Cytotoxicity of different intracavernous vasoactive drugs on cultured endothelial cells of human corpus cavernosum penis.
OBJECTIVE
To investigate the cytotoxic effect of prostaglandin E(1) (PGE(1)), a standard combination of papaverine/phentolamine, and a triple mixture of these agents on human cavernosal endothelial cells using a cell culture model. The endothelial layer of the corpus cavernosum plays an important role in signal transduction of penile erection and is directly exposed to vasoactive agents after intracavernous injection for erectile dysfunction.


METHODS
Primary endothelial cells were obtained from the corpus cavernosum of 13 potent patients undergoing penile surgery. Cultured cells were exposed for 30 minutes to physiologic dilutions of 20 microg PGE(1), 30 mg papaverine/1 mg phentolamine, or the same dosages of the triple mixture of these agents, each dissolved in 5 to 50 mL sodium chloride. Lactate dehydrogenase release as a cytotoxicity marker was measured 6 hours after drug exposure, and the total cell metabolic activity was quantified after 48 hours with a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)-based assay. Additionally, the amount of viable cells was identified with a dual fluorescent staining procedure.


RESULTS
The initial release of lactate dehydrogenase was elevated up to 3.2-fold in the concentrated papaverine/phentolamine and triple mixture group compared with PGE(1) and the control. After 48 hours, the papaverine-containing formulations led to a significant dose-dependent decrease in the viable cell count and metabolic activity of the cultures that was not noticed with PGE(1).


CONCLUSIONS
These in vitro data strongly suggest an unfavorable effect of vasoactive agents containing papaverine on cavernosal endothelial cells. Before fibrotic changes of the smooth muscle stroma, the functionally important endothelium of the corpus cavernosum might suffer significantly from intracavernous injection therapy. Therefore, papaverine should no longer be used for this indication.
Schultheiss
Dirk
D
Department of Urology and Pediatric Urology, Hannover Medical School, Germany.
Pilatz
Adrian
A
Gabouev
Alexander I
AI
Schlote
Norbert
N
Wefer
Jörg
J
Mertsching
Heike
H
Sohn
Michael
M
Jonas
Udo
U
Stief
Christian G
CG
D000527:Alprostadil / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D007172:Erectile Dysfunction / Q000188:drug therapy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D010208:Papaverine / Q000633:toxicity*; D010413:Penis / Q000098:blood supply*; D010646:Phentolamine / Q000633:toxicity*; D014665:Vasodilator Agents / Q000633:toxicity*
D014665:Vasodilator Agents; D010208:Papaverine; D007770:L-Lactate Dehydrogenase; D000527:Alprostadil; D010646:Phentolamine