Endothelin-1 induces organ-specific histamine liberation and neutrophil granulocyte accumulation in the rat

Enhanced production of endothelin-1 (ET-1) and the activation of mast cells (MCs) have been implicated in granulocyte sequestration. We compared local consequences of transient increases in circulating ET-1 in three separate circulatory beds in pentobarbital-anesthetized Wistar rats.

We determined whether pretreatment with ET-A receptor antagonist ETR-P1/fl peptide and MC stabilizer sodium cromoglycate would influence histamine- and granulocyte responses induced by 1 nmol/kg ET-1 iv. Plasma and tissue histamine contents were monitored, myeloperoxidase (MPO) level was determined from heart, lung and intestinal biopsies.

The ET-1 infusion caused significant plasma histamine elevations, enhanced MPO activity in all organs, decreased tissue histamine content in the lung and small bowel by approx. 50% , while the histamine content of heart did not change. ETR-P1/fl significantly decreased ET-1-induced intestinal and heart MPO changes, and inhibited histamine depletion in the small intestine but not in lung and heart tissues. Sodium cromoglycate inhibited the ET-1-induced neutrophil accumulation in the heart and intestine and did not influence MPO activity in the lung.

ET-1 release participates in the process of histamine liberation and subsequent secondary granulocyte accumulation through tissue-specific activation of ET-A receptors. ET-1-induced direct effects are predominating in pulmonary neutrophil activation, while MC-associated secondary changes play important roles in intestinal granulocyte recruitment.