The Selective Rho-kinase Inhibitor Azaindole-1 Has Long-lasting Erectile Activity in the Rat

Lasker, George F.; Pankey, Edward A.; Allain, Alexander V.; Murthy, Subramanyam N.; Stasch, Johannes‐Peter; Kadowitz, Philip J.

doi:10.1016/j.urology.2012.10.039

Cited by 17 publications

(15 citation statements)

References 28 publications

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“…ODQ (Cayman) was also dissolved in the Transcutol-Cremophor vehicle. The dose of ODQ used in these experiments was determined from pilot experiments and reports in the literature (17). No financial support was provided by Bayer.…”

Section: Methodsmentioning

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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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: 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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“…More recently developed ROCK inhibitors, including azaindole-1 and SAR407899, have shown promise in recovering erections in preclinical rat studies. 45–47 Azaindole-1, a more selective ROCK inhibitor with less secondary kinase inhibition than Y-27632 and fasudil, demonstrated both antihypertensive and proerectile effects. 45,46 …”

Section: No and Rhoa–rock In Ed Pathologymentioning

confidence: 99%

“…Azaindole-1, a newer, selective ROCK inhibitor, improves ED in rats after nerve-crush injury and has antihypertensive effects when given systemically, but it is not currently being evaluated for ED in a clinical trial. 45,46 …”

Section: Current Clinical Use Of Rock Inhibitorsmentioning

confidence: 99%

Understanding and targeting the Rho kinase pathway in erectile dysfunction

Sopko¹,

Hannan²,

Bivalacqua³

2014

Nat Rev Urol

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Erectile dysfunction (ED) is a common disorder that affects a quarter of US men, and has many causes, including endothelial impairment, low testosterone levels, prior surgical manipulation, and/or psychogenic components. Penile erection is a complex process requiring neurally mediated relaxation of arteriolar smooth muscle and engorgement of cavernosal tissues, mediated by nitric oxide (NO). Current medical therapies for ED largely seek to maximize endogenous NO signalling. Certain aetiologies, including diabetes, are difficult to treat with current modalities, emphasizing the need for new molecular targets. Research has demonstrated the importance of RhoA–Rho-associated protein kinase (ROCK) signalling in maintaining a flaccid penile state, and inhibition of RhoA–ROCK signalling potentiates smooth-muscle relaxation in an NO-independent manner. The mechanisms and effects of RhoA–ROCK signalling and inhibition suggest that the RhoA–ROCK pathway could prove to be a new therapeutic target for the treatment of ED.

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“…The isolated enzyme studies of Zhao and Marletta showed that ODQ had no effect on basal activity of sGC but blocked the activation of sGC by NO (89). Treatment with ODQ will inhibit the erectile response to NO donors, to cavernosal nerve stimulation, and to sGC stimulators like BAY 41-8543 (50,51). However, when sGC is inactivated by ODQ, the effect of the sGC activator BAY 60-2770, which has potent erectile activity, will be increased (51a).…”

Section: Sgc Stimulators and Activatorsmentioning

confidence: 99%

“…These studies demonstrated that the heme-free enzyme could be activated to increase the formation of cGMP from GTP and led to the concept that new classes of agents could be effective in targeting an oxidized or heme-free enzyme (33,44,72,79,80). In experimental animals, sGC can be inhibited and made insensitive to NO by treatment with 1H [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), an agent that has been shown to oxidize the heme iron on the enzyme in many isolated tissue studies and in a few in vivo studies (18,23,51,56,57,65,89). The isolated enzyme studies of Zhao and Marletta showed that ODQ had no effect on basal activity of sGC but blocked the activation of sGC by NO (89).…”

Section: Sgc Stimulators and Activatorsmentioning

confidence: 99%

Modulation of Soluble Guanylate Cyclase for the Treatment of Erectile Dysfunction

2013

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Nitric oxide (NO) is the principal mediator of penile erection, and PDE-5 inhibitors are the first-line agents used to treat erectile dysfunction (ED). When NO formation or bioavailability is decreased by oxidative stress and PDE-5 inhibitors are no longer effective, a new class of agents called soluble guanylate cyclase (sGC) stimulators like BAY 41-8543 will induce erection. sGC stimulators bind to the normally reduced, NO-sensitive form of sGC to increase cGMP formation and promote erection. The sGC stimulators produce normal erectile responses when NO formation is inhibited and the nerves innervating the corpora cavernosa are damaged. However, with severe oxidative stress, the heme iron on sGC can be oxidized, rendering the enzyme unresponsive to NO or sGC stimulators. In this pathophysiological situation, another newly developed class of agents called sGC activators can increase the catalytic activity of the oxidized enzyme, increase cGMP formation, and promote erection. The use of newer agents that stimulate or activate sGC to promote erection and treat ED is discussed in this brief review article.

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The Selective Rho-kinase Inhibitor Azaindole-1 Has Long-lasting Erectile Activity in the Rat

Cited by 17 publications

References 28 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

Understanding and targeting the Rho kinase pathway in erectile dysfunction

Modulation of Soluble Guanylate Cyclase for the Treatment of Erectile Dysfunction

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