Role of tachykinin NK receptors on the local and remote injuries following ischaemia and reperfusion of the superior mesenteric artery in the rat

Neuropeptides acting on tachykinin NK receptors play an important role in the amplification of inflammatory responses. We have assessed the effects of tachykinin NK receptor blockade on the injuries following intestinal ischaemia and reperfusion (I/R) in rats. The tachykinin NK1 receptor antagonist SR140333 dose‐dependently (0.05 to 0.5 mg kg−1) suppressed the local (intestine) and remote (lung) increases in vascular permeability and neutrophil recruitment following mild I/R injury. A structurally‐distinct NK1 receptor antagonist, CP99,994, but not tachykinin NK2 or NK3 receptor antagonists also suppressed mild I/R injury. Neonatal pretreatment with capsaicin effectively depleted sensory neurons and abrogated the injuries following mild I/R. Treatment with SR140333 (0.5 mg kg−1) significantly reversed severe reperfusion‐induced local and remote increases in vascular permeability, neutrophil recruitment, intestinal haemorrhage and blood neutropaenia, but did not prevent the lethality associated with severe I/R. Post‐ischaemic treatment with SR140333 significantly inhibited the elevations of TNF‐α in the intestine and lung, but not serum, following severe I/R. The increase in the concentrations of IL‐10 in the lung and serum were also suppressed. Post‐ischaemic blockade of tachykinin NK1 receptors markedly inhibited the local and remote injuries, but not lethality, following reperfusion of the SMA in rats. Neuropeptides, possibly substance P, released from sensory nerves appear to account for the activation of these tachykinin NK1 receptors. Antagonists of the tachykinin NK1 receptor may be useful adjuncts in the treatment of the injuries which occur following reperfusion of an ischaemic vascular territory. British Journal of Pharmacology (2002) 135, 303–312; doi:10.1038/sj.bjp.0704464