PURPOSE: We investigated forskolin, a direct adenylate cyclase activator, as an intracavernosal vasoactive agent in management of vasculogenic impotence. MATERIALS AND METHODS: Concentration responses for forskolin and prostaglandin E1 induced relaxation of phenylephrine precontracted strips of human corpus cavernosum smooth muscle were constructed in vitro. Cyclic adenosine monophosphate (cAMP) synthesis was determined with papaverine, phentolamine, prostaglandin E1 and forskolin in human corpus cavernosum smooth muscle cell cultures. Dose-dependent hemodynamic responses to intracavernosal forskolin (5 to 20 micrograms) were evaluated in a New Zealand White rabbit model. Safety and efficacy outcome data were obtained in vasculogenically impotent patients who signed informed consent and met strict inclusion and exclusion criteria that included having had standard self-injection therapies fail. RESULTS: In vitro forskolin and prostaglandin E1 alone caused concentration dependent relaxation with an EC50 of approximately 200 nm. and 16 nm., respectively. When the 2 agents were combined, the concentration response curve for relaxation shifted to the left. cAMP production was highest in cells treated with prostaglandin E1 and forskolin and was unaffected by papaverine or phentolamine. In 3 animals, equilibrium intracavernosal pressure and duration of erection had a dose dependent increase. Clinical investigation in 31 patients showed no adverse events with a mean of 14 +/- 4, range 11 to 18 months of followup. Overall 61% reported improvement in rigidity and/or erection duration using intracavernosal forskolin (98 micrograms./ml.), papaverine (29 mg./ml.), phentolamine (0.98 mg./ml.) and prostaglandin E1 (9.8 micrograms./ml.). CONCLUSIONS: Forskolin is a United States Food and Drug Administration nonapproved vasoactive agent that acts in synergism with prostaglandin E1 to induce smooth muscle relaxation. In combination with other vasoactive agents, forskolin has demonstrated preliminary safety and efficacy in patients with vasculogenic impotence resistant to standard 3-agent pharmacotherapy.
PURPOSE: We investigated forskolin, a direct adenylate cyclase activator, as an intracavernosal vasoactive agent in management of vasculogenic impotence. MATERIALS AND METHODS: Concentration responses for forskolin and prostaglandin E1 induced relaxation of phenylephrine precontracted strips of human corpus cavernosum smooth muscle were constructed in vitro. Cyclic adenosine monophosphate (cAMP) synthesis was determined with papaverine, phentolamine, prostaglandin E1 and forskolin in human corpus cavernosum smooth muscle cell cultures. Dose-dependent hemodynamic responses to intracavernosal forskolin (5 to 20 micrograms) were evaluated in a New Zealand White rabbit model. Safety and efficacy outcome data were obtained in vasculogenically impotentpatients who signed informed consent and met strict inclusion and exclusion criteria that included having had standard self-injection therapies fail. RESULTS: In vitro forskolin and prostaglandin E1 alone caused concentration dependent relaxation with an EC50 of approximately 200 nm. and 16 nm., respectively. When the 2 agents were combined, the concentration response curve for relaxation shifted to the left. cAMP production was highest in cells treated with prostaglandin E1 and forskolin and was unaffected by papaverine or phentolamine. In 3 animals, equilibrium intracavernosal pressure and duration of erection had a dose dependent increase. Clinical investigation in 31 patients showed no adverse events with a mean of 14 +/- 4, range 11 to 18 months of followup. Overall 61% reported improvement in rigidity and/or erection duration using intracavernosal forskolin (98 micrograms./ml.), papaverine (29 mg./ml.), phentolamine (0.98 mg./ml.) and prostaglandin E1 (9.8 micrograms./ml.). CONCLUSIONS:Forskolin is a United States Food and Drug Administration nonapproved vasoactive agent that acts in synergism with prostaglandin E1 to induce smooth muscle relaxation. In combination with other vasoactive agents, forskolin has demonstrated preliminary safety and efficacy in patients with vasculogenic impotence resistant to standard 3-agent pharmacotherapy.
Authors: K Joseph Hurt; Sena F Sezen; Gwen F Lagoda; Biljana Musicki; Gerald A Rameau; Solomon H Snyder; Arthur L Burnett Journal: Proc Natl Acad Sci U S A Date: 2012-09-24 Impact factor: 11.205