Phosphoramidon blocks big-endothelin-1 but not endothelin-1 enhancement of vascular permeability in the rat.
1. Changes in vascular permeability following intravenous injections of human big-endothelin-1 (big-ET-1) and endothelin-1 (ET-1) were measured by extravasation of Evans blue dye (EB, 20 mg kg-1) in selected tissues. 2. A low dose of big-ET-1 (40 pmol kg-1) failed to alter vascular permeability but a dose of 400 pmol kg-1 increased EB extravasation in the trachea, upper and lower bronchi, and lung parenchyma by 55 to 69% (P < 0.05). Vascular permeability was also enhanced in the liver, spleen, kidney, heart, and diaphragm by 20, 14, 41, 25, and 67%, respectively (P < 0.05). 3. Upon injection of ET-1 (400 pmol kg-1), EB extravasation increased in the upper and lower bronchi, lung parenchyma, liver, pancreas, kidney, heart, and diaphragm. 4. Administration of ET-1 and big-ET-1 was not associated with significant systemic responses. 5. Pretreatment with phosphoramidon (PA) blocked the response to big-ET-1 in all tissues examined but this inhibitor failed to alter the response to ET-1. 6. We conclude from these results that the dose-dependent increase in vascular permeability induced by big-ET-1 in various tissues follows its conversion to ET-1 by the endothelin converting enzyme, a PA-sensitive process.
Lehoux
S
S
Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.
Plante
G E
GE
Sirois
M G
MG
Sirois
P
P
D'Orléans-Juste
P
P
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001980:Bronchi / Q000098:blood supply; D002199:Capillary Permeability / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects; D019332:Endothelin-1; D016232:Endothelins / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D005070:Evans Blue / Q000378:metabolism; D006020:Glycopeptides / Q000494:pharmacology*; D007275:Injections, Intravenous; D007668:Kidney / Q000098:blood supply; D008168:Lung / Q000098:blood supply; D008297:Male; D011498:Protein Precursors / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000098:blood supply; D014132:Trachea / Q000098:blood supply
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; D005070:Evans Blue; C008890:phosphoramidon