Effects of the PAF receptor antagonist UK74505 on local and remote reperfusion injuries following ischaemia of the superior mesenteric artery in the rat - PubMed (original) (raw)

Effects of the PAF receptor antagonist UK74505 on local and remote reperfusion injuries following ischaemia of the superior mesenteric artery in the rat

D G Souza et al. Br J Pharmacol. 2000 Dec.

Abstract

The effects of the long lasting and potent PAF receptor antagonist UK74505 were assessed on the local and remote injuries following ischaemia and reperfusion (I/R) of the superior mesenteric artery (SMA) in rats. In a severe model of ischaemia (120 min) and reperfusion (120) injury, in addition to the local and remote increases in vascular permeability and neutrophil accumulation, there was significant tissue haemorrhage, blood neutropenia, systemic hypotension and elevated local and systemic TNF-alpha levels. Post-ischaemic treatment with the selectin blocker fucoidin (10 mg kg(-1)) prevented neutrophil accumulation in tissue and, in consequence, all the local and systemic injuries following severe I/R. Treatment with an optimal dose of UK74505 (1 mg kg(-1)) also reversed local and remote neutrophil accumulation, increases in vascular permeability and intestinal haemorrhage. UK74505 partially inhibited blood neutropenia and reperfusion-induced hypotension. Interestingly, both fucoidin and UK74505 prevented the local, but not systemic, increases of TNF-alpha levels following severe I/R injury, demonstrating an important role of migrating cells for the local production of TNF-alpha. However, the results do not support a role for PAF as an intermediate molecule in the production of systemic TNF-alpha. The beneficial effects of UK74505 and other PAF receptor antagonists in models of I/R injury in animals and the safety of UK74505 use in man warrant further investigations of the use of this drug as preventive measure for I/R injury in humans.

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Figures

Figure 1

Figure 1

Dose-dependent effects of the post-ischaemic treatment with the PAF receptor antagonist, UK74505, on the changes in vascular permeability in the (A) intestine, (B) mesentery and (C) lung following mild ischaemia (30 min) and reperfusion (30 min) injury of the SMA in rats. Changes in vascular permeability were assessed by evaluating the extravasation of Evans blue dye. UK74505 (0.01 to 1.0 mg kg−1) was given i.v. 5 min prior to reperfusion. Control animals received phosphate buffered saline. Results are shown as μg Evans blue per 100 mg of tissue and are the mean±s.e.mean of 4–6 animals in each group. *P<0.01 when compared to sham-operated animals and #P<0.05 when compared to mild I/R animals.

Figure 2

Figure 2

Dose-dependent effects of the post-ischaemic treatment with the PAF receptor antagonist, UK74505, on the accumulation of neutrophils in the (A) intestine, (B) mesentery and (C) lung following mild ischaemia (30 min) and reperfusion (30 min) injury of the SMA in rats. Neutrophil accumulation was assessed by evaluating the tissue levels of myeloperoxidase (MPO). UK74505 (0.01 to 1.0 mg kg−1) was given i.v. 5 min prior to reperfusion. Control animals received phosphate buffered saline. Results are shown as number of neutrophils per 100 mg of tissue and are the mean±s.e.mean of 4–6 animals in each group. *P<0.01 when compared to sham-operated animals and #P<0.01 when compared to mild I/R animals.

Figure 3

Figure 3

Effects of the post-ischaemic treatment with the selectin blocker, fucoidin, or the PAF receptor antagonist, UK74505, on the changes in vascular permeability in the (A) intestine, (B) mesentery and (C) lung following prolonged ischaemia (120 min) and reperfusion (120 min) of the SMA in rats. Changes in vascular permeability were assessed by evaluating the extravasation of Evans blue dye. Fucoidin (10 mg kg−1) or UK74505 (1 mg kg−1) were given i.v. 5 min prior to reperfusion. Control animals received phosphate buffered saline. Results are shown as μg Evans blue per 100 mg of tissue and are the mean±s.e.mean of 6–7 animals in each group. *P<0.01 when compared to sham-operated animals and #P<0.01 when compared to severe I/R animals.

Figure 4

Figure 4

Effects of the post-ischaemic treatment with the selectin blocker, fucoidin, or the PAF receptor antagonist, UK74505, on the accumulation of neutrophils in the (A) intestine, (B) mesentery and (B) lung following prolonged ischaemia (120 min) and reperfusion (120 min) of the SMA in rats. Neutrophil accumulation was assessed by evaluating the tissue levels of myeloperoxidase. Fucoidin (10 mg kg−1) or UK74505 (1 mg kg−1) were given i.v. 5 min prior to reperfusion. Control animals received phosphate buffered saline. Results are shown as number of neutrophils per 100 mg of tissue and are the mean±s.e.mean of 6–7 animals in each group. *P<0.01 when compared to sham-operated animals and #P<0.01 when compared to severe I/R animals.

Figure 5

Figure 5

Effects of the post-ischaemic treatment with the PAF receptor antagonist, UK74505, on the histopathological changes and tissue haemorrhage following prolonged ischaemia (120 min) and reperfusion (120 min) of the SMA in rats. Light photomicrographs of transverse sections of duodenum of vehicle-treated animals (A). In (A), note the increased number of infiltrating neutrophils, epithelial shedding, tissue oedema and haemorrhage (Haematoxylin and eosin stain, ×33). In the insert, note the presence of neutrophils (arrow heads) and loose epithelial cells (×200). Following treatment with UK74505 (B), note only the very mild oedema and scarce number of cells scattered throughout the tissue (×33). Tissue haemorrhage (C) was assessed by evaluating the tissue levels of haemoglobin. Fucoidin (10 mg kg−1) or UK74505 (1 mg kg−1) were given i.v. 5 min prior to reperfusion. Control animals received phosphate buffered saline. Results are shown as mg haemoglobin per mg of tissue and are the mean±s.e.mean of 6–7 animals in each group. *P<0.01 when compared to sham-operated animals and #P<0.01 when compared to severe I/R animals.

Figure 6

Figure 6

Effects of the post-ischaemic treatment with the selectin blocker, fucoidin, or the PAF receptor antagonist, UK74505, on the rapid fall of blood pressure following prolonged ischaemia (120 min) and reperfusion (120 min) of the SMA in rats. Time 0 represents the time when reperfusion occurred. Fucoidin (10 mg kg−1) or UK74505 (1 mg kg−1) were given i.v. 5 min prior to reperfusion. Control animals received phosphate buffered saline. Results are shown as mmHg and are the mean±s.e.mean of five animals in each group. *P<0.05 when compared to sham-operated animals and #P<0.05 when compared to severe I/R animals.

Figure 7

Figure 7

Effects of the post-ischaemic treatment with the selectin blocker, fucoidin, or the PAF receptor antagonist, UK74505, on the levels of circulating neutrophils following prolonged ischaemia (120 min) and reperfusion (120 min) of the SMA in rats. The arrow represents the time when reperfusion started. Fucoidin (10 mg kg−1) or UK74505 (1 mg kg−1) were given i.v. 5 min prior to reperfusion. Control animals received phosphate buffered saline. Results are shown as the number of neutrophils×106 per ml of blood and are the mean±s.e.mean of 5–6 animals in each group. *P<0.01 when compared to sham-operated animals and #P<0.05 when compared to severe I/R animals.

Figure 8

Figure 8

Effects of the post-ischaemic treatment with the selectin blocker, fucoidin, or the PAF receptor antagonist, UK74505, on the (A) systemic and (B) intestinal levels of TNF-α following prolonged ischaemia (120 min) of the SMA in rats. Fucoidin (10 mg kg−1) or UK74505 (1 mg kg−1) were given i.v. 5 min prior to reperfusion. Control animals received phosphate buffered saline. Results are shown as pg TNF-α per ml of plasma or as pg TNF-α per 100 mg of tissue and are the mean±s.e.mean of 5–6 animals in each group. *P<0.01 when compared to sham-operated animals and #P<0.05 when compared to severe I/R animals.

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