Antiangiogenic effects of spironolactone and other potassium-sparing diuretics in human umbilical vein endothelial cells and in fibrin gel chambers implanted in rats.
OBJECTIVE
Potassium-sparing diuretics have different effects on angiogenesis that may mediate some abilities to treat cardiovascular diseases. The aim of the current study was to compare the effects of spironolactone and an active metabolite, canrenone, or a derivative, eplerenone, and amiloride, a diuretic without affecting mineralocorticoid activity, on the proliferation of human umbilical vein endothelial cells (HUVEC) and on angiogenesis in fibrin gel chambers implanted in rats.


METHODS
We measured the effects of spironolactone, canrenone, eplerenone, and amiloride on the proliferation of HUVEC in the presence or absence of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). We also examined the effects of these compounds on migration and capillary tube formation by HUVEC. Finally, the effects of the compounds on neovessel formation in vivo were investigated by implanting Wistar rats for 14 days with perforated Plexiglas chambers containing rat fibrin.


RESULTS
Spironolactone and amiloride inhibited the proliferation of HUVEC, but canrenone and eplerenone had no effect. The inhibitory effect of spironolactone was not prevented by VEGF or bFGF. Aldosterone had no effect on spironolactone-induced inhibition of HUVEC proliferation. Spironolactone induced a dose-dependent reduction of both cell chemotaxis and capillary tube formation. In fibrin gel chambers, spironolactone and amiloride significantly reduced the numbers of both peripheral and central neovessels. Canrenone and eplerenone, in contrast, had no antiangiogenic effect.


CONCLUSIONS
Spironolactone and amiloride significantly inhibited angiogenesis in vitro and in the fibrin gel chamber in vivo. Spironolactone antiangiogenic effects are unrelated to antimineralocorticoid activity.
Miternique-Grosse
Anne
A
Laboratoire de Recherche sur l'Angiogenèse, Université Louis Pasteur, Faculté de Médecine, Strasbourg F-67085, France.
Griffon
Christophe
C
Siegel
Luz
L
Neuville
Agnès
A
Weltin
Denis
D
Stephan
Dominique
D
D000584:Amiloride / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D000077545:Eplerenone; D005337:Fibrin / Q000502:physiology; D006801:Humans; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology*; D014471:Umbilical Veins / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D026941:Sodium Channel Blockers; D013148:Spironolactone; D000077545:Eplerenone; D000584:Amiloride; D005337:Fibrin