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The journal of sexual medicine  2012;10(3):704-718.
Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) and in pathophysiologic conditions where NO formation or bioavailability is impaired, erectile dysfunction (ED) occurs.
The aim of this study was to investigate erectile responses to the sGC stimulator BAY 41-8543 in physiologic and pathophysiologic conditions.
Increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 41-8543 were investigated in the anesthetized rat.
Main Outcome Measures
Increases in ICP/MAP in response to ic injections of BAY 41-8543 and the interaction of BAY 41-8543 with exogenous and endogenously released NO were investigated and the effect of the sGC stimulator on cavernosal nerve injury was assessed. The mechanism of the increase in ICP/MAP in response to ic injection of acetylcholine was investigated.
The ic injections of BAY 41-8543 increased ICP/MAP and the duration of the response. BAY 41-8543 was less potent than SNP and ic injections of BAY 41-8543 and SNP produced a larger response than the algebraic sum of responses to either agent alone. Simultaneous ic injection of BAY 41-8543 and cavernosal nerve stimulation produced a greater response than either intervention alone. Atropine and cavernosal nerve crush injury decreased the response to nerve stimulation and ic injection of BAY 41-8543 restored the response.
These data show that BAY 41-8543 has significant erectile activity and can synergize with exogenous and endogenously released NO. This study shows that atropine and nerve crush attenuate the response to cavernosal nerve stimulation and that BAY 41-8543 can restore the response. The results with atropine, L-NAME and hexamethonium indicate that the response to ic injection of acetylcholine is mediated by muscarinic receptors and the release of NO with no significant role for nicotinic receptors. These results suggest that BAY 41-8543 would be useful in the treatment of ED.
PMCID: PMC3594361  PMID: 22989320
9.  The selective rho-kinase inhibitor Azaindole-1 has long lasting erectile activity in the rat 
Urology  2013;81(2):465.e7-465.e14.
To investigate the effects of the selective Rho-kinase (ROCK) inhibitor azaindole-1 on erectile function under physiologic and pathophysiologic conditions in the rat.
The effect of intracavernosal (i.c.) injections of azaindole-1 on change in ICP, ICP/MAP, AUC, and response duration were investigated in the anesthetized rat under control conditions and when NANC neurotransmission and cholinergic function or sGC were inhibited or after cavernosal nerve crush injury.
The i.c. injections of azaindole-1 produced dose-related increases in ICP/MAP and AUC that were long lasting at the highest doses studied when compared with the prototypical ROCK-inhibitor fasudil. Erectile responses were not altered by 7-NI and atropine in doses that reduced the response to cavernosal nerve stimulation by 86%, indicating that they were independent of NO release by cavernosal nerves or activation of muscarinic receptors in the corpora cavernosa. Erectile responses to azaindole-1 were not altered by the sGC inhibitor ODQ in a dose that attenuated responses to the NO donor SNP indicating that they were independent of an action on sGC. The erectile response to ic injections of azaindole-1 or Y-27632 which was reported to be NO/cGMP- dependent were not attenuated after cavernosal nerve crush injury.
The present studies indicate azaindole-1 has long lasting erectile activity that is independent of NO release, muscarinic receptor, or sGC activation or the integrity of the cavernosal nerves.
PMCID: PMC3564057  PMID: 23374844
Azaindole-1; selective Rho-kinase inhibitor; erectile dysfunction; oxidative stress; impaired cavernosal nerve function
10.  Riociguat Reduces Infarct Size and Post-Infarct Heart Failure in Mouse Hearts: Insights from MRI/PET Imaging 
PLoS ONE  2013;8(12):e83910.
Stimulation of the nitric oxide (NO) – soluble guanylate (sGC) - protein kinase G (PKG) pathway confers protection against acute ischaemia/reperfusion injury, but more chronic effects in reducing post-myocardial infarction (MI) heart failure are less defined. The aim of this study was to not only determine whether the sGC stimulator riociguat reduces infarct size but also whether it protects against the development of post-MI heart failure.
Methods and Results
Mice were subjected to 30 min ischaemia via ligation of the left main coronary artery to induce MI and either placebo or riociguat (1.2 µmol/l) were given as a bolus 5 min before and 5 min after onset of reperfusion. After 24 hours, both, late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) and 18F-FDG-positron emission tomography (PET) were performed to determine infarct size. In the riociguat-treated mice, the resulting infarct size was smaller (8.5±2.5% of total LV mass vs. 21.8%±1.7%. in controls, p = 0.005) and LV systolic function analysed by MRI was better preserved (60.1%±3.4% of preischaemic vs. 44.2%±3.1% in controls, p = 0.005). After 28 days, LV systolic function by echocardiography treated group was still better preserved (63.5%±3.2% vs. 48.2%±2.2% in control, p = 0.004).
Taken together, mice treated acutely at the onset of reperfusion with the sGC stimulator riociguat have smaller infarct size and better long-term preservation of LV systolic function. These findings suggest that sGC stimulation during reperfusion therapy may be a powerful therapeutic treatment strategy for preventing post-MI heart failure.
PMCID: PMC3877128  PMID: 24391843
11.  The Soluble Guanylate Cyclase Activator BAY 58-2667 Protects against Morbidity and Mortality in Endotoxic Shock by Recoupling Organ Systems 
PLoS ONE  2013;8(8):e72155.
Sepsis and septic shock are associated with high mortality rates and the majority of sepsis patients die due to complications of multiple organ failure (MOF). The cyclic GMP (cGMP) producing enzyme soluble guanylate cyclase (sGC) is crucially involved in the regulation of (micro)vascular homeostasis, cardiac function and, consequently, organ function. However, it can become inactivated when exposed to reactive oxygen species (ROS). The resulting heme-free sGC can be reactivated by the heme- and nitric oxide (NO)-independent sGC activator BAY 58-2667 (Cinaciguat). We report that late (+8 h) post-treatment with BAY 58-2667 in a mouse model can protect against lethal endotoxic shock. Protection was associated with reduced hypothermia, circulating IL-6 levels, cardiomyocyte apoptosis, and mortality. In contrast to BAY 58-2667, the sGC stimulator BAY 41-2272 and the phosphodiesterase 5 inhibitor Sildenafil did not have any beneficial effect on survival, emphasizing the importance of the selectivity of BAY 58-2667 for diseased vessels and tissues. Hemodynamic parameters (blood pressure and heart rate) were decreased, and linear and nonlinear indices of blood pressure variability, reflective for (un)coupling of the communication between the autonomic nervous system and the heart, were improved after late protective treatment with BAY 58-2667. In conclusion, our results demonstrate the pivotal role of the NO/sGC axis in endotoxic shock. Stabilization of sGC function with BAY 58-2667 can prevent mortality when given in the correct treatment window, which probably depends on the dynamics of the heme-free sGC pool, in turn influenced by oxidative stress. We speculate that, considering the central role of sGC signaling in many pathways required for maintenance of (micro)circulatory homeostasis, BAY 58-2667 supports organ function by recoupling inter-organ communication pathways.
PMCID: PMC3756074  PMID: 24015214
12.  The Soluble Guanylyl Cyclase Activator Bay 58-2667 Selectively Limits Cardiomyocyte Hypertrophy 
PLoS ONE  2012;7(11):e44481.
Although evidence now suggests cGMP is a negative regulator of cardiac hypertrophy, the direct consequences of the soluble guanylyl cyclase (sGC) activator BAY 58-2667 on cardiac remodeling, independent of changes in hemodynamic load, has not been investigated. In the present study, we tested the hypothesis that the NO•-independent sGC activator BAY 58-2667 inhibits cardiomyocyte hypertrophy in vitro. Concomitant impact of BAY 58-2667 on cardiac fibroblast proliferation, and insights into potential mechanisms of action, were also sought. Results were compared to the sGC stimulator BAY 41-2272.
Neonatal rat cardiomyocytes were incubated with endothelin-1 (ET1, 60nmol/L) in the presence and absence of BAY 41-2272 and BAY 58-2667 (0.01–0.3 µmol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined. The impact of both sGC ligands on basal and stimulated cardiac fibroblast proliferation in vitro was also determined.
We now demonstrate that BAY 58-2667 (0.01–0.3 µmol/L) elicited concentration-dependent antihypertrophic actions, inhibiting ET1-mediated increases in cardiomyocyte 2D area and de novo protein synthesis, as well as suppressing ET1-induced cardiomyocyte superoxide generation. This was accompanied by potent increases in cardiomyocyte cGMP accumulation and activity of its downstream signal, vasodilator-stimulated phosphoprotein (VASP), without elevating cardiomyocyte cAMP. In contrast, submicromolar concentrations of BAY 58-2667 had no effect on basal or stimulated cardiac fibroblast proliferation. Indeed, only at concentrations ≥10 µmol/L was inhibition of cardiac fibrosis seen in vitro. The effects of BAY 58-2667 in both cell types were mimicked by BAY 41-2272.
Our results demonstrate that BAY 58-2667 elicits protective, cardiomyocyte-selective effects in vitro. These actions are associated with sGC activation and are evident in the absence of confounding hemodynamic factors, at low (submicromolar) concentrations. Thus this distinctive sGC ligand may potentially represent an alternative therapeutic approach for limiting myocardial hypertrophy.
PMCID: PMC3492396  PMID: 23144773
13.  Soluble Guanylate Cyclase as an Emerging Therapeutic Target in Cardiopulmonary Disease 
Circulation  2011;123(20):2263-2273.
PMCID: PMC3103045  PMID: 21606405
cardiovascular diseases; hypertension; pulmonary; soluble guanylate cyclase; nitric oxide; riociguat
15.  Fluorescence Dequenching Makes Haem-Free Soluble Guanylate Cyclase Detectable in Living Cells 
PLoS ONE  2011;6(8):e23596.
In cardiovascular disease, the protective NO/sGC/cGMP signalling-pathway is impaired due to a decreased pool of NO-sensitive haem-containing sGC accompanied by a reciprocal increase in NO-insensitive haem-free sGC. However, no direct method to detect cellular haem-free sGC other than its activation by the new therapeutic class of haem mimetics, such as BAY 58-2667, is available. Here we show that fluorescence dequenching, based on the interaction of the optical active prosthetic haem group and the attached biarsenical fluorophor FlAsH can be used to detect changes in cellular sGC haem status. The partly overlap of the emission spectrum of haem and FlAsH allows energy transfer from the fluorophore to the haem which reduces the intensity of FlAsH fluorescence. Loss of the prosthetic group, e.g. by oxidative stress or by replacement with the haem mimetic BAY 58-2667, prevented the energy transfer resulting in increased fluorescence. Haem loss was corroborated by an observed decrease in NO-induced sGC activity, reduced sGC protein levels, and an increased effect of BAY 58-2667. The use of a haem-free sGC mutant and a biarsenical dye that was not quenched by haem as controls further validated that the increase in fluorescence was due to the loss of the prosthetic haem group. The present approach is based on the cellular expression of an engineered sGC variant limiting is applicability to recombinant expression systems. Nevertheless, it allows to monitor sGC's redox regulation in living cells and future enhancements might be able to extend this approach to in vivo conditions.
PMCID: PMC3157391  PMID: 21858179

Results 1-25 (65)