ED is closely associated with its comorbidities (hypertension, dyslipidemia and lower urinary tract symptoms (LUTS)). Therefore, several drugs have been prescribed simultaneously with PDE5 inhibitors. If a specific medication for ED comorbidities has enhancing effects on PDE5 inhibitors, it offers alternative combination therapy in nonresponders to monotherapy with PDE5 inhibitors and allows clinicians to treat ED and its comorbidities simultaneously. To establish theoretical basis of choosing an appropriate medication for ED and concomitant disease, we examined the effects combining a PDE5 inhibitor with representative drugs for hypertension, dyslipidemia and LUTS on relaxing the corpus cavernosum of rabbits using the organbath technique. The effect of mirodenafil on relaxing phenylephrine-induced cavernosal contractions was significantly enhanced by the presence of 10 À4 M losartan, 10 À6 M nifedipine, 10 À6 M amlodipine, 10 À7 M doxazosin and 10 À9 M tamsulosin (Po0.05). The maximum relaxation effects were 47.2 ± 3.8%, 57.6 ± 2.6%, 64.0 ± 3.7%, 76.1 ± 5.7% and 71.7 ± 5.4%, respectively. Enalapril and simvastatin had no enhancing effects. The relaxation induced by sodium nitroprusside alone (39.0±4.0%) was significantly enhanced in the presence of the 10 À4 M losartan (66.0 ± 6.0%, Po0.05). Tetraethylammonium (1 mM) significantly inhibited the enhancement effects of tamsulosin and doxazosin on mirodenafil-induced relaxation (doxazosin: 76.1 ± 5.7% vs 45.3 ± 2.3%; tamsulosin: 71.7±5.4% vs 48.1±3.5%). On the basis of these findings, losartan seemed to induce synergistic effects through an interaction with nitric oxide. In addition, K þ channel activation could be one of the mechanisms for the synergistic effect of combining mirodenafil with doxazosin or tamsulosin. We believe that the combination of a PDE5 inhibitor with losartan, nifedipine, amlodipine, doxazosin or tamsulosin could be a pharmacologic strategy for simultaneously treating ED and its comorbidities and increasing response rates to PDE5 inhibitors.International Journal of Impotence Research (2012) 24, 221--227; doi:10.1038/ijir.2012; published online 5 July 2012Keywords: comorbidity; ED; PDE5 inhibitor INTRODUCTION ED is a common condition, with a reported prevalence of 52% in men aged 40--70 years in the United States 1 and 49% in men aged 50--80 years in Europe.2 It can affect patients' lives in different ways, including disrupting interpersonal relationships, interfering with sexual life, causing problems with partners and increasing stress, all of which make ED a major quality of life issue.