EFFECTS OF SILDENAFIL ON THE RELAXATION OF HUMAN CORPUS CAVERNOSUM TISSUE IN-VITRO AND ON THE ACTIVITIES OF CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE ISOZYMES

Purpose: Sildenafil, an inhibitor of cGMP-specific phosphodiesterase 5 (PDE5), is currently undergoing evaluation as an oral therapy for pen ile erectile dysfunction. The aims of this study were to investigate t he mechanism of action of sildenafil on the neurogenic relaxation of h uman corpus cavernosum (HCC) in vitro and to determine the activity of sildenafil against a full range of PDE isozymes. Materials and Method s: Strips of HCC tissue were precontracted with phenylephrine. Relaxat ion responses resulting from electrical field stimulation (EFS) were t hen determined in the presence and absence of sildenafil. The effects of sildenafil on PDE1 to 5 prepared from human tissues and PDE6 from b ovine retina were determined by measuring the conversion of [H-3]-cGMP or [H-3]-cAMP to their respective [H-3]-5'-mononucleotides. Results: Sildenafil (0.001 to 1 mu M) enhanced the EFS-induced, nitric oxide (N O) dependent, relaxation of HCC in a concentration-dependent manner to a maximum of 3 times the pretreatment level at 1 mu M sildenafil. Com pared with zaprinast, an early PDE5 inhibitor, sildenafil was approxim ately 240-fold more potent, inhibiting PDE5 from HCC with a geometric mean IC50 of 3.5 nM. For sildenafil, IC50 values for inhibition of PDE 1 to 4 were 80 to more than 8500 times greater than that for PDE5 and the IC50 for PDE6 (33 nM) was approximately 9-fold greater. Conclusion s: The data support the proposal that enhancement of penile erection b y sildenafil in patients with erectile dysfunction involves potentiati on of the NO-stimulated cGMP signal mediating relaxation of cavernosal smooth muscle during sexual stimulation. Sildenafil is a potent inhib itor of PDE5 from HCC, with high selectivity for PDE5 relative to othe r PDE isozymes.