The role of B₁ and B₂ kinin receptors in oedema formation after long-term treatment with Mycobacterium bovis bacillus Calmette-Guérin (BCG)

Abstract

1. The present study was designed to investigate the influence of long-term systemic treatment with Mycobacterium bovis bacillus Calmette-Guérin (BCG, 1 dose per animal, containing 6×10⁴ colony-forming-units (CFu), 5 to 75 days beforehand) on oedema formation induced by intradermal injection of B₁ and B₂ selective agonists. The interaction between the B₁ agonist des-Arg⁹-bradykinin and bradykinin was also investigated.

2. Intradermal injection (i.d.) of the B₂ selective agonist tyrosine⁸-bradykinin (1–10 nmol) in naive (saline pretreated) animals, or in animals that had received BCG (30 days beforehand), caused dose-related and very similar oedema formation (ED₅₀; 1.1 and 1.0 nmol/paw, respectively). I.d. injection of the selective B₁ agonists des-Arg⁹-bradykinin (100 nmol) or des-Arg¹⁰-kallidin in naive animals caused very little paw oedema (0.04±0.06 and 0.07±0.02 ml, respectively, n=5). However, i.d. injection of des-Arg⁹-bradykinin (10–300 nmol) or des-Arg¹⁰-kallidin (3–100 nmol) in animals pretreated with BCG, 30 days previously, resulted in dose-related and marked oedema formation, with mean ED₅₀ values of 20.1 and 5.5 nmol/paw, respectively.

3. Oedema caused by i.d. injection of des-Arg⁹-bradykinin (100 nmol/paw) in rats pretreated with BCG was evident 5 days after treatment, 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 the selective B₁ antagonists des-Arg⁹[Leu⁸]-bradykinin (200 nmol), des-Arg¹⁰[Leu⁹]-bradykinin (30 nmol) and des-Arg⁹-NPC 17731 (30 nmol) significantly (18±3, 34±2 and 56±4%, respectively) prevented the paw oedema caused by i.d. injection of des-Arg⁹-bradykinin (100 nmol) in rats treated with BCG. These effects were selective, because the i.d. injection of the B₁ selective antagonist des-Arg¹⁰[Leu⁹]-kallidin (30 nmol), at the same dose that consistently antagonized des-Arg⁹-bradykinin (100 nmol)-mediated paw oedema, had no significant effect against tyrosine⁸-bradykinin (3 nmol)-induced oedema in animals that had been treated previously with BCG. On the other hand, the i.d. co-injection of the selective B₂ antagonist, Hoe 140 (10 nmol) at a dose which markedly inhibited tyrosine⁸-bradykinin (3 nmol)-induced oedema by 55±4%, did not significantly affect des-Arg⁹-bradykinin-induced paw oedema in animals pretreated with BCG.

5. Treatment 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 oedema caused by des-Arg⁹-bradykinin (100 nmol), but did not affect the paw oedema caused by tyrosine⁸-bradykinin (3 nmol) in animals pretreated with BCG.

6. Indomethacin (2 mg kg⁻¹, i.p.), administered 1 h before experiments, significantly inhibited des-Arg⁹-bradykinin (100 nmol)-induced oedema formation, and, to a lesser extent, the paw oedema caused by tyrosine⁸-bradykinin (3 nmol) (44±4 and 20±4%, respectively).

7. These findings show that the long-term systemic treatment of rats with BCG promoted a time-dependent and consistent paw oedema formation to B₁ agonists, des-Arg⁹-bradykinin and des-Arg¹⁰-kallidin, leaving responses to the B₂ agonist tyrosine⁸-bradykinin unaffected. The upregulation of B₁ receptors after BCG treatment was inhibited by dexamethasone, suggesting the possible involvement of de novo protein synthesis. Finally, our results also show that in BCG-treated animals, the B₁ agonist des-Arg⁹-bradykinin interacts in a synergistic manner with bradykinin. Therefore, both B₁ and B₂ kinin receptors appear to play a relevant role in modulating chronic inflammatory processes.

Full Text

The Full Text of this article is available as a PDF (346.7 KB).