Upregulation of B₁ receptor mediating des‐Arg₉‐BK‐induced rat paw oedema by systemic treatment with bacterial endotoxin

Abstract

1 The effect of pretreatment with bacterial endotoxin (LPS, 10 pg, i.v., 24 h) on the bradykinin B1 and B2 receptor-induced oedema in the rat paw, and the interaction of B,-mediated responses with other inflammatory mediators, was investigated. 2 Intraplantar (i.pl.) injection of the selective B1 agonist, des-Arg9-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 B2-selective agonist, tyrosine8-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 ED50 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 E2 (PGE2, 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, antagonist, des-Arg9[Leu8]-BK (100-300 nmol), produced dose-dependent inhibition of DABK (100 nmol)-induced paw oedema in LPS-treated animals with mean IC50 of 134 nmol, while the selective B2 antagonists, Hoe 140 and NPC 17731 (each 10 nmol), had no effect.5 Treatment of animals with dexamethasone (0.5 mg kg-', 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 LPSpretreated 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 PGE2, prostacyclin (PGI2), calcitonin-generelated 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: PGE2 + DABK (0.31 + 0.03), PG12 + 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 B1 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 ID50s (nmol) of: 180, 160, 139 and 135 in the presence of PGE2, PGI2, SP and 5-HT, respectively.

Neutral Endopeptidase Up-Regulation in Isolated Human Umbilical Artery: Involvement in Desensitization of Bradykinin-Induced Vasoconstrictor Effects

“…Similar findings have been reported in other models in which sensitization of responses mediated by BKB 1 receptor is associated with a clear reduction of BKB 2 receptor-mediated effects (Cruwys et al, 1994;Campos et al, 1996;El Sayah et al, 2006). For instance, Campos et al (1996) have shown that LPS causes an increase in BKB 1 receptor-mediated rat paw edema, accompanied by a patent drop in the BKB 2 receptor-mediated edematogenic response. Recently, El Sayah et al (2006) have reported that BKinduced contractile responses in isolated LPS-treated pig iris sphincter muscle are markedly reduced in a time-dependent process.…”

“…This molecular phenomenon results in a marked sensitization of responses elicited by BKB 1 receptor agonists (Marceau et al, 1998). In contrast, it has been shown that BKB 2 receptor-mediated responses can be desensitized, through mechanisms not yet fully elucidated, after prolonged exposure to proinflammatory stimuli (Cruwys et al, 1994;Campos et al, 1996;El Sayah et al, 2006). Although it has been shown that BK-induced contractile responses in human umbilical artery (HUA) are mediated by BKB 2 receptor subtype activation (Feletou et al, 1995;Abbas et al, 1998), possible changes in BK-mediated effects after prolonged in vitro incubation have not been yet analyzed in this tissue.…”

In vitro-induced human airway hyperresponsiveness to bradykinin

“…The B 1 type receptor has, however, attracted interest because of its apparent ❏ upregulation following some types of tissue inflammation and, consequently, the view that B 2 receptors dominate kinin pharmacology may be tempered by the fact that inflamed tissue may exhibit an enhanced response to kinins through B 1 receptor upregulation [21]. Indeed, upregulation of response to the B 1 receptor agonist des-Arg 9 -bradykinin and de novo synthesis of B 1 receptor was demonstrated after prolonged incubation of tissues in Krebs solution [22,23] and was increased by LPS [24] or IL-1β [25,26]. B 1 receptor upregulation within only 1 h is unlikely.…”

Bach1 Deficiency Ameliorates Hepatic Injury in a Mouse Model

“…Carrageenin, a waterextractable polysaccharide obtained from various seaweeds, induces macrophage accumulation in fluid exudates from subcutaneous chambers in dogs (Hou et al 2004). Carrageenin activates kinin release and induces kinin B1 receptor (Campos et al 1996;Decarie et al 1996;Ni et al 2003). Bradykinin, one of kinins, enhances vascular permeability and then causes inflammatory edema.…”