bay-58-2667 and Heart-Failure

The burden of heart failure (HF) increases worldwide with an aging population, and there is a high unmet medical need in both, heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). The nitric oxide (NO) pathway is a key regulator in the cardiovascular system and modulates vascular tone and myocardial performance. Disruption of the NO-cyclic guanosine monophosphate (cGMP) signaling axis and impaired cGMP formation by endothelial dysfunction could lead to vasotone dysregulation, vascular and ventricular stiffening, fibrosis, and hypertrophy resulting in a decline of heart as well as kidney function. Therefore, the NO-cGMP pathway is a treatment target in heart failure. Exogenous NO donors such as nitrates have long been used for treatment of cardiovascular diseases but turned out to be limited by increased oxidative stress and tolerance. More recently, novel classes of drugs were discovered which enhance cGMP production by targeting the NO receptor soluble guanylate cyclase (sGC). These compounds, the so-called sGC stimulators and sGC activators, are able to increase the enzymatic activity of sGC to generate cGMP independently of NO and have been developed to target this important signaling cascade in the cardiovascular system.This review will focus on the role of sGC in cardiovascular (CV) physiology and disease and the pharmacological potential of sGC stimulators and sGC activators therein. Preclinical data will be reviewed and summarized, and available clinical data with riociguat and vericiguat, novel direct sGC stimulators, will be presented. Vericiguat is currently being studied in a Phase III clinical program for the treatment of heart failure with reduced ejection fraction (HFrEF).

Topics: Benzoates; Cyclic GMP; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Nitric Oxide; Pyrazoles; Pyrimidines; Signal Transduction; Soluble Guanylyl Cyclase; Stroke Volume

The European Society of Cardiology held their annual congress in Amsterdam between the 31st of August and 4 September 2013 to discuss the latest developments in the field. The meeting included an update of the latest treatments currently under investigation for the treatment of heart failure. Updates were provided on the RELAX-AHF study that had, for the first time, demonstrated an improvement in post-discharge outcome in patients with acute heart failure treated with seralaxin. The meeting also gave the opportunity to highlight the latest goings on from the promising agent omecamtiv mecarbil as shown in the ATOMIC-AHF study. Indeed, its unique inotropic effect showed a potential to improve dyspnea without increasing myocardial oxygen consumption. Other presentations at the meeting included: a recent study evaluating ultrafiltration in the treatment of acute HF with renal impairment and the effects of the vasodilator cinaciguat. The unremarkable results from the recent ASTRONAUT study with aliskiren were also touched upon. It is important to note that while the data from seralaxin and omecamtiv mecarbil has been promising, the long term benefits of these therapies in heart failure still need to be evaluated. The authors also highlight the need for these promising agents to be further evaluated in women and other ethnic groups.

Topics: Amides; Benzoates; Cardiac Resynchronization Therapy; Cardiotonic Agents; Fumarates; Heart Failure; Humans; Recombinant Proteins; Relaxin; Ultrafiltration; Urea

Vasoactive and inotropic drugs provide effective symptomatic and hemodynamic relief in the short term but can increase mortality in the long-term. Consequently, their use should be restricted to the indications described in clinical practice guidelines. The present article reviews the main drugs and the available evidence on their use.

Topics: Acute Disease; Benzoates; Cardiotonic Agents; Clinical Trials as Topic; Heart Failure; Hemodynamics; Humans; Mineralocorticoid Receptor Antagonists; Natriuretic Agents; Nitric Oxide Donors; Phosphodiesterase Inhibitors; Practice Guidelines as Topic; Recombinant Proteins; Relaxin; Renin-Angiotensin System; Sympathomimetics; Vasodilator Agents

Acute heart failure is a major cause of emergency hospital admission, with significant impact on health resources and patient outcomes. With no new treatments for over 20 years, the advent of new innovative therapies may facilitate a radical change in our approach to such patients. In this article, we examine the current evidence for the use of current intravenous vasodilators in AHF management, and review the potential of novel therapies currently in development.

Topics: Acute Disease; Administration, Intravenous; Atrial Natriuretic Factor; Benzoates; Heart Failure; Humans; Natriuretic Agents; Natriuretic Peptide, Brain; Natriuretic Peptides; Nitrates; Peptide Fragments; Recombinant Proteins; Relaxin; Snake Venoms; Vasodilator Agents

Heart failure is an important public health problem that is increasing in prevalence throughout the world. Not only is this condition common, but it is associated with significant morbidity and mortality as well as high costs to medical care systems. Vasodilator drugs help unload the heart and may have other effects that could benefit heart failure patients. Consequently, they have emerged as an important therapeutic approach for patients with this condition. Novel vasodilator therapies that are currently in development target new pathways, potentially giving clinicians alternate options for improving outcomes in this vulnerable population. This review focuses on investigational drugs that have the ability to dilate blood vessels amongst their therapeutic properties. These drugs include the natriuretic peptides that activate particulate guanylate cyclase, the novel agent cinaciguat that activates the soluble guanylate cyclase system, and finally a recombinant form of the naturally occurring vasodilating agent relaxin, a hormone that mediates many of the changes that allows the cardiovascular system to successfully adapt to pregnancy.

Topics: Atrial Natriuretic Factor; Benzoates; Diuretics; Guanylate Cyclase; Heart Failure; Humans; Natriuretic Peptides; Peptide Fragments; Relaxin; Vasodilator Agents

This review summarizes the role of soluble guanylate cyclase (sGC)-cyclic guanosine 3', 5'-monophosphate pathways in heart failure and several new drugs that modify guanylate cyclase. The sGC activators and stimulators as modulators of sGC are promising drugs in the therapy for decompensated heart failure and pulmonary hypertension. Cinaciguat is a nitric oxide (NO)-independent direct activator of sGC, which also may be effective under oxidative stress conditions resulting in oxidized or heme-free sGC refractory to organic nitrates. Riociguat is an NO-independent direct stimulator of sGC with beneficial effects in patients with decompensated heart failure and pulmonary hypertension. The sGC modulators play an important role in patients with heart failure and pulmonary hypertension.

Topics: Benzoates; Cardiovascular Agents; Guanylate Cyclase; Heart Failure; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Signal Transduction

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients' outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1-2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice.

Topics: Acute Disease; Atrial Natriuretic Factor; Benzoates; Elapid Venoms; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nitrates; Peptide Fragments; Prognosis; Pyridines; Receptors, Endothelin; Relaxin; Tetrazoles; Vasoconstriction; Vasodilator Agents

In this review we investigate the role of particulate and soluble guanylate cyclase (pGC and sGC, respectively) pathways in heart failure, and several novel drugs that modify guanylate cyclase. Nesiritide and ularitide/urodilatin are natriuretic peptides with vasodilating, natriuretic and diuretic effects, acting on pGC, whilst cinaciguat (BAY 58-2667) is a novel sGC activator. Cinaciguat has a promising and novel mode of action because it can stimulate cyclic guanosine-3',5'-monophosphate synthesis by targeting sGC in its nitric oxide-insensitive, oxidised ferric (Fe(3+)) or haem-free state. Thus, cinaciguat may also be effective under oxidative stress conditions resulting in oxidised or haem-free sGC refractory to traditional organic nitrate therapies. Preliminary studies of cinaciguat in patients with acute decompensated heart failure show substantial improvements in haemodynamics and symptoms, whilst maintaining renal function.

Topics: Animals; Atrial Natriuretic Factor; Benzoates; Creatinine; Disease Progression; Diuretics; Dose-Response Relationship, Drug; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Natriuretic Peptide, Brain; Oxidative Stress; Peptide Fragments

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5'-guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by promoting vasodilation and inhibiting vascular smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In pathophysiological states with endothelial dysfunction this signaling pathway is impaired. Activation of sGC has traditionally been achieved with nitrovasodilators; however, these drugs are associated with the development of tolerance and potentially deleterious cGMP-independent actions. In this review the actions of BAY 41-2272, the prototype of a new class of NO-independent sGC stimulators, in cardiovascular disease models is discussed. BAY 41-2272 binds to a regulatory site on the alpha-subunit of sGC and stimulates the enzyme synergistically with NO. BAY 41-2272 had antihypertensive actions and attenuated remodeling in models of systemic arterial hypertension. It also unloaded the heart in experimental congestive heart failure. BAY 41-2272 reduced pulmonary vascular resistance in acute and chronic experimental pulmonary arterial hypertension. Furthermore, BAY 41-2272 inhibited platelet aggregation in vitro and leukocyte adhesion in vivo. These findings make direct sGC stimulation with BAY 41-2272 a promising new therapeutic strategy for cardiovascular diseases and warrant further studies. Finally, the significance of the novel NO- and heme-independent sGC activator BAY 58-2667, which activates two forms of NO-insensitive sGC, is briefly discussed.

Topics: Animals; Antihypertensive Agents; Benzoates; Cardiovascular Diseases; Cell Adhesion; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Enzyme Activation; Enzyme Activators; Guanylate Cyclase; Heart Failure; Heme; Humans; Hypertension; Hypertension, Pulmonary; Inflammation; Leukocytes; Nitric Oxide; Platelet Aggregation; Pyrazoles; Pyridines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vasodilator Agents

A major problem with using nitrates in the treatment of ischemic heart disease is that tolerance develops to their vasodilatory actions. YC-1 was used as the lead compound to synthesize further nitric oxide-independent soluble guanylate cyclase activators, including BAY-41-2272 and BAY-41-8543. A nitric oxide and heme-independent activator of soluble guanylate cyclase, BAY-58-2667, was subsequently discovered by high-throughput screening. Tolerance to the vasodilatory actions of BAY-41-8543 and BAY-58-2667 does not develop. Results from animal studies have suggested that these compounds may have potential in the treatment of ischemic heart disease, essential and pulmonary hypertension, congestive heart failure, glomerulonephritis and erectile dysfunction.

Topics: Animals; Benzoates; Enzyme Activators; Glomerulonephritis; Guanylate Cyclase; Heart Failure; Humans; Hypertension; Morpholines; Myocardial Ischemia; Nitric Oxide; Pyrimidines

Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator. This study evaluated the haemodynamic effect and safety of cinaciguat added to standard therapy in patients with acute decompensated heart failure (ADHF).. In this placebo-controlled, phase IIb study (NCT00559650), 139 patients admitted with ADHF, pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, left ventricular ejection fraction <40%, and a pre-existing need for invasive haemodynamic monitoring were randomized 2:1 to cinaciguat:placebo (continuous i.v. infusion). The dose was titrated for 8 h and maintained for 16-40 h (starting dose: 100 μg/h). At 8 h, mean PCWP changed from 25.7 ± 5.0 mmHg by -7.7 mmHg with cinaciguat and from 25.0 ± 5.3 mmHg by -3.7 mmHg with placebo (P < 0.0001). The mean right atrial pressure changed from 12.4 ± 5.3 mmHg by -2.7 mmHg with cinaciguat and from 11.8 ± 4.9 mmHg by -0.6 mmHg with placebo (P= 0.0019). Cinaciguat also decreased the pulmonary and systemic vascular resistance and the mean arterial pressure, and increased the cardiac index (all P < 0.0001 vs. placebo). Systolic blood pressure changed by -21.6 ± 17.0 mmHg with cinaciguat and -5.0 ± 14.5 mmHg with placebo. Adverse events were experienced by 71 and 45% of patients receiving cinaciguat and placebo, respectively. No adverse effects on the 30-day mortality were seen; however, the trial was stopped prematurely due to an increased occurrence of hypotension at cinaciguat doses ≥200 µg/h.. Cinaciguat unloaded the heart in patients with ADHF. However, high doses were associated with hypotension.

Topics: Acute Disease; Benzoates; Dose-Response Relationship, Drug; Double-Blind Method; Early Termination of Clinical Trials; Female; Glomerular Filtration Rate; Guanylate Cyclase-Activating Proteins; Heart Failure; Hemodynamics; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Tachycardia, Ventricular; Treatment Outcome

Cinaciguat (BAY 58-2667) is a soluble guanylate cyclase (sGC) activator that, in a previous study among patients with acute heart failure syndromes (AHFS), improved pulmonary capillary wedge pressure (PCWP) at the expense of significant hypotension at doses ≥200 µg/h. The aim of the COMPOSE programme was to investigate the safety and efficacy of fixed, low doses of intravenous cinaciguat (<200 µg/h for 24-48 h) as add-on to standard therapy in adults hospitalized with AHFS.. COMPOSE comprised three randomized, double-blind, placebo-controlled studies in patients with [COMPOSE 1 and 2 (NCT01065077 and NCT01067859)] or without [COMPOSE EARLY (NCT01064037)] a requirement for invasive haemodynamic monitoring. COMPOSE 1 and COMPOSE EARLY assessed the effects of cinaciguat (50, 100, and 150 µg/h) on haemodynamics and dyspnoea, respectively. COMPOSE 2 assessed the haemodynamic effects of 10 and 25 µg/h cinaciguat. COMPOSE was terminated early due to an excess of non-fatal hypotension and recruitment difficulties. In COMPOSE 1 (n = 12), cinaciguat reduced PCWP at 8 h compared with placebo, but there was no relevant change in cardiac index. In COMPOSE EARLY (n = 62), no meaningful difference in dyspnoea was shown between cinaciguat and placebo.. In this limited database, short-term use of intravenous cinaciguat decreased blood pressure without improving dyspnoea or cardiac index. Given the lack of effect on dyspnoea and cardiac index and the hypotensive effect seen even with low doses, it is doubtful that further studies with intravenous cinaciguat would prove beneficial in this patient population.

Topics: Acute Disease; Adjuvants, Pharmaceutic; Aged; Aged, 80 and over; Benzoates; Blood Pressure; Double-Blind Method; Dyspnea; Enzyme Activation; Female; Glomerular Filtration Rate; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Syndrome

Cinaciguat (BAY 58-2667) is the first of a new class of soluble guanylate cyclase activators in clinical development for acute decompensated heart failure. We aimed to assess the hemodynamic effects, safety, and tolerability of intravenous cinaciguat in patients with acute decompensated heart failure (pulmonary capillary wedge pressure > or =18 mm Hg).. After initial dose finding (part A; n=27), cinaciguat was evaluated in the nonrandomized, uncontrolled proof-of-concept part of the study (part B; n=33) using a starting dose of 100 microg/h, which could be titrated depending on hemodynamic response. Patients were categorized as responders if their pulmonary capillary wedge pressure decreased by > or =4 mm Hg compared with baseline. Final doses of cinaciguat after 6 hours of infusion in part B were 50 microg/h (n=2), 200 microg/h (n=12), and 400 microg/h (n=16). Compared with baseline, a 6-hour infusion of cinaciguat led to significant reductions in pulmonary capillary wedge pressure (-7.9 mm Hg), mean right atrial pressure (-2.9 mm Hg), mean pulmonary artery pressure (-6.5 mm Hg), pulmonary vascular resistance (-43.4 dynes . s . cm(-5)), and systemic vascular resistance (-597 dynes . s . cm(-5)), while increasing heart rate by 4.4 bpm and cardiac output by 1.68 L/min. The responder rate was 53% after 2 hours, 83% after 4 hours, and 90% after 6 hours. Cinaciguat was well tolerated, with 13 of 60 patients reporting 14 drug-related treatment-emergent adverse events of mild to moderate intensity, most commonly hypotension.. Cinaciguat has potent preload- and afterload-reducing effects, increasing cardiac output. Further investigation of cinaciguat for acute decompensated heart failure is warranted.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Benzoates; Blood Pressure; Cardiac Output; Enzyme Activation; Female; Guanylate Cyclase; Heart Failure; Heart Rate; Hemodynamics; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Pulmonary Wedge Pressure; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vascular Resistance; Vasodilator Agents

Cinaciguat, a soluble guanylate cyclase (sGC) activator, was under clinical development for use in acute decompensated heart failure (ADHF), but was discontinued due to occurrence of hypotension. We hypothesized that short-term activation of sGC in ADHF patients would exert a vasodilative effect without hypotension irrespective of disease state, using a novel short-acting sGC activator, TY-55002. The objective of this study was to investigate the vasodilation and hemodynamic effects of TY-55002 in comparison with those of cinaciguat. TY-55002 and cinaciguat activated both normal and heme-oxidized sGC in a dose-dependent manner and caused rapid relaxation of phenylephrine-contracted rat aorta. However, TY-55002 had a milder effect than cinaciguat in enhancing the dose-activity response between normal and oxidized sGC. Therefore, we suggest that the pharmacological effect of TY-55002 is less subject than cinaciguat to oxidative stress associated with complications such as cardiovascular disease or diabetes. In normal dogs, the effects of intravenous TY-55002 or cinaciguat on blood pressure were evaluated in conjunction with the plasma concentrations of the compounds, and pharmacokinetic (PK)-pharmacodynamic (PD) analyses were carried out. The plasma-to-effect-site transfer rate constant (Ke

Topics: Animals; Benzoates; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Half-Life; Heart Failure; Hemodynamics; Humans; Hypotension; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Soluble Guanylyl Cyclase; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents

This open-label, parallel-group, single-dose study assessed the safety and pharmacokinetics of cinaciguat, a novel soluble guanylate cyclase activator in clinical development for the treatment of acute decompensated heart failure, in individuals with mild, moderate, or severe renal impairment compared with individuals with normal renal function. Cinaciguat was administered as a 100 µg/h continuous infusion over 4 hours. Plasma concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry. Renal function had only minor effects on the pharmacokinetics of cinaciguat. The apparent volume of distribution at steady state was slightly increased in individuals with renal impairment. The total body clearance from plasma showed a slight tendency to increase with progression of renal impairment, which can be explained by an increased hematocrit in individuals with renal impairment. No relevant influence was found on the terminal half-life. The fraction of cinaciguat unbound in plasma was very low (<1%) in all groups. Pharmacokinetic variability tended to be somewhat increased in individuals with renal impairment. Adverse events were mostly mild, and their incidence was similar in all groups. In conclusion, cinaciguat, a promising drug candidate for the treatment of acute decompensated heart failure, will not require dose adjustment based on renal function.

Topics: Adult; Aged; Benzoates; Chromatography, High Pressure Liquid; Female; Guanylate Cyclase; Half-Life; Heart Failure; Humans; Male; Mass Spectrometry; Middle Aged; Receptors, Cytoplasmic and Nuclear; Renal Insufficiency; Soluble Guanylyl Cyclase

Topics: Benzoates; Female; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Male

Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator in clinical development for the treatment of acute decompensated heart failure (ADHF). In patients with ADHF, intravenously administered cinaciguat results in potent unloading of the heart with arterial vasodilation. The aims of this study were to define the structural pharmacokinetic and pharmacodynamic models of cinaciguat in patients with ADHF, to characterize interindividual variability and to explore the effects of potential covariates.. Modelling was performed using NONMEM version V software, based on data from 56 adult patients with ADHF (pulmonary capillary wedge pressure > or = 18 mmHg) participating in a phase II study.. Cinaciguat pharmacokinetics were well described using an open, two-compartment model with an 'effect compartment' and elimination from the central compartment. The population mean estimates for the clearance and volume of distribution at steady state were 26.4 L/h and 18.4 L, respectively. The pharmacokinetics were linear, with no dose-dependent or time-dependent effects on the clearance or volume of distribution, and with moderate interindividual variability. Covariate analyses showed that cardiac output significantly affected clearance, whereas patient age, bodyweight and renal function did not. Time delays between plasma concentrations and effect compartment concentrations, as described by the dissipation rate constant from the effect compartment, ranged from 0.32 h(-1) to 0.86 h(-1) for the different haemodynamic parameters of the final pharmacokinetic/pharmacodynamic model. A 50% recovery to pharmacodynamic baseline values was estimated to occur within 1 hour and a complete return to baseline was estimated to occur within 3-4 hours after the end of infusion.. Intravenously administered cinaciguat had predictable pharmacokinetic and haemodynamic effects in patients with ADHF.

Topics: Acute Disease; Aged; Benzoates; Dose-Response Relationship, Drug; Female; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Male; Nonlinear Dynamics; Vasodilator Agents

The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine-3',5'-monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by producing vasodilation and inhibiting platelet aggregation and vascular smooth muscle proliferation. The NO/SGC/cGMP pathway is disrupted in patients with heart failure as a result of a decrease in NO bioavailability and an increase in NO-insensitive forms of sGC, resulting in insufficient vasodilation. Drugs that activate sGC in a NO-independent manner may provide considerable therapeutic advantages in treating these patients. Cinaciguat (BAY-58-2667), currently in development by Bayer AG, preferentially activates sGC in its oxidized or heme-free state, when the enzyme is insensitive to both NO and nitrovasodilators. Cinaciguat exhibits potent vasodilator and antiplatelet activity, a long-lasting antihypertensive effect and a hemodynamic profile similar to that of nitrates. In clinical trials in patients with acute decompensated heart failure, cinaciguat potently unloaded the heart, increased cardiac output and renal blood flow, and preserved renal function and sodium and water excretion without further neurohumoral activation. The pharmacokinetics of cinaciguat demonstrated dose-proportionality with low individual variability and a low incidence of adverse events. The phase I and II clinical trials performed with cinaciguat so far, however, are insufficient to provide convincing evidence on the efficacy and safety of the drug. Thus, caution should be exerted before extrapolating the present preliminary data to the clinical practice.

Topics: Acute Disease; Animals; Benzoates; Cardiovascular System; Clinical Trials as Topic; Drug Evaluation, Preclinical; Enzyme Activators; Guanylate Cyclase; Heart Failure; Hemodynamics; Humans; Male; Vasodilator Agents

Topics: Benzoates; Clinical Trials as Topic; Endothelium, Vascular; Enzyme Activation; Guanylate Cyclase; Heart Failure; Heme; Humans; Morpholines; Nitric Oxide; Pyrazoles; Pyridines; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Vasodilator Agents; Vasomotor System

Topics: Animals; Benzoates; Dose-Response Relationship, Drug; Enzyme Activation; Guanylate Cyclase; Heart; Heart Failure; Heme; Humans; Kidney; Oxidation-Reduction; Solubility

Soluble guanylate cyclase is a heterodimeric enzyme with a prosthetic heme group that, on binding of its main ligand, NO, generates the second messenger cGMP. Unlike conventional nitrovasodilators, the novel direct NO- and heme-independent soluble guanylate cyclase activator BAY 58-2667 is devoid of non-cGMP actions, lacks tolerance development, and preferentially activates NO-insensitive heme-free or oxidized soluble guanylate cyclase. BAY 58-2667, therefore, represents a novel therapeutic advance in mediating vasodilation. To date, its cardiorenal actions in congestive heart failure (CHF) are undefined. We, therefore, hypothesized that BAY 58-2667 would have beneficial preload- and afterload-reducing actions in experimental severe CHF together with renal vasodilating properties. We assessed the cardiorenal actions of intravenous administration of 2 doses of BAY 58-2667 (0.1 and 0.3 microg/kg per minute, respectively) in a model of tachypacing-induced severe CHF. In CHF, BAY 58-2667 dose-dependently reduced mean arterial, right atrial, pulmonary artery, and pulmonary capillary wedge pressure (from baseline 19+/-1 to 12+/-2 mm Hg). Cardiac output (2.4+/-0.3 to 3.2+/-0.4 L/min) and renal blood flow increased. Glomerular filtration rate and sodium and water excretion were maintained. Consistent with cardiac unloading, atrial and B-type natriuretic peptide decreased. Plasma renin activity (P=0.31) and aldosterone remained unchanged (P=0.19). In summary, BAY 58-2667 in experimental CHF potently unloaded the heart, increased cardiac output and renal blood flow, and preserved glomerular filtration rate and sodium and water excretion without further neurohumoral activation. These beneficial properties make direct soluble guanylate cyclase stimulation with BAY 58-2667 a promising new therapeutic strategy for cardiovascular diseases, such as heart failure.

Topics: Animals; Atrial Natriuretic Factor; Benzoates; Blood Vessels; Cardiovascular System; Dogs; Dose-Response Relationship, Drug; Guanylate Cyclase; Heart Failure; Heme; Kidney; Male; Natriuretic Peptide, Brain; Oxidation-Reduction; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vasodilation