Endotoxin sensitization to kinin B₁ receptor agonist in a non‐human primate model: haemodynamic and pro‐inflammatory effects

Abstract

1 Although endotoxaemia induces kinin B 1 receptors in several animal models, this condition is not documented in primates. This study examined the up-regulation of haemodynamic and proin¯ammatory responses to the B 1 agonist des-Arg 10 -kallidin (dKD) in a non-human primate model. 2 Green monkeys (Cercopithecus aethiops St Kitts) received lipopolysaccharide (LPS; 90 mg kg 71 ) or saline intravenously. After 4 h, anaesthetized monkeys were canulated via the carotid artery to monitor blood pressure changes following intra-arterial injections of dKD or the B 2 agonist bradykinin (BK). Oedema induced by subcutaneous kinin administration was evaluated as the increase in ventral skin folds in anaesthetized monkeys injected with captopril at 4 h to 56 days post-LPS. 3 LPS increased rectal temperature but did not a ect blood pressure after 4 h. dKD reduced blood pressure (E max : 27+4 mmHg; EC 50 : 130 pmol kg 71 ) and increased heart rate (E max : 33 b.p.m.) only after LPS. In contrast, the dose-dependent fall in blood pressure with BK was comparable in all groups. The selective B 1 antagonist [Leu 9 ]dKD (75 ng kg 71 min 71 , intravenously) abolished responses to dKD but not BK. 4 dKD injection induced oedema dose-dependently (2.4+0.1 mm at 150 nmol) only following LPS (at 4 h to 12 days but not 56 days). In contrast, BK-induced oedema was present and stable in all monkeys. Co-administration of [Leu 9 ]dKD (150 nmol) signi®cantly reduced oedema induced by dKD (50 nmol). 5 These results suggest LPS up-regulation of B 1 receptor e ects in green monkeys. This non-human primate model may be suitable for testing new, selective B 1 antagonists with therapeutic potential as anti-in¯ammatory agents.

The Kallikrein-Kinin System: Current and Future Pharmacological Targets

“…Vasodilatation is normally mediated by B2R (274), but under inflammatory conditions, B1R up-regulation mediates kinin-induced vasodilatation and hypotension (275,276). BK-related peptides act as vasodilators through endothelial cells from which secondary mediators are released to affect the vascular smooth muscle.…”

Endogenous Aminopeptidase N Decreases the Potency of Peptide Agonists and Antagonists of the Kinin B1Receptors in the Rabbit Aorta

“…B 1 receptor mediation of ischemia-driven angiogenesis has been shown (Emanueli et al, 2002). Of relevance to sepsis, vascular B 1 receptor expression-mediating hypotension also occurs following sublethal lipopolysaccharide treatments in various species (McLean et al, 1999;Schanstra et al, 2000;deBlois and Horlick, 2001;Leeb-Lundberg et al, 2005). Whether inducible B 1 receptors mediate a part of the therapeutic or This work was supported by the Canadian Institutes of Health Research Grant MOP-14077 and the Fonds de la Recherche en Santé du Québec (studentship award to J.-P.F.…”

Expression of kinin B1 receptor in fresh or cultured rabbit aortic smooth muscle: role of NF-κB

“…The B 1 R is now widely recognized as an inducible gene, as certain forms of tissue injury trigger its de novo synthesis in tissues. For instance, bacterial lipopolysaccharide (LPS) injection in several animal species induces B 1 R expression at the vascular cell level (14,27,32). The analysis of isolated rabbit blood vessel contractility has provided early insight into the inducible behavior, as the preparations, initially insensitive to kinins, specifically developed increasing maximal response (E max ) in response to B 1 R agonists in a time-, temperature-, and metabolism-dependent manner (7,40).…”