Potentiation of erectile response and cAMP accumulation by combination of prostaglandin E1 and rolipram, a selective inhibitor of the type 4 phosphodiesterase (PDE 4).

摘要

PURPOSE: Phosphodiesterases (PDEs) are an important component of the signal transduction pathway during the erectile response. To determine the PDE isoforms in the corpora cavernosa in the cat and to establish the functional presence of PDE 4 in human cavernosal tissue, the erectile response to intracavernosal phosphodiesterase (PDE) inhibitors alone and the combination of PDE inhibitors and prostaglandin E1 (PGE1) was evaluated in the anesthetized cat. The in vitro formation of cAMP and cGMP in human cavernosal smooth muscle cells (HCSMCs) treated with PGE1 and rolipram in primary culture was also measured. MATERIALS AND METHODS: In pentobarbital-anesthetized cats, increases in intracavernosal pressure, penile length, and duration of erectile response were determined after intracavernosal injections of (i) the type 3 cAMP-specific, cGMP-inhibitable PDE inhibitor, milrinone, (ii) the type 4 cAMP-specific PDE inhibitor, rolipram, (iii) the type 5 cGMP-specific PDE inhibitor, zaprinast, and (iv) the combination of rolipram and PGE1. Systemic arterial pressure was concurrently assessed in these experiments. All responses to PDE inhibitors were compared with a control triple-drug combination comprised of papaverine (1.65 mg.), PGE1 (0.5 microg.), and phentolamine (25 microg.). HCSMCs were incubated with PGE1 (3 microM) and rolipram (10 microM) individually or in combination up to 2 hours at 37C. The intracellular cAMP and cGMP was extracted by cold absolute ethanol and measured (pmol./10(6) cells) by a commercially available EIA kit. RESULTS: Milrinone (3 to 100 microg.), rolipram (3 to 100 microg.), and zaprinast (3 to 100 microg.) induced dose-dependent increases in intracavernosal pressure and penile length (p <0.05) when administered intracavernosally. The maximum increase in cavernosal pressure in response to zaprinast was associated with no significant change in systemic arterial pressure. When rolipram was combined with PGE1 (0.1 microg.), the increases in intracavernosal pressure and the duration of erectile response were significantly higher (p <0.05) and longer (p <0.05) than those observed when rolipram alone was injected intracavernosally. PGE1 (3 microM) and rolipram (10 microM) produced significant increases (p <0.05) in the accumulation of intracellular cAMP levels in HCSMCs in primary culture above those of the baseline values while intracellular levels of cGMP did not change. CONCLUSIONS: PDE inhibitors administered intracavernosally caused dose-dependent increases in cavernosal pressure in the cat. When a specific cAMP PDE inhibitor was combined with PGE1, the erectile response was enhanced and intracellular levels of cAMP were increased in HCSMCs in primary culture. These data suggest further exploration of the combination of various PDE inhibitors and PGE1 in the pharmacologic treatment of erectile dysfunction and provide functional evidence for the presence of PDE 4 isoenzyme in human penile cavernosal cells.