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

Abstract

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.

Vasodilator responses to acetylcholine are not mediated by the activation of soluble guanylate cyclase or TRPV4 channels in the rat

“…The inhibition of sGC by ODQ is induced by oxidation of the heme iron on the enzyme reducing the sensitivity to NO and increasing responses to sGC activator agents (35,43,52). The present data are consistent with previous results and show that responses to a low or subthreshold dose of the sGC activator BAY 60-2770 are markedly enhanced by ODQ, suggesting that the inactivated or oxidized enzyme is stimulated by a subthreshold dose sGC activator (30,35). The enhanced pressor response to angiotensin II in the pulmonary vascular bed observed after treatment with ODQ was not antagonized by apocyanin, suggesting that acute responses were not dependent on NADPH oxidase activation and may involve an effect of the peptide on NO formation, which is counterregulatory and can be observed when NO-sGC-cGMP signaling is inhibited.…”

Soluble Guanylyl Cyclase (sGC) Degradation and Impairment of Nitric Oxide-Mediated Responses in Urethra from Obese Mice: Reversal by the sGC Activator BAY 60-2770

“…BAY 58-2667-induced responses were greater in the aorta from spontaneously hypertensive rats and the mesocolon arteries from type 2 diabetic patients (Stasch et al, 2006). Additionally, the positive interaction of ODQ with the sGC activator on cGMP concentrations has been previously reported in porcine endothelial cells (Stasch et al, 2006) and corpus cavernosum (Lasker et al, 2013). Therefore, it is likely that the heme group of sGC is oxidized in the USM of obese mice.…”

“…Direct sGC stimulation causes cGMP-dependent urethral relaxations (Costa et al, 2001) in a synergistic fashion with NO (Toque et al, 2008 . These compounds are reported to protect sGC from heme oxidation in smooth muscle tissues (Stasch et al, 2006;Meurer et al, 2009;Jones et al, 2010;Lasker et al, 2013), ameliorating OAB in obese mice (Leiria et al, 2013). Additionally, long-term sGC stimulation counteracts the voiding dysfunction in chronically NO-deficient rats (Mónica et al, 2011).…”

New concepts for the treatment of male lower urinary tract symptoms

“…An alternative way to increase cGMP levels is to boost cGMP synthesis through activation or stimulation of soluble guanylyl cyclase (sGC), the enzyme responsible for cGMP synthesis. BAY 60-2770, an sGC activator, was able to induce beneficial effects on erection in normal rats, and in rats with cavernosal nerve crush injury [55], and was shown to reduce urodynamic signs of bladder overactivity in obese mice [56]. When BAY 60-2770, an sGC activator, and BAY 41-2272, an sGC stimulator, were tested urodynamically in rats with urethral obstruction-related bladder overactivity, they both reduced urodynamic signs of bladder overactivity, which were similar to the urodynamic effects of vardenafil [57].…”