Upregulation of B 1 receptor mediating des‐Arg 9 ‐BK‐induced rat paw oedema by systemic treatment with bacterial endotoxin

1 The effect of pretreatment with bacterial endotoxin (LPS, 10 μg, i.v., 24 h) on the bradykinin B 1 and B 2 receptor‐induced oedema in the rat paw, and the interaction of B 1 ‐mediated responses with other inflammatory mediators, was investigated. 2 Intraplantar (i.pl.) injection of the selective B 1 agonist, des‐Arg 9 ‐BK (DABK, 100 nmol) in naive animals pretreated with the angiotensin converting enzyme inhibitor, captopril caused a small increase in paw volume (0.04±0.003 ml, mean±s.e.mean, n = 6), while the B 2 ‐selective agonist, tyrosine 8 ‐bradykinin (T‐BK, 3 nmol) induced marked oedema (0.36±0.02 ml). However, i.pl. injection of DABK (3–300 nmol) in rats pretreated with LPS (24 h beforehand) resulted in a marked dose‐ and time‐related increase in paw volume, with mean ED 50 of 24.1 nmol. In contrast, oedema caused by T‐BK (3 nmol) was reduced by 79±4% in animals treated with LPS when compared with naive animals. 3 Oedema caused by prostaglandin E 2 (PGE 2 , 10 nmol) was unaffected by LPS treatment, while oedema induced by histamine (100 nmol), 5‐hydroxytryptamine (5‐HT, 10 nmol) and substance P (SP, 3 nmol) was reduced ( P <0.05). 4 The selective B 1 antagonist, des‐Arg 9 [Leu 8 ]‐BK (100–300 nmol), produced dose‐dependent inhibition of DABK (100 nmol)‐induced paw oedema in LPS‐treated animals with mean IC 50 of 134 nmol, while the selective B 2 antagonists, Hoe 140 and NPC 17731 (each 10 nmol), had no effect. 5 Treatment of animals with dexamethasone (0.5 mg kg −1 , s.c.) 24 or 48 h prior to LPS injection resulted in a graded inhibition of DABK (100 nmol)‐induced oedema formation (58±3 and 82±2%, respectively), and almost reversed to control value oedema formation induced by T‐BK (3 nmol) in LPS‐pretreated rats. Cycloheximide (1 mg kg −1 , s.c.) or indomethacin (2 mg kg −1 , i.p.) pretreatment 24 and 1 h prior to LPS injection, respectively, markedly inhibited DABK (100 nmol)‐induced paw oedema (98±2 and 50±4%, respectively). 6 Intraplantar injection of submaximal dose of DABK (10 nmol) in LPS‐treated rats produced modest paw oedema (0.09±0.03 ml). However, i.pl. injections of PGE 2 , prostacyclin (PGI 2 ), calcitonin‐gene‐related peptide (CGRP), SP, 5‐HT, or platelet activating factor (PAF) (each 1 nmol), which alone caused little or no paw oedema, resulted in a potentiation of the DABK‐induced oedema. The increases in paw volume (in ml) were: PGE 2 + DABK (0.31±0.03), PGI 2 + DABK (0.39±0.02), CGRP + DABK (0.35±0.04), DABK + SP (0.33±0.04), DABK + 5‐HT (0.40±0.02) and DABK + PAF (0.38±0.016) ml. In contrast, histamine (1 nmol) was ineffective in potentiating the response to DABK. 7 The selective B 1 receptor antagonist, DALBK (100–300 nmol), produced dose‐dependent inhibition of paw oedema potentiation induced by co‐injection of DABK and other mediators with mean ID 50 s (nmol) of: 180, 160, 139 and 135 in the presence of PGE 2 , PGI 2 , SP and 5‐HT, respectively. 8 These results demonstrate that DABK‐induced increase in paw volume in LPS‐treated rats is probably mediated by induction of B 1 receptors, associated with downregulation of B 2 receptors. The induction of B 1 receptors by LPS is sensitive to dexamethasone and cycloheximide treatment and requires activation of cyclo‐oxygenase pathway. In addition, B 1 receptors, when upregulated following LPS treatment, can interact in a synergistic manner with several inflammatory mediators such as PGI 2 , PGE 2 , CGRP, PAF and 5‐HT. Such results indicate that induction of the B 1 receptor might have a significant pathophysiological role in modulating chronic inflammatory diseases.