Influence of dopexamine on leukocyte adherence and vascular permeability during endotoxemia in rat mesenteric venules

Introduction

Dopexamine is a β2-adrenoceptor agonist with dopamine 1 and 2 receptor properties. It was recently shown that dopexamine was able to preserve the hepatic ultrastructure in a porcine sepsis model [1]. It seemed likely that the anti-inflammatory properties of dopexamine were associated with β2-adrenoceptor properties. The adherence of leukocytes to the vascular endothelium is an important step in the development of sepsis. The objective of this study was to investigate whether pretreatment with dopexamine could attenuate leukocyte adherence to venular endothelium and influence vascular permeability in post-capillary venules of the rat mesentery during endotoxemia.

Materials and methods

Male Wistar rats were laparotomized under pentobarbital anesthesia and mesentery was exposed under an in vivo videomicroscope. Endotoxemia was induced by infusion of 2 mg/kg/h lipopolysaccharides (LPS). Leukocyte adherence (LA) and vascular permeability (VP) in postcapillary mesenteric venules were determined before (0 min) and 120 min after induction of endotoxemia. Capillary leakage was determined by measuring the extravasation of FITC-labeled albumin given prior endotoxemia. Venular wall shear rate was calculated by measuring mean erythrocyte velocity and venular diameter. Group B (n = 8) was treated with dopexamine (2.5 μg/kg/h). The infusion was started 30 min prior endotoxemia. Group A (n = 8) only received an equivalent volume of NaCl. Group C (n = 8) was treated with dopexamine (2.5 μg/kg/h), as well, but the β2-effect was antagonized by the β2-adrenoceptor antagonist ICI 118551. Data are mean ± SD. Statistical analysis was performed using two-way ANOVA followed by Scheffe's test.

Results

In the group treated with NaCl (group A) the number of adherent leukocytes increased from 4 ± 1 per 100 μm venule length at 0 min to 13 ± 1 at 120 min. In the dopexamine group (group B) LA increased from 4 ± 1 per 100 μm venule length at 0 min to only 8 ± 2 at 120 min, showing a significant difference between the groups after 120 min (P < 0.01). In the dopexamine + ICI 118551 treated group (group C) LA increased, as well (4 ± 1 at 0 min and 8 ± 2 at 120 min), but was significantly lower compared to group A (P < 0.01). Venular wall shear rates were significantly higher in the groups treated with dopexamine (groups B and C). Vascular permeability expressed as ratio of graylevels of the video frame in and outside of the investigated venule increased in the NaCl-treated rats from 7 ± 1% at 0 min to 48 ± 12% at 120 min. In the dopexamine group it increased, as well, but only from 8 ± 2% to 30 ± 12%, showing a significant difference between the groups at 120 min (P < 0.01). In group C the ratio increased from 9 ± 1% to 38 ± 12%. This was significantly higher compared to group B.

Discussion

Dopexamine is able to attenuate leukocyte adherence and vascular permeabilty in post-capillary venules during endotoxemia. The beneficial effect of dopexamine on leukocyte adherence could not be antagonized by the β2-adrenoceptor antagonist. This suggests that a higher wall shear rate caused by a higher blood flow in the venules is mainly responsible for the lower LA. However, the attenuating effect of dopexamine on vascular permeability during sepsis is apparently a β2-adrenoceptor mediated process.