Vasoactive agents induce cytotoxicity in cultured human penile smooth muscle cells.

摘要

OBJECTIVES: To evaluate the direct in vitro cytotoxicity of vasoactive agents (papaverine, phentolamine, and prostaglandin E(1) [PGE(1)]) to human penile cavernosal smooth muscle cells. Intracavernous pharmacotherapy with vasoactive agents for male erectile dysfunction has been associated with long-term complications such as a reduction in penile smooth muscle content and fibrosis. METHODS: Human penile cavernosal tissue explants (1 to 2 mm(3) size) were obtained with proper institutional review board approval from patients undergoing penile prosthesis implantation. Primary culture was initiated in Dulbecco's modified Eagles medium containing 10% fetal bovine serum, and monolayer cavernosal cells were grown in 48-well tissue culture dishes. At 60% to 80% confluence, cells were labeled overnight with (51)Na(2)CrO(4) (1.5 microCi) and then incubated with therapeutic concentrations of papaverine (1.5 to 30 mg/mL), phentolamine (0.5 mg/mL), and PGE(1) (5 microg/mL) alone, as well as in combination, for 30 minutes at 37 degrees C. At the end of incubation, an aliquot of supernatant was collected in scintillation vials. The release of cell-free chromium in supernatants was determined in a liquid scintillation counter, and results were expressed as the percentage of cytotoxicity. RESULTS: Papaverine induced a significant dose-dependent increase in chromium release from the cavernosal cells. At therapeutic concentrations, papaverine (30 mg/mL) produced up to 60% cytotoxicity; PGE(1) (5 microg/mL) resulted in 40% toxicity. The combination of papaverine with either PGE(1) or phentolamine had a cumulative toxic effect, and maximal toxicity (70%) was observed with the triple combination. CONCLUSIONS: Papaverine-induced cytotoxicity to cavernosal smooth muscle cells may contribute to the fibrosis and loss of smooth muscle content associated with the intracavernous pharmacotherapy. Quantitative evaluation of in vitro cytotoxicity in human cavernosal smooth muscle cell culture may be important in the development of new intracavernosal vasoactive agents.