© 1992 by European Society of Cardiology
Copyright © 1992, European Society of Cardiology
WEB 2086 inhibits neutrophil dependent increases in coronary resistance in blood perfused rabbit heart
Cardiovascular Research Unit, Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, United Kingdom: J R Tippins, J W Antoniw, A Maseri
Department of Histopathology, Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, United Kingdom: M R Alison
Department of Haematology, Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, United Kingdom: B Garvey
Correspondence to Dr Tippins, at Biochemistry Department, Imperial College of Science, Technology and Medicine, London SW7 2AY.
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.
KEYWORDS platelet activating factor; vascular resistance; neutrophil; formyl-methionyl-leucyl-phenylalanine; coronary
We thank Hammersmith and Queen Charlotte's Special Health Authority and Pfizer Central Research, UK for funding, Boehringer Ingelheim Ltd for the gift of WEB 2086. and the staff of the Haematology Department, Hammersmith Hospital, for carrying out the rabbit blood cell counts.
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