Analysis of Erectile Responses to BAY 41-8543 and Muscarinic Receptor Stimulation in the Rat

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

doi:10.1111/j.1743-6109.2012.02912.x

Cited by 16 publications

(19 citation statements)

References 31 publications

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“…Cavernosal nerve stimulation was carried out as previously described in the literature (16). For nerve stimulation, the bladder and prostate were exposed through a midline abdominal incision.…”

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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“…All injections were administered in a total volume of 150 lL, and a washout period of 15-30 min was observed between injections. Cavernosal nerve stimulation in a separate group of rats was carried out as previously described [23,24].…”

Section: In Vivo Rat Studiesmentioning

confidence: 99%

Mirabegron causes relaxation of human and rat corpus cavernosum: could it be a potential therapy for erectile dysfunction?

et al. 2016

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ObjectiveTo examine the effects of mirabegron, a selective b 3 -adrenoceptor agonist that has recently been approved for the treatment of overactive bladder (OAB), on erectile function. Stimulation of b 3 -adrenoceptors localised in cavernosal smooth muscle cells may play a physiological role in mediating penile erection, and offer a beneficial pharmacological action for patients who have OAB and erectile dysfunction (ED). Materials and MethodsCorpus cavernosal (CC) specimens were obtained from patients with ED and Peyronie's disease undergoing penile prosthesis implantation. Erectile responses were also evaluated in vivo after intracavernosal injection (ICI) of mirabegron in anaesthetised rats. Mirabegron-elicited relaxation responses (10 -8 -10-3 M) on phenylephrine-induced contraction were seen in human CC (HCC) and rat CC strips in isolated organbath studies. The effects of inhibitors, namely L-NAME [N G -nitro-L-arginine methyl ester, a competitive inhibitor of nitric oxide synthase (NOS), 100 lM], ODQ [1H-(1,2,4) oxadiazolo (4,3-a) quinoxalin-1-one, a soluble guanylyl cyclase (sGC) inhibitor, 30lM], methylene blue (a NOS and sGC inhibitor, 20lM), SR59230A (b 3 -adrenoceptor blocker, 1 lM), and fasudil [Rho-associated protein kinase (ROCK) inhibitor, 0.1 lM], on mirabegron-induced relaxation responses were evaluated. Responses to mirabegron were compared with responses to isoprenaline and nebivolol. Immunohistochemistry was used to localise b 3 -adrenoceptors and ROCK in CC smooth muscle cells. In vivo rat data were expressed as intracavernosal pressure (ICP)/mean arterial pressure, and total ICP. ResultsMirabegron resulted in a relaxation of phenylephrineevoked CC contractions in a concentration-dependent manner and SR59230A antagonised the mirabegron-induced relaxations in HCC and rat CC. Other inhibitors, L-NAME, ODQ, and methylene blue, did not affect the mirabegroninduced relaxation responses. Mirabegron relaxation responses at concentrations (0.1-10 lM) were enhanced by fasudil (ROCK inhibitor) in rat but not in HCC strips. KCl-induced contractions in HCC and rat CC were partially inhibited by mirabegron. In vivo, ICI of mirabegron (doses of 0.1-1 mg/kg) had a minor effect on ICP when compared with vehicle administration. Immunohistochemistry data showed b 3 -adrenoceptors localised in the smooth muscle cells of the HCC and rat CC. ConclusionsMirabegron markedly relaxed isolated CC strips by activating b 3 -adrenoceptors independently of the NO-cGMP pathway. There is also evidence of the existence of a close functional link between b 3 -adrenoceptors and the RhoA/ROCK pathway. These results may support further clinical studies using combinations of mirabegron with ROCK and phosphodiesterase type 5 inhibitors (PDE5i) for the treatment of ED, especially in patients who do not respond to PDE5i therapy.

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“…In another study, the erectile response to cavernosal nerve stimulation was significantly attenuated at frequencies of 2-16 Hz following administration of atropine 1 mg/kg iv. The erectile response to intracavernosal injection of ACh was attenuated, and the response to intracavernosal injection of the NO donor sodium nitroprusside was not altered at the time the response to cavernosal nerve stimulation was significantly attenuated (50). These results suggest that ACh released from cholinergic nerves in response to cavernosal nerve stimulation may mediate ϳ30% of the erectile response in the rat (50,73).…”

mentioning

confidence: 73%

“…Figure the corporal smooth muscle cells and activates sGC (FIGURES 1 AND 2). The role of muscarinic receptormediated NO release from the endothelium of the corpora cavernosa in erection is controversial, although recent studies suggest a significant role for the contribution of muscarinic receptor activation by ACh released from cholinergic nerve terminals in the penis (50,73). It has been reported that injection of atropine in a dose of 1 mg/kg iv had no significant effect on the erectile response to pelvic nerve stimulation in the anesthetized dog (22).…”

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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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Analysis of Erectile Responses to BAY 41-8543 and Muscarinic Receptor Stimulation in the Rat

Cited by 16 publications

References 31 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

Mirabegron causes relaxation of human and rat corpus cavernosum: could it be a potential therapy for erectile dysfunction?

Modulation of Soluble Guanylate Cyclase for the Treatment of Erectile Dysfunction

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