Potentiation of erectile response and cAMP accumulation by combination of prostaglandin E-1 and rolipram, a selective inhibitor of the type 4 phosphodiesterase (PDE 4)

Purpose: Phosphodiesterases (PDEs) are an important component of the signal transduction pathway during the erectile response. To determine the PDE is oforms in the corpora cavernosa in the cat and to establish the functional presence of PDE 4 in human cavernosal tissue, the erectile response to intr acavernosal phosphodiesterase (PDE) inhibitors alone and the combination of PDE inhibitors and prostaglandin E-1 (PGE(1)) was evaluated in the anesthe tized cat. The in vitro formation of cAMP and cGMP in human cavernosal smoo th muscle cells (HCSMCs) treated with PGE(1) and rolipram in primary cultur e was also measured. Materials and Methods: In pentobarbital-anesthetized cats, increases in int racavernosal pressure, penile length, and duration of erectile response wer e determined after intracavernosal injections of(i) the type 3 cAMP-specifi c, cGMP-inhibitable PDE inhibitor, milrinone, (ii) the type 4 cAMP-specific PDE inhibitor, rolipram, (iii) the type 5 cGMP-specific PDE inhibitor, zap rinast, and (iv) the combination of rolipram and PGE(1). Systemic arterial pressure was concurrently assessed in these experiments. All responses to P DE inhibitors were compared with a control triple-drug combination comprise d of papaverine (1.65 mg.), PGE(1) (0.5 mu g.), and phentolamine (25 mu g.) . HCSMCs were incubated with PGE(1) (3 mu M) and rolipram (10 mu M) individ ually or in combination up to 2 hours at 37C. The intracellular cAMP and cG MP was extracted by cold absolute ethanol and measured (pmol./10(6) cells) by a commercially available EIA kit. Results: Milrinone(3 to 100 mu g.), rolipram (3 to 100 mu g.), and zaprinas t (3 to 100 mu g.) induced dose-dependent increases in intracavernosal pres sure and penile length (p <0.05) when administered intracavernosally. The m aximum increase in cavernosal pressure in response to zaprinast was associa ted with no significant change in systemic arterial pressure. When rolipram was combined with PGE(1) (0.1 mu g.), the increases in intracavernosal pre ssure and the duration of erectile response were significantly higher (p <0 .05) and longer (p <0.05) than those observed when rolipram alone was injec ted intracavernosally. PGE(1) (3 mu M) and rolipram (10 mu M) produced sign ificant increases (p <0.05) in the accumulation of intracellular cAMP level s in HCSMCs in primary culture above those of the baseline values while int racellular levels of cGMP did not change. Conclusions: PDE inhibitors administered intracavernosally caused dose-depe ndent increases in cavernosal pressure in the cat;. When a specific cAMP PD E inhibitor was combined with PGE(1), the erectile response was enhanced an d intracellular levels of cAMP were increased in HCSMCs in primary culture. These data suggest further exploration of the combination of various PDE i nhibitors and PGE(1) in the pharmacologic treatment of erectile dysfunction and provide functional evidence for the presence of PDE 4 isoenzyme in hum an penile cavernosal cells.