8)-bradykinin (3 nmol)-induced oede ma in animals that had been treated previously with BCG. On the other hand, the i.d. co-injection of the selective B-2 antagonist. Hoe 140 ( 10 nmol) at a dose which markedly inhibited tyrosine(8)-bradykinin (3 nmol)-induced oedema by 55 +/- 4%, did not significantly affect des-Ar g(9)-bradykinin-induced paw oedema in animals pretreated with BCG. 5 T reatment of animals with dexamethasone (0.5 mg kg(-1), s.c.) every 24 h, from day 0 to day 30, inhibited significantly (67 +/- 4%) the oedem a caused by des-Arg(9)-bradykinin (100 nmol), but did not affect the p aw oedema caused by tyrosine(8)-bradykinin (3 nmol) in animals pretrea ted with BCG. 6 Indomethacin (2 mg kg(-1), i.p.), administered 1 h bef ore experiments, significantly inhibited des-Arg(9)-bradykinin (100 nm ol)-induced oedema formation, and, to a lesser extent, the paw oedema caused by tyrosine(8)-bradykinin (3 nmol) (44 +/- 4 and 20 +/- 4%, res pectively). 7 These findings show that the long-term systemic treatmen t of rats with BCG promoted a time-dependent and consistent paw oedema formation to B-1 agonists, des-Arg(9)-bradykinin and des-Arg(10)-kall idin, leaving responses to the B-2 agonist tyrosine(8)-bradykinin unaf fected. The upregulation of B-1 receptors after BCG treatment was inhi bited by dexamethasone, suggesting the possible involvement of de novo protein synthesis. Finally our results also show that in BCG-treated animals, the B-1 agonist des-Arg(9)-bradykinin interacts in a synergis tic manner with bradykinin. Therefore, both B-1 and B-2 kinin receptor s appear to play a relevant role in modulating chronic inflammatory pr ocesses.