WEB 2086 inhibits neutrophil dependent increases in coronary resistance in blood perfused rabbit heart

Objective: The aim was to investigate the mechanism of the pressor action of the chemotactic peptide formyl-mefhionyl-Ieucyl-phenylalanine in the blood perfused Langendorff preparation of the isolated rabbit heart; and in particular to establish whether the response was dependent on the presence of neutrophils and whether the release of platelet activating factor contributed to the pressor effect. Methods: An isolated rabbit heart was perfused with blood from an anaesthetised support rabbit. Formyl-methionyl-leucyl-phenylalanine was injected intra-arterially proximal to the isolated heart and measures of cardiac performance recorded. In some experiments the support animal was depleted of neutrophils by pretreatment with mechlorethamine while in others the specific platelet activating factor receptor antagonist WEB 2086 was given to the support animal before formyl-mefhionyl-leucyl-phenylalanine. Differential blood cell counts were determined throughout the course of each experiment. Each heart was examined histologically after the experiment. Results: Formyl-methionyl-leucyl-phenylalanine caused a significant rise in perfusion pressure which was virtually abolished by leucocyte depletion of the support animal. The response could also be reduced by about 80% with intravenous WEB 2086. Histological examination of the perfused hearts showed that the number of accumulated neutrophils was very variable and not correlated with the rise in perfusion pressure. There was no significant difference between control hearts and those receiving WEB 2086. Conclusions: The results confirm previous reports that the response to formyl-methionyl-leucyl-phenylalanine is neutrophil dependent and show that this model of a blood perfused heart can be used successfully to examine the response to a leucocyte dependent stimulus. The results also suggest that the response to formyl-methionyl-leucyl-phenylalanine may not only be due to physical obstruction of the coronary circulation or "neutrophil plugging", but may also be due to the release of platelet activating factor.