Treating erectile dysfunction when PDE5 inhibitors fail

McMahon, Chelsea N; Smith, Christopher J.; Shabsigh, Ridwan

doi:10.1136/bmj.332.7541.589

Cited by 121 publications

(70 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, more than 30% of diabetic patients with ED do not respond to PDE-5 inhibitor therapy. For these patients, endogenous NO production may be so impaired that inhibition of cGMP degradation does not provide a significant benefit (McMahon et al, 2006). Currently, two different classes of drugs have been developed that directly target sGC, increasing cGMP formation and promoting penile erection.…”

Section: Introductionmentioning

confidence: 99%

Beneficial Effect of the Soluble Guanylyl Cyclase Stimulator BAY 41-2272 on Impaired Penile Erection in db/db^−/− Type II Diabetic and Obese Mice

Nunes

Teixeira

Priviero

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Type 2 diabetes mellitus (DM2) and obesity are major risk factors for erectile dysfunction (ED). In diabetes, increased oxidative stress leads to decreased nitric oxide (NO) bioavailability, and diabetic patients appear to be less responsive to conventional therapy with phosphodiesterase type 5 inhibitors. We investigated whether the soluble guanylyl cyclase stimulator BAY 41-2272 (5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo [3,4-b] pyridine-3-yl]pyrimidin-4ylamine) is effective in improving impaired corpus cavernosum (CC) relaxation in obese DM2 mice by reducing oxidative stress. Adult db/db 2/2 mice or their lean db /1 littermates were used to assess vascular function, cGMP levels, antioxidant status, NADPH oxidase expression, and superoxide formation in the absence or presence of BAY 41-2272. Results showed that BAY 41-2272 (10 28 to 10 25 M) potently relaxed CC from db /1 or db/db 2/2 mice in a similar manner. BAY 41-2272 significantly enhanced both endotheliumdependent and nitrergic relaxation induced by electrical field stimulation (EFS), and improved the impaired relaxation to acetylcholine and EFS in the diabetic animals in a concentrationdependent manner (10 28 to 10 27 M). BAY 41-2272 increased cGMP levels and potentiated relaxation responses to exogenous NO in CC. Total antioxidant status was reduced in plasma and urine whereas expression of vascular NADPH oxidase subunits (gp91phox, p22phox, and p47phox) was increased in the CC of db/db 2/2 mice, suggesting a state of oxidative stress. These effects were prevented by BAY 41-2272 in a concentrationdependent manner. These results suggest that BAY 41-2272 improves CC relaxation in db/db 2/2 mice by increasing cGMP and augmenting antioxidant status, making this drug is a potential novel candidate to treat ED.

show abstract

Section: Introductionmentioning

confidence: 99%

Beneficial Effect of the Soluble Guanylyl Cyclase Stimulator BAY 41-2272 on Impaired Penile Erection in db/db^−/− Type II Diabetic and Obese Mice

Nunes

Teixeira

Priviero

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…The reported 62% prescription renewal rate at 3-4 months of follow-up, which drops to approximately 30% by 6-12 months, suggests that patients stop taking the drug for reasons other than treatment failure. 2,3 The use of PDE-5 inhibitors may result in side effects, such as visual disturbance, headache, facial flushing, rhinitis and indigestion. Other treatments for ED include injection therapy within the penis or penile implants.…”

Section: Introductionmentioning

confidence: 99%

The relaxation effect and mechanism of action of higenamine in the rat corpus cavernosum

Kam

Choi

et al. 2011

Int J Impot Res

View full text Add to dashboard Cite

Higenamine mediates cardiotonic, vascular relaxation and bronchodilator effects. The relaxation effects and the mechanism of action of higenamine on the rat corpus cavernosum (CC) were assessed to investigate the effect of higenamine on penile erection. Strips of CC and aorta were used in organ baths for isometric tension studies. Tension was measured with isometric force transducers, and muscle relaxation was expressed as the percent decrease in precontraction induced by phenylephrine (PE). The relaxation reactions were investigated in an endothelial-denuded group and groups pretreated with N(G)-nitro-L-arginine methyl ester (NO synthesis inhibitor), propranolol (b-receptor blocker), indomethacin (COX inhibitor), glibenclamide (K þ ATP channel inhibitor), 4-aminopyridine (membrane potential-dependent potassium channel inhibitor) and methylene blue (guanylyl cyclase inhibitor) for 30 min. Intracavernous pressure (ICP) was assessed in rats after the intravenous administration of higenamine, and changes in guanosine 3 0 ,5 0 -cyclic monophosphate and adenosine 3 0 ,5 0 -cyclic monophosphate (cAMP) concentrations were measured on the basis of the higenamine concentration. Also, the combined reaction of higenamine and the phosphodiesterase type-5 (PDE-5) inhibitors was assessed. Higenamine induced relaxation of the CC and the aortic strips precontracted with PE in a dose-dependent manner. The CC was significantly more relaxed than the aortic rings in response to the same higenamine concentration (Po0.05). The CC relaxation reaction was suppressed by the b-receptor blocker propranolol. The cAMP concentration increased gradually with increased higenamine concentration (Po0.05). The ICP also increased with increased higenamine concentration in vivo (Po0.05). In the group pretreated with 10 À7 M higenamine, the relaxation reaction of CC induced by the PDE-5 inhibitor increased significantly, compared with CC exposed to the PDE-5 inhibitor but not pretreated with higenamine (Po0.05). In conclusion, higenamine induced relaxation of the rat CC in a dose-dependent manner. The effect may be mediated through b-adrenoceptors. The results suggest that higenamine may be valuable as a new lead compound for treating erectile dysfunction.

show abstract

“…Alternatives include vacuum-constriction devices and intracavernosal injection of vaso-active drugs (both level 1C evidence). Finally, although not discussed in this chapter, for those patients failing to respond to any pharmaco or physical therapies, referral to a urologist for the consideration of penile prosthesis might be considered (38). Similarly, patients with local and structural penile abnormalities such as Peyronie's disease warrant referral to a urologist.…”

Section: Discussionmentioning

confidence: 94%

“…For those men who do not respond to oral PDE-5 inhibitors alone, there is some logic in combining agents (17,38), although direct evidence from randomized controlled trials is still lacking (level 1C evidence). Alternatives include vacuum-constriction devices and intracavernosal injection of vaso-active drugs (both level 1C evidence).…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Erectile Dysfunction in Diabetes

Boulton¹

Type 2 Diabetes Mellitus

View full text Add to dashboard Cite

Treating erectile dysfunction when PDE5 inhibitors fail

Cited by 121 publications

References 25 publications

Beneficial Effect of the Soluble Guanylyl Cyclase Stimulator BAY 41-2272 on Impaired Penile Erection in db/db^−/− Type II Diabetic and Obese Mice

Beneficial Effect of the Soluble Guanylyl Cyclase Stimulator BAY 41-2272 on Impaired Penile Erection in db/db^−/− Type II Diabetic and Obese Mice

The relaxation effect and mechanism of action of higenamine in the rat corpus cavernosum

Erectile Dysfunction in Diabetes

Contact Info

Product

Resources

About

Treating erectile dysfunction when PDE5 inhibitors fail

Cited by 121 publications

References 25 publications

Beneficial Effect of the Soluble Guanylyl Cyclase Stimulator BAY 41-2272 on Impaired Penile Erection in db/db−/− Type II Diabetic and Obese Mice

Beneficial Effect of the Soluble Guanylyl Cyclase Stimulator BAY 41-2272 on Impaired Penile Erection in db/db−/− Type II Diabetic and Obese Mice

The relaxation effect and mechanism of action of higenamine in the rat corpus cavernosum

Erectile Dysfunction in Diabetes

Contact Info

Product

Resources

About

Beneficial Effect of the Soluble Guanylyl Cyclase Stimulator BAY 41-2272 on Impaired Penile Erection in db/db^−/− Type II Diabetic and Obese Mice

Beneficial Effect of the Soluble Guanylyl Cyclase Stimulator BAY 41-2272 on Impaired Penile Erection in db/db^−/− Type II Diabetic and Obese Mice