Endotoxin sensitization to kinin B(1) 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 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.

Figure 1

Dose-dependent decrease in mean arterial blood pressure in response to intra-arterial injections of (a) dKD or (b) BK in green monkeys anaesthetized 4 h after intravenous injection of LPS (90 ;μg kg⁻¹) or saline vehicle. ^*Significantly different (P<0.05) from response in saline-pretreated monkeys (n=5–6 per group).

Figure 2

Representative tracing of blood pressure changes in response to intra-arterial bolus injection of saline vehicle (100 ;μl), des-Arg¹⁰-kallidin (dKD) or bradykinin (BK) in anaesthetized green monkeys. Animals were anaesthetized 4 h after intravenous injection of LPS (90 ;μg kg⁻¹).

Figure 3

Time course for the decrease in mean arterial blood pressure and increase in heart rate in response to intra-arterial injection of (a) dKD (1 ;μmol kg⁻¹) or (b) BK (1 ;μmol kg⁻¹) in green monkeys. Heart rate before dKD or BK injection was 157±3 and 153±4 b.p.m., respectively. Animals were anaesthetized 4 h after intravenous injection of LPS (90 ;μg kg⁻¹). ^* Significantly different (P<0.05) from pre-injection values (n=6 per group).

Figure 4

Decrease in mean arterial blood pressure in response to intra-arterial injection of (a) dKD (1 nmol kg⁻¹) or (b) BK (100 pmol kg⁻¹) during intravenous infusion of [Leu⁹]dKD (75 nmol kg⁻¹ min⁻¹) or 5 min after the end of [Leu⁹]dKD infusion in green monkeys. Animals were anaesthetized 4 h after intravenous injection of LPS (90 μg kg⁻¹). ^* Significantly different (P<0.05) from response obtained during [Leu⁹]dKD infusion (n=6 per group).

Figure 5

Oedema development in response to sub-cutaneous injections of Ringer's lactate vehicle (100 μl), dKD (75 nmol) or BK (100 nmol) in ventral skin of anaesthetized green monkeys at (a) 24 h following pre-treatment with saline (1 ml; n=7), or at (b) 4 h (n=3) (c) 24 h (n=6) and (d) 12 days (n=8) following pre-treatment with LPS (90 μg kg⁻¹). ^* Significantly different (P<0.05) from response induced by vehicle.

Figure 6

Dose-response relationship for maximal oedema development in response to subcutaneous injection of dKD (1–150 >nmol) in ventral skin of green monkeys anaesthetized 4 h after pre-treatment with LPS (90 μg kg⁻¹; n=7).

Figure 7

Inhibition by [Leu⁹]dKD (150 nmol) of oedema induced by subcutaneous injection of dKD (50 nmol) in green monkeys. [Leu⁹]dKD was co-injected with dKD. ^* Significantly different (P−0.05) from response without [Leu⁹]dKD (n=7).