ED 13. Effects of combined use of phosphodiesterase-5 inhibitor and medications for hypertension, lower urinary tract symptoms and dyslipidemia on tone of corporal tissue

Objective: Erectile dysfunction (ED) is closely associated with its comorbidities (hypertension, dyslipidemia, and lower urinary tract symptoms). Therefore, several drugs have been prescribed simultaneously with phosphodiesterase-5 (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 of combination Phosphodiesterase 5 inhibitor (PDE5I) with drug for ED comorbidities (hypertension, lower urinary tract symptoms, and dyslipidemia) on relaxation of rabbit corpus cavernosum (CC).

Methods: Contractility of CC strips was studied in organ baths. Concentration-response curves to mirodenafil were generated on phenylephrine (PE) (10^-5 M)-precontracted strips before and after preincubation of losartan (10^-5 M, 10^-4 M), amlodipine (10^-7 M, 10^-6 M), nifedipine (10^-7 M, 10^-6 M), enalapril (10^-6 M, 10^-5 M), doxazosin (10^-8 M, 10^-7 M), tamsulosin (10^-10 M, 10^-9 M), or simvastatin(10^-6 M, 10^-5 M). Another organ bath studies were done to determine the losartan/nitric oxide interaction on CC smooth muscle function. We also determined role of potassium channel opening in synergistic effect of mirodenafil and alpha adrenergic blockers.

Results: The effect of mirodenafil to relax PE-induced CC tone was significantly enhanced by preincubation of losartan, nifedipine, amlodipine, tamsulosin, and doxazosin. The maximal effect was 35.8±2.0% of inhibition of PE-induced tone for mirodenafil alone vs. 47.2±3.8% for preincubation of 10^-4 M losartan, 57.6±2.6% for 10^-6 M nifedipine, 64.0±3.7% for 10^-6 M amlodipine, 76.1±5.7% for 10^-7 M doxazosin, and 71.7±5.4% for 10^-9 M tamsulosin. But enalapril and simvastatin had no additional effect. Relaxation of CC smooth muscle induced by the nitric oxide donor sodium nitroprusside (SNP) was potentiated by losartan (P<0.05). The maximal responses to SNP alone (39.0±4.0%) were significantly enhanced in the presence of the 10^-4 M losartan (66.0±6.0%). Nonselective K+ inhibitor tetraethylammonium (1 mM) significantly inhibited enhancement effect of tamsulosin or doxazosin on mirodenafilinduced relaxation.

Conclusions: Amlodipine, nifedipine, losartan, doxazosin, and tamsulosin enhancd relaxation effect of mirodenafil in CC. Losartan seems to exert enhancing effect by interaction with nitric oxide. And potassium channel opening effect of PDE5I and alpha adrenergic blocker could be one of action mechanism for enhancing effect. Combination of PDE5I with losartan, nifedipine, amlodipine, doxazosin, or tamsulosin could be a possible pharmacologic strategy to simultaneously treat erectile dysfunction and its comorbidities and to increase response rate to PDE5I.