UP-REGULATION OF B-1 RECEPTOR MEDIATING DES-ARG(9)-BK-INDUCED RAT PAWEDEMA BY SYSTEMIC TREATMENT WITH BACTERIAL-ENDOTOXIN

1 The effect of pretreatment with bacterial endotoxin (LPS, 10 mu g; i .v., 24 h) on the bradykinin B-1 and B-2 receptor-induced oedema in th e rat paw, and the interaction of B-1-mediated responses with other in flammatory mediators, was investigated. 2 Intraplantar (i.pl.) injecti on of the selective B-1 agonist, des-Arg(9)-BK (DABK, 100 nmol) in nai ve 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 mi). 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 incr ease 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 w ith LPS when compared with naive animals. 3 Oedema caused by prostagla ndin E(2) (PGE(2), 10 nmol) was unaffected by LPS treatment, while oed ema induced by histamine (100 nmol), 5-hydroxytryptamine (5-HT, 10 nmo l) and substance P (SP, 3 nmol) was reduced (P < 0.05). 4 The selectiv e 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-trea ted animals with mean IC50 of 134 nmol, while the selective B-2 antago nists, Hoe 140 and NPC 17731 (each 10 nmol), had no effect. 5 Treatmen t 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)-in duced oedema formation (58 +/- 3 and 82 +/- 2%, respectively), and alm ost reversed to control value oedema formation induced by T-BK (3 nmol ) in LPS-pretreated rats. Cycloheximide (1 mg kg(-1), s.c.) or indomet hacin (2 mg kg(-1), i.p.) pretreatment 24 and 1 h prior to LPS injecti on, respectively, markedly inhibited DABK (100 nmol)-induced paw oedem a (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 mi). However, i.pl. injections of PGE(2), pr ostacyclin (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-induc ed oedema. The increases in paw volume (in mi) were: PGE(2) + DABK (0. 31 +/- 0.03), PGI(2) + DABK (0.39 +/- 0.02), CGRP + DABK (0.35 +/- 0.0 4), DABK + SP (0.33 +/- 0.04), DABK + 5-HT (0.40 +/- 0.02) and DABK PAF (0.38 +/- 0.016) mi. In contrast, histamine (1 nmol) was ineffecti ve in potentiating the response to DABK. 7 The selective B-1 receptor antagonist, DALBK (100-300 nmol), produced dose-dependent inhibition o f paw oedema potentiation induced by co-injection of DABK and other me diators with mean ID(50)s (nmol) of: 180, 160, 139 and 135 in the pres ence of PGE(2), PGI(2), SP and 5-HT, respectively. 8 These results dem onstrate that DABK-induced increase in paw volume in LPS-treated rats is probably mediated by induction of B-1 receptors, associated with do wnregulation of B-2 receptors. The induction of B-1 receptors by LPS i s sensitive to dexamethasone and cycloheximide treatment and requires activation of cyclo-oxygenase pathway. In addition, B-1 receptors, whe n upregulated following LPS treatment, can interact in a synergistic m anner with several inflammatory mediators such as PGI(2), PGE(2), CGRP , PAF and 5-HT. Such results indicate that induction of the B-1 recept or might have a significant pathophysiological role in modulating chro nic inflammatory diseases.