A Review of the Pathophysiology and Novel Treatments for Erectile Dysfunction

Lasker, George F.; Maley, Jason H.; Kadowitz, Philip J.

doi:10.1155/2010/730861

Cited by 28 publications

(25 citation statements)

References 101 publications

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“…A P value of Ͻ0.05 was used as the criterion for statistical significance. formation, and induce vasodilation and erection (15). In contrast, only sGC activators will have the capacity to increase the catalytic activity of oxidized or heme free sGC as shown by Schmidt et al (24) and induce vasodilation and erection (Fig.…”

Section: Methodsmentioning

confidence: 94%

“…erectile dysfunction; oxidative stress; impaired cavernosal nerve function NITRIC OXIDE (NO) is the principal mediator of penile erection, and a decrease in NO formation or bioavailability will result in erectile dysfunction (ED) (2,11,15). The treatment of ED with phosphodiesterase type 5 (PDE-5) inhibitors is effective in most patients; however, some patients do not respond to these agents because of very low endogenous NO formation and increased oxidative stress which can inactivate NO and inhibit the activity of soluble guanylate cyclase (sGC) (Fig.…”

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confidence: 99%

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The sGC activator BAY 60-2770 has potent erectile activity in the rat

Lasker

Pankey

Frink

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Nitric oxide (NO) is the principal mediator of penile erection, and soluble guanylate cyclase (sGC) is the receptor for NO. In pathophysiological conditions when sGC is inactivated and not responsive to NO or sGC stimulators a new class of agents called sGC activators increase the activity of NO-insensitive sGC and produce erection. The aim of this study was to investigate erectile responses to BAY 60-2770, a sGC activator, under physiological and pathophysiological conditions. In the present study increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 60-2770 were investigated under baseline conditions, when sGC was inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), when nitric oxide synthase (NOS) was inhibited by N-nitro-L-arginine methyl ester (L-NAME), and after cavernosal nerve crush injury. Under baseline conditions ic injections of BAY 60-2770 increase ICP, ICP/mean arterial pressure (MAP), and area under the ICP curve (AUC) and produce small decreases in MAP at the highest doses studied. BAY 60-2770 was very potent in its ability to induce erection and responses to BAY 60-2770 were enhanced by ODQ which attenuates erectile responses to sodium nitroprusside (SNP), diethylamine NONOate (DEA/NO), and cavernosal nerve stimulation. Responses to BAY 60-2770 were not altered by L-NAME or cavernosal nerve crush injury. These data indicate that BAY 60-2770 has potent erectile activity that is enhanced by ODQ and show that responses to BAY 60-2770 are not attenuated by NOS inhibition or cavernosal nerve injury. These results suggest that BAY 60-2770 would be effective in the treatment of erectile dysfunction when NO bioavailability is reduced, after pelvic nerve injury, and when sGC is oxidized.

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Section: Methodsmentioning

confidence: 94%

mentioning

confidence: 99%

The sGC activator BAY 60-2770 has potent erectile activity in the rat

Lasker

Pankey

Frink

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Currently, two different classes of drugs have been developed that directly target sGC, increasing cGMP formation and promoting penile erection. These agents are called sGC stimulators and sGC activators Lasker et al, 2010Lasker et al, , 2013. The sGC stimulators are agents that directly activate sGC and increase its catalytic activity independent of NO availability, thereby increasing cGMP formation and leading to penile erection (Evgenov et al, 2006).…”

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

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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.

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“…This neurotransmitter is the main vasoactive agent involved in the erectile response because of its ability to relax corporal smooth muscle cells in the penis, and it has been implicated in many of the known etiologies and comorbidities of ED (for review, see Lasker et al. [29]).…”

Section: Resultsmentioning

confidence: 99%

Genetics of Erectile Dysfunction: A Review of the Interface between Sex and Molecular Biomarkers

Andersen

Guindalini

Tufik

2011

The Journal of Sexual Medicine

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Introduction In recent years, new tools for the study of molecular biology and genetics have resulted in significant contributions to the scientific community. The potential use of genetic variations as biomarkers in the management of current and future conditions is generating considerable excitement in health care for disorders such as erectile dysfunction (ED). Aim This review briefly describes the molecular and genetic mechanisms involved in ED and provides an overall view of the literature relevant to possible relationships between genetic factors and ED. Methods This is a narrative review of studies on the potential influence of polymorphisms on the risk of developing ED. Main Outcome Measure We reviewed genetic association studies involving polymorphisms and the ED phenotype. Results There is growing evidence for the influence of genetic polymorphisms on the risk of ED and on the interindividual variability in sildenafil treatment. Conclusions Although this field is still in its infancy, genetic association studies aimed at defining a molecular basis for ED have provided some important evidence that a patient's genotype may be used in the future to assess risk, as well as to plan treatment and prevention programs in the clinic.

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A Review of the Pathophysiology and Novel Treatments for Erectile Dysfunction

Cited by 28 publications

References 101 publications

The sGC activator BAY 60-2770 has potent erectile activity in the rat

The sGC activator BAY 60-2770 has potent erectile activity in the rat

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

Genetics of Erectile Dysfunction: A Review of the Interface between Sex and Molecular Biomarkers

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A Review of the Pathophysiology and Novel Treatments for Erectile Dysfunction

Cited by 28 publications

References 101 publications

The sGC activator BAY 60-2770 has potent erectile activity in the rat

The sGC activator BAY 60-2770 has potent erectile activity in the rat

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

Genetics of Erectile Dysfunction: A Review of the Interface between Sex and Molecular Biomarkers

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