Endotoxin sensitization to kinin B(1) receptor agonist in a non-human primate model: haemodynamic and pro-inflammatory effects.
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 pro-inflammatory 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 microg kg(-1)) or saline intravenously. After 4 h, anaesthetized monkeys were cannulated 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 affect blood pressure after 4 h. dKD reduced blood pressure (E(max): 27+/-4 mmHg; EC(50): 130 pmol kg(-1)) 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(-1) min(-1), 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) significantly reduced oedema induced by dKD (50 nmol). 5. These results suggest LPS up-regulation of B(1) receptor effects in green monkeys. This non-human primate model may be suitable for testing new, selective B(1) antagonists with therapeutic potential as anti-inflammatory agents.
deBlois
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University of Montreal Hospital (CHUM) Research Center, 3840 St. Urbain St., room 7-132B, Montreal, Quebec H2W 1T8, Canada. debloisd@pharmco.umontreal.ca
Horlick
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000473:pathology; D004731:Endotoxins / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007249:Inflammation / Q000473:pathology*; D007609:Kallidin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000819:agonists*
D004731:Endotoxins; D008070:Lipopolysaccharides; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; D001920:Bradykinin