[The effect of endothelin on granulocyte-endothelium interaction].
OBJECTIVE
The interaction of activated granulocytes and endothelial cells influences not only capillary permeability but also increases pulmonary vascular resistance. The aim of this study was to evaluate the role of endothelin-1 (ET-1) during the granulocyte-mediated increase in pulmonary pressure.


METHODS
The experiments were performed on isolated and ventilated rabbit lungs perfused with a blood-free buffer solution. Isolated, washed human granulocytes were injected into the pulmonary artery and stimulated by 10(-6) M N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP). Pulmonary arterial pressure (PAP) was continuously registered, and perfusate samples were taken to determine ET-1 and eicosanoid levels. To analyse the role of ET-1, six lung preparations were pretreated with the ETA receptor antagonist BQ123 (10(-6) M) prior to FMLP injection. To analyse the role of thromboxane A2, six additional lung preparations were pretreated with the cyclooxygenase inhibitor diclofenac (10 micrograms/ml). Additionally, granulocytes were stimulated in vitro with FMLP for 15 min, and ET-1 concentration was measured in the supernatant.


RESULTS
Immediately after FMLP injection, PAP increased to 18.5 +/- 1.6 mmHg, descending to values 4.8 +/- 0.8 mmHg above the baseline after 15 min. At this time, ET-1 could be detected in the perfusate. The concentrations of the cyclooxygenase products thromboxane A2 and prostacyclin remained nearly unchanged during the observation period. Pretreatment with the ETA receptor antagonist BQ123 significantly reduced the pressure response after FMLP injection (p < 0.01 at 5 and 10 min; p < 0.05 at 15 and 30 min). Pretreatment with the cycloocygenase inhibitor diclofenac failed to inhibit the pressure reaction evoked by activated granulocytes. In contrast to this, ET-1 was not detected after in vitro stimulation of granulocytes.


CONCLUSIONS
ET-1 is involved as a mediator of pulmonary vasoconstriction due to granulocyte activation. Since in vitro FMLP-stimulation of human granulocytes did not induce ET-1 production, it seems likely that isolated activated granulocytes would not produce ET-1, but provoke the endothelial cells to release ET-1 in the pulmonary circulation.
Schmeck
J
J
Institut für Anaesthesiologie und Operative Intensivmedizin, Fakultät für Klinische Medizin Mannheim, Universität Heidelberg.
Janzen
R
R
Koch
T
T
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006098:Granulocytes / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000166:cytology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D013268:Stimulation, Chemical
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D009240:N-Formylmethionine Leucyl-Phenylalanine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
Bedeutung von Endothelin bei der Granulozyten-Endothel-Interaktion.