cyclic-gmp and Heart-Diseases

Cyclic nucleotide phosphodiesterases comprise an 11-member superfamily yielding near 100 isoform variants that hydrolyze cAMP or cGMP to their respective 5'-monophosphate form. Each plays a role in compartmentalized cyclic nucleotide signaling, with varying selectivity for each substrate, and conveying cell and intracellular-specific localized control. This review focuses on the 5 phosphodiesterases (PDEs) expressed in the cardiac myocyte capable of hydrolyzing cGMP and that have been shown to play a role in cardiac physiological and pathological processes. PDE1, PDE2, and PDE3 catabolize cAMP as well, whereas PDE5 and PDE9 are cGMP selective. PDE3 and PDE5 are already in clinical use, the former for heart failure, and PDE1, PDE9, and PDE5 are all being actively studied for this indication in patients. Research in just the past few years has revealed many novel cardiac influences of each isoform, expanding the therapeutic potential from their selective pharmacological blockade or in some instances, activation. PDE1C inhibition was found to confer cell survival protection and enhance cardiac contractility, whereas PDE2 inhibition or activation induces beneficial effects in hypertrophied or failing hearts, respectively. PDE3 inhibition is already clinically used to treat acute decompensated heart failure, although toxicity has precluded its long-term use. However, newer approaches including isoform-specific allosteric modulation may change this. Finally, inhibition of PDE5A and PDE9A counter pathological remodeling of the heart and are both being pursued in clinical trials. Here, we discuss recent research advances in each of these PDEs, their impact on the myocardium, and cardiac therapeutic potential.

Topics: Animals; Cardiovascular Agents; Cyclic GMP; Heart Diseases; Humans; Myocardium; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Second Messenger Systems

3',5'-Cyclic guanosine monophosphate (cGMP) is a ubiquitous second messenger, which critically regulates cardiac pump function and protects from the development of cardiac hypertrophy by acting in various subcellular microdomains. Although clinical studies testing the potential of cGMP elevating drugs in patients suffering from cardiac disease showed promising results, deeper insight into the local actions of these drugs at the subcellular level are indispensable to inspire novel therapeutic strategies. Detailed information on the spatio-temporal dynamics of cGMP production and degradation can be provided by the use of fluorescent biosensors that are capable of monitoring this second messenger at different locations inside the cell with high temporal and spatial resolution. In this review, we will summarize how these emerging new tools have improved our understanding of cardiac cGMP signaling in health and disease, and attempt to anticipate future challenges in the field.

Topics: Animals; Biosensing Techniques; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Fluorescence Resonance Energy Transfer; Guanylate Cyclase; Heart Diseases; Humans; Kinetics; Molecular Imaging; Myocardium; Phosphoric Diester Hydrolases; Second Messenger Systems

The 3',5'-cyclic guanosine monophosphate (cGMP)-dependent protein kinase type I (cGKI aka PKGI) is a major cardiac effector acting downstream of nitric oxide (NO)-sensitive soluble guanylyl cyclase and natriuretic peptides (NPs), which signal through transmembrane guanylyl cyclases. Consistent with the wide distribution of the cGMP-generating guanylyl cyclases, cGKI, which usually elicits its cellular effects by direct phosphorylation of its targets, is present in multiple cardiac cell types including cardiomyocytes (CMs). Although numerous targets of cGMP/cGKI in heart were identified in the past, neither their exact patho-/physiological functions nor cell-type specific roles are clear. Herein, we inform about the current knowledge on the signal transduction downstream of CM cGKI. We believe that better insights into the specific actions of cGMP and cGKI in these cells will help to guide future studies in the search for predictive biomarkers for the response to pharmacological cGMP pathway modulation. In addition, targets downstream of cGMP/cGKI may be exploited for refined and optimized diagnostic and therapeutic strategies in different types of heart disease and their causes. Importantly, key functions of these proteins and particularly sites of regulatory phosphorylation by cGKI should, at least in principle, remain intact, although upstream signaling through the second messenger cGMP is impaired or dysregulated in a stressed or diseased heart state.

Topics: Animals; Cardiovascular Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Heart Diseases; Humans; Myocytes, Cardiac; Phosphorylation; Second Messenger Systems; Substrate Specificity

Cyclic nucleotide phosphodiesterases (PDEs) form an 11-member superfamily comprising 100 different isoforms that regulate the second messengers cyclic adenosine or guanosine 3',5'-monophosphate (cAMP or cGMP). These PDE isoforms differ with respect to substrate selectivity and their localized control of cAMP and cGMP within nanodomains that target specific cellular pools and synthesis pathways for the cyclic nucleotides. Seven PDE family members are physiologically relevant to regulating cardiac function, disease remodeling of the heart, or both: PDE1 and PDE2, both dual-substrate (cAMP and cGMP) esterases; PDE3, PDE4, and PDE8, which principally hydrolyze cAMP; and PDE5A and PDE9A, which target cGMP. New insights regarding the different roles of PDEs in health and disease and their local signaling control are broadening the potential therapeutic utility for PDE-selective inhibitors. In this review, we discuss these PDEs, focusing on the different mechanisms by which they control cardiac function in health and disease by regulating intracellular nanodomains.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cardiovascular Physiological Phenomena; Cyclic AMP; Cyclic GMP; Heart Diseases; Humans; Nanoparticles; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Protein Domains; Second Messenger Systems; Signal Transduction

An important hallmark of cardiac failure is abnormal second messenger signaling due to impaired synthesis and catabolism of cyclic adenosine 3',5'- monophosphate (cAMP) and cyclic guanosine 3',5'- monophosphate (cGMP). Their dysregulation, altered intracellular targeting, and blunted responsiveness to stimulating pathways all contribute to pathological remodeling, muscle dysfunction, reduced cell survival and metabolism, and other abnormalities. Therapeutic enhancement of either cyclic nucleotides can be achieved by stimulating their synthesis and/or by suppressing members of the family of cyclic nucleotide phosphodiesterases (PDEs). The heart expresses seven of the eleven major PDE subtypes - PDE1, 2, 3, 4, 5, 8, and 9. Their differential control over cAMP and cGMP signaling in various cell types, including cardiomyocytes, provides intriguing therapeutic opportunities to counter heart disease. This review examines the roles of these PDEs in the failing and hypertrophied heart and summarizes experimental and clinical data that have explored the utility of targeted PDE inhibition.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cardiomyopathy, Dilated; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Cyclic Nucleotide Phosphodiesterases, Type 2; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Diseases; Heart Failure; Humans; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Signal Transduction

The protective role of cyclic guanosine monophosphate (cGMP)-stimulated protein kinase G (PKG) in the heart makes it an attractive target for therapeutic drug development to treat a variety of cardiac diseases. Phosphodiesterases degrade cGMP, thus phosphodiesterase inhibitors that can increase PKG are of translational interest and the subject of ongoing human trials. PKG signaling is complex, however, and understanding its downstream phosphorylation targets and upstream regulation are necessary steps toward safe and efficacious drug development. Proteomic technologies have paved the way for assays that allow us to peer broadly into signaling minutia, including protein quantity changes and phosphorylation events. However, there are persistent challenges to the proteomic study of PKG, such as the impact of the expression of different PKG isoforms, changes in its localization within the cell, and alterations caused by oxidative stress. PKG signaling is also dependent upon sex and potentially the genetic and epigenetic background of the individual. Thus, the rigorous application of proteomics to the field will be necessary to address how these effectors can alter PKG signaling and interfere with pharmacological interventions. This review will summarize PKG signaling, how it is being targeted clinically, and the proteomic challenges and techniques that are being used to study it.

Topics: Amino Acid Sequence; Animals; Cattle; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Drug Discovery; Heart; Heart Diseases; Humans; Mice; Rats; Signal Transduction

Overstimulation of the orthosympathetic system leads to cardiovascular cell and tissue damage through prolonged activation of β-1-2 adrenergic receptors (BARs). The more recent identification of the third isotype of BAR (B3AR) in cardiac myocytes and endothelial cells with a distinctive coupling and effect on cardiac function and remodelling introduced a new facet to this paradigm. In particular, B3AR is up-regulated in cardiac disease and less prone to homologous desensitization, which may reinforce its influence on the diseased myocardium. Mice with transgenic cardiac-specific expression of the human B3AR are protected from cardiac hypertrophy and fibrosis in response to neurohormonal stimulation. B3AR has also been implicated in cardiac protection after ischaemia-reperfusion and the benefits of exercise on the heart. Many of these salvage mechanisms are mediated by B3AR coupling to nitric oxide synthase (eNOS and nNOS) and downstream cGMP/protein kinase G signalling. Notably, B3AR exerts antioxidant protective effects on these and other signalling elements, which may subserve its protective properties in the setting of chronic heart failure. Additional vasorelaxing properties and paracrine NO-mediated signalling by B3AR in endothelium, together with systemic metabolic effects on beige/brown fat complete the pleiotropic protective properties of this new therapeutic target.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Endothelial Cells; Heart Diseases; Humans; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Receptors, Adrenergic, beta-3; Signal Transduction; Thiazoles; Ventricular Remodeling

The second messenger cyclic guanosine 3'5' monophosphate (cGMP) and its downstream effector protein kinase G (PKG) have been discovered more than 40 years ago. In vessels, PKG1 induces smooth muscle relaxation in response to nitric oxide signalling and thus lowers systemic and pulmonary blood pressure. In platelets, PKG1 stimulation by cGMP inhibits activation and aggregation, and in experimental models of heart failure (HF), PKG1 activation by inhibiting cGMP degradation is protective. The net effect of the above-mentioned signalling is cardiovascular protection. Yet, while modulation of cGMP-PKG has entered clinical practice for treating pulmonary hypertension or erectile dysfunction, translation of promising studies in experimental HF to clinical success has failed thus far. With the advent of new technologies, novel mechanisms of PKG regulation, including mechanosensing, redox regulation, protein quality control, and cGMP degradation, have been discovered. These novel, non-canonical roles of PKG1 may help understand why clinical translation has disappointed thus far. Addressing them appears to be a requisite for future, successful translation of experimental studies to the clinical arena.

Topics: Animals; Cardiovascular Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Heart Diseases; Humans; Molecular Targeted Therapy; Myocardium; Oxidation-Reduction; Phosphodiesterase 5 Inhibitors; Proteasome Endopeptidase Complex; Protein Kinase Inhibitors; Signal Transduction; Stress, Physiological; TRPC Cation Channels

cGMP inhibits hypertrophy, decreases fibrosis, and protects against cardiac ischemia-reperfusion (I/R) injury. Gene-targeting studies have not defined a clear role for its major downstream effector, cGMP-dependent protein kinase I (cGKI), in cardiac hypertrophy, but do implicate cGMP-cGKI signaling in fibrosis and I/R injury. No direct cGKI activators have advanced to clinical trials, whereas cardiac trials of agents that modulate cGMP via particulate or soluble guanylyl cyclases (GCs) and phosphodiesterase 5 (PDE5) are ongoing. Here we review concerns arising from preclinical and clinical studies that question whether targeting the cGMP pathway remains an encouraging concept for management of heart dysfunction. So far, trial results for GC modulators are inconclusive, and sildenafil, a PDE5 inhibitor, although cardioprotective in mouse models, has not shown positive clinical results. Preclinical cardioprotection observed for sildenafil may result from inhibition of PDE5 in non-cardiomyocytes or off-target effects, possibly on PDE1C. On the basis of such mechanistic considerations, re-evaluation of the cellular localization of drug target(s) and intervention protocols for cGMP-elevating agents may be needed.

Topics: Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Diseases; Humans; Phosphodiesterase 5 Inhibitors

Altered cyclic nucleotide-mediated signaling plays a critical role in the development of cardiovascular pathology. By degrading cAMP/cGMP, the action of cyclic nucleotide PDEs is essential for controlling cyclic nucleotide-mediated signaling intensity, duration, and specificity. Altered expression, localization and action of PDEs have all been implicated in causing changes in cyclic nucleotide signaling in cardiovascular disease. Accordingly, pharmacological inhibition of PDEs has gained interest as a treatment strategy and as an area of drug development. While targeting of certain PDEs has the potential to ameliorate cardiovascular disease, inhibition of others might actually worsen it. This review will highlight recent research on the physiopathological role of cyclic nucleotide signaling, especially with regard to PDEs. While the physiological roles and biochemical properties of cardiovascular PDEs will be summarized, the primary emphasis will be pathological. Research into the potential benefits and hazards of PDE inhibition will also be discussed.

Topics: Animals; Cyclic AMP; Cyclic GMP; Drug Discovery; Heart Diseases; Humans; Molecular Targeted Therapy; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases

The regulation of myocardial function by constitutive nitric oxide synthases (NOS) is important for the maintenance of myocardial Ca(2+) homeostasis, relaxation and distensibility, and protection from arrhythmia and abnormal stress stimuli. However, sustained insults such as diabetes, hypertension, hemodynamic overload, and atrial fibrillation lead to dysfunctional NOS activity with superoxide produced instead of NO and worse pathophysiology.. Major strides in understanding the role of normal and abnormal constitutive NOS in the heart have revealed molecular targets by which NO modulates myocyte function and morphology, the role and nature of post-translational modifications of NOS, and factors controlling nitroso-redox balance. Localized and differential signaling from NOS1 (neuronal) versus NOS3 (endothelial) isoforms are being identified, as are methods to restore NOS function in heart disease.. Abnormal NOS signaling plays a key role in many cardiac disorders, while targeted modulation may potentially reverse this pathogenic source of oxidative stress.. Improvements in the clinical translation of potent modulators of NOS function/dysfunction may ultimately provide a powerful new treatment for many hearts diseases that are fueled by nitroso-redox imbalance.

Topics: Animals; Arginase; Autocrine Communication; Biopterins; Calcium Signaling; Cyclic GMP; Diabetes Mellitus; Disease Progression; Enzyme Activation; Enzyme Induction; Heart Diseases; Heart Failure; Humans; Hypertension; Myocardium; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase; Paracrine Communication; Protein Processing, Post-Translational; Protein Structure, Tertiary; Protein Transport; Signal Transduction; Superoxides

ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling is an important aspect of all drug developments. The pharmaceutical industry must always consider ADMET properties in order to optimize drug candidates and to introduce new formulations against existing marketed drugs. Consequently, candidate drug development may be halted early in the discovery phase or during the more costly drug development process because of their poor ADMET properties.. The main focus of this article is ADMET profiling, pharmacokinetic (PK) drug interactions, mechanisms and possible adverse drug reactions (ADRs) for approved phosphodiesterase-5 inhibitors (PDE5Is). The authors also look at the efficacy and non-erectogenic benefits of current PDE5Is, which are widely used by patients with erectile dysfunction (ED). The authors also discuss other unapproved PDE5Is such as aildenafil and udenafil, which are currently in use in clinical trials.. The authors believe that the enhancing effect of PDE5Is on the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway means that PDE5Is could be used to treat various conditions. An important issue in their development is 'cross-talk' between PDE5 and other PDEs and thus their specificity for other PDEs. But while it might be difficult to achieve the ideal ADMET profile, it should not necessarily prevent further development of a lead PDE5I. The risk assessment of PDE5Is, with respect to their ADMET properties, is therefore very important for predicting drug-drug interactions, possible side effects, ADRs and its future clinical applications.

Topics: Adsorption; Cyclic GMP; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Food-Drug Interactions; Gastrointestinal Diseases; Gastrointestinal Tract; Hearing; Heart; Heart Diseases; Humans; Nervous System Diseases; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Reproduction; Tissue Distribution

Cyclic GMP (cGMP) and its effector kinase PKG regulate diverse cellular functions. In cardiac myocytes, cGMP is produced by soluble and particulate guanylyl cyclases (GCs), the former stimulated by nitric oxide and the latter by natriuretic peptides, and is hydrolyzed to inactive 5'-GMP by cGMP-phosphodiesterases (PDEs). cGMP-PKG modulates cardiac contractility, hypertrophy and remodeling, and exerts cardioprotection. Although early research efforts have mostly focused on cGMP synthetic pathways, recent studies have revealed that cGMP degradation controlled by PDEs plays a critical role in the physiological action of cGMP. Among several cGMP-PDEs, cGMP-specific PDE5 has been intensively investigated. Studies in experimental animal models and humans consistently demonstrate benefits from PDE5 inhibitors in various cardiac pathologies. Several clinical trials are ongoing or planned to test the efficacy of PDE5 inhibitors in human heart disease, including a large multicenter clinical trial (RELAX) led by the NIH evaluating sildenafil efficacy in heart failure with preserved ejection fraction. This review underscores the current understanding of cGMP-PKG signal regulation and its pathophysiological role in the heart, focusing on cardiac myocytes.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Diseases; Humans; Multicenter Studies as Topic; Muscle Proteins; Myocytes, Cardiac; Phosphodiesterase 5 Inhibitors; Second Messenger Systems

Topics: Active Transport, Cell Nucleus; Animals; Atrial Natriuretic Factor; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Heart Diseases; Humans; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Natriuretic peptides are a family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. The mammalian members are atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide, and possibly osteocrin/musclin. Three single membrane-spanning natriuretic peptide receptors (NPRs) have been identified. Two, NPR-A/GC-A/NPR1 and NPR-B/GC-B/NPR2, are transmembrane guanylyl cyclases, enzymes that catalyze the synthesis of cGMP. One, NPR-C/NPR3, lacks intrinsic enzymatic activity and controls the local concentrations of natriuretic peptides through constitutive receptor-mediated internalization and degradation. Single allele-inactivating mutations in the promoter of human NPR-A are associated with hypertension and heart failure, whereas homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux. The physiological effects of natriuretic peptides are elicited through three classes of cGMP binding proteins: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. In this comprehensive review, the structure, function, regulation, and biological consequences of natriuretic peptides and their associated signaling proteins are described.

Topics: Animals; Cyclic GMP; Growth Disorders; Heart Diseases; Humans; Hypertension; Natriuretic Peptides; Obesity; Protein Structure, Tertiary; Receptor Cross-Talk; Receptors, Peptide; Signal Transduction

Biochemical studies have established the presence of a NO pathway in the heart, including sources of NO and various effectors. Several cardiac ion channels have been shown to be modified by NO, such as L-type Ca(2+), ATP-sensitive K(+), and pacemaker f-channels. Some of these effects are mediated by cGMP, through the activity of three main proteins: the cGMP-dependent protein kinase (PKG), the cGMP-stimulated phosphodiesterase (PDE2) and the cGMP-inhibited PDE (PDE3). Other effects appear independent of cGMP, as for instance the NO modulation of the ryanodine receptor-Ca(2+) channel. In the case of the cardiac L-type Ca(2+) channel current (I(Ca,L)), both cGMP-dependent and cGMP-independent effects have been reported, with important tissue and species specificity. For instance, in rabbit sinoatrial myocytes, NO inhibits the beta-adrenergic stimulation of I(Ca,L) through activation of PDE2. In cat and human atrial myocytes, NO potentiates the cAMP-dependent stimulation of I(Ca,L) through inhibition of PDE3. In rabbit atrial myocytes, NO enhances I(Ca,L) in a cAMP-independent manner through the activation of PKG. In ventricular myocytes, NO exerts opposite effects on I(Ca,L): an inhibition mediated by PKG in mammalian myocytes but by PDE2 in frog myocytes; a stimulation attributed to PDE3 inhibition in frog ventricular myocytes but to a direct effect of NO in ferret ventricular myocytes. Finally, NO can also regulate cardiac ion channels by a direct action on G-proteins and adenylyl cyclase.

Topics: Adenylyl Cyclases; Animals; Calcium; Cats; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Heart Diseases; Heart Ventricles; Humans; Hypertrophy; Ion Channels; Ions; Muscle Cells; Myocardium; Myocytes, Cardiac; Nitric Oxide; Potassium; Rabbits; Signal Transduction; Tissue Distribution

The prognostic importance of levels of urinary excretion of cyclic GMP (cGMPu), the second messenger of the atrial natriuretic factor (ANF) was studied in different cardiac pathologies in 31 patients (19 males and 12 females, average age 66 +/- 15 years) and compared with 31 control subjects of the same age (+/- 4 years) and sex. In the control group, the average cGMPu was 0.35 +/- 0.17 mumoles/24 hours/m2, and, with respect to urinary creatinine, increased with age (r = 0.54, p = 0.002). In the 16 patients with cardiac failure, the cGMPu was very high (1.03 +/- 0.59 mumoles/24 hours/m2, p less than 0.001) without any significant correlation with NYHA functional class although it fell after treatment. After myocardial infarction (8 cases including 3 with cardiac failure), the cGMPu was also high (0.49 +/- 0.33 mumoles/24 hours/m2) but it did not differ significantly from the control values in the 9 atrial arrhythmias without cardiac failure. The cGPMu was related to the cardiothoracic ratio but not to any blood gas parameter or echocardiographic measurement. In conclusion, the cGMPu is more stable and easier to measure than the ANF. It would seem to be a sensitive marker of cardiac failure complicating the most common cardiac pathologies observed in clinical practice.

Topics: Adult; Aged; Aged, 80 and over; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Cyclic GMP; Female; Heart Atria; Heart Diseases; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cyclic GMP; Diuretics; Glomerular Filtration Rate; Heart Diseases; Hemodynamics; Humans; Hypertension; Muscle, Smooth; Muscle, Smooth, Vascular; Renal Circulation; Renin-Angiotensin System

Topics: Adenosine Triphosphatases; Animals; Calcium; Cardiomegaly; Cyclic AMP; Cyclic GMP; Electrophysiology; Heart; Heart Diseases; Humans; Hypertrophy; In Vitro Techniques; Microsomes; Mitochondria; Muscle Proteins; Myocardium; Myofibrils; Oxygen Consumption; Protein Biosynthesis; Protein Kinases; Sarcoplasmic Reticulum

Human atrial natriuretic peptide (h-ANP) elicits biological effects such as natriuresis, diuresis, and vasodilation, and plays a role in regulating pulmonary circulation. We conducted this clinical study to define its role and elucidate its mechanisms.. Twelve consecutive adult patients scheduled to undergo cardiac surgery with cardiopulmonary bypass (CPB) were prospectively selected for this study. After the completion of surgery, h-ANP was infused from the right atrium through a Swan-Ganz (S-G) catheter. Blood samples for measurement of ANP and cyclic guanosine monophosphate (cGMP), the second messenger of ANP, were drawn from the pulmonary artery (PA) through the S-G catheter and from the left atrium (LA) through the left atrial pressure line, before and after the infusion of h-ANP. Hemodynamic values were measured at the same time.. After the h-ANP infusion, the plasma levels of ANP were significantly lower in the LA than in the PA, whereas the plasma levels of cGMP were significantly higher in the LA than in the PA. The infusion of h-ANP decreased the mean PA pressure significantly, and the systolic PA pressure remarkably.. The infusion of h-ANP after cardiac surgery stimulates the secretion of cGMP from the pulmonary vascular bed and dilates the PA, thereby decreasing the PA pressure.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Cyclic GMP; Female; Heart Diseases; Hemodynamics; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Artery; Pulmonary Circulation; Vasodilator Agents

Hypertonic-iso/hyperoncotic solutions have been the subject of numerous studies, mostly used in a fixed dosage (4 mL/kg bw or 250 mL). Nearly no study exists to prove whether this is the appropriate dosage especially in cardiac risk patients with accompanying diseases. We have compared preoperative volume loading with either 10% hydroxyethyl-starch/7.5% NaCl (HHT-HES) or 10% hydroxyethyl-starch/.9% NaCl (HES) in 50 mL bolus infusions. Volume loading was done with either HES or HHT-HES in 2 x 20 patients before aortic aneurysmectomy. The endpoint of stepwise infusion represented the highest cardiac index (CI) at the lowest possible wedge pressure (PCWP) (turning point of each individual Frank Starling relation). 167.5 mL (+/- 45.5 mL = 2.41 mL/kg bw) of HHT-HES and 440 mL (+/- 26.15 mL = 6.33 mL/kg bw) of HES were necessary. We observed a significant higher increase of the CI in the HHT-HES group. Significant increases of PCWP, pulmonary artery pressure, and central venous pressure occurred within the groups without any significant differences between the groups (p < .05). Results of the study showed: 1) The commonly used fixed dosage of 4 mL/kg bw of HHT-HES is too high in cardiac risk patients with slight hypovolemia. 2) HHT-HES should be given in an individual titration. 3) In the HHT-HES group we observed a positive inotropic effect (higher CI). 4) With the individual titration of HHT-HES no negative side effects occurred (especially no hypotension).

Topics: Aged; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Cardiac Output; Cyclic GMP; Drug Evaluation; Heart Diseases; Heart Rate; Hemodynamics; Humans; Hypertonic Solutions; Male; Middle Aged; Myocardial Infarction; Osmolar Concentration; Oxygen; Premedication; Pulmonary Wedge Pressure; Risk Factors; Sodium; Systole; Time Factors; Venous Pressure; Ventricular Function, Left; Ventricular Function, Right

Rewarming from hypothermia is associated with severe complications, one of which is hypothermia-induced cardiac dysfunction. This condition is characterized by decreased cardiac output accompanied by increased total peripheral resistance. This contributes to mortality rate approaching 40%. Despite this, no pharmacological interventions are recommended for these patients below 30 °C. Raising the intracellular levels of cAMP and/or cGMP, through PDE3- and PDE5-inhibitors respectively, have showed the ability to alleviate hypothermia-induced cardiac dysfunction in vivo. Drugs that raise levels of both cAMP and cGMP could therefore prove beneficial in patients suffering from hypothermia-induced cardiac dysfunction.. The unselective PDE-inhibitor pentoxifylline was investigated to determine its ability to reach the intracellular space, inhibit PDE3 and PDE5 and inhibit cellular efflux of cAMP and cGMP at temperatures 37, 34, 30, 28, 24 and 20 °C. Recombinant human PDE-enzymes and human erythrocytes were used in the experiments. IC. At 20 °C, the IC. This study shows that pentoxifylline has minimal temperature-dependent pharmacodynamic changes, and that it can inhibit elimination of both cAMP and cGMP at low temperatures. This can potentially be effective treatment of hypothermia-induced cardiac dysfunction.. Not applicable.

Topics: Cyclic AMP; Cyclic GMP; Heart Diseases; Humans; Hypothermia; Pentoxifylline

β-blockers are widely used in therapy for heart failure and hypertension. β-blockers are also known to evoke additional diversified pharmacological and physiological effects in patients. We aim to characterize the underlying molecular signalling and effects on cardiac inotropy induced by β-blockers in animal hearts.. Wild-type mice fed high-fat diet (HFD) were treated with carvedilol, metoprolol, or vehicle and echocardiogram analysis was performed. Heart tissues were used for biochemical and histological analyses. Cardiomyocytes were isolated from normal and HFD mice and rats for analysis of adrenergic signalling, calcium handling, contraction, and western blot. Biosensors were used to measure β-blocker-induced cyclic guanosine monophosphate (cGMP) signal and protein kinase A activity in myocytes. Acute stimulation of myocytes with carvedilol promotes β1 adrenergic receptor (β1AR)- and protein kinase G (PKG)-dependent inotropic cardiac contractility with minimal increases in calcium amplitude. Carvedilol acts as a biased ligand to promote β1AR coupling to a Gi-PI3K-Akt-nitric oxide synthase 3 (NOS3) cascade and induces robust β1AR-cGMP-PKG signal. Deletion of NOS3 selectively blocks carvedilol, but not isoproterenol-induced β1AR-dependent cGMP signal and inotropic contractility. Moreover, therapy with carvedilol restores inotropic contractility and sensitizes cardiac adrenergic reserves in diabetic mice with minimal impact in calcium signal, as well as reduced cell apoptosis and hypertrophy in diabetic hearts.. These observations present a novel β1AR-NOS3 signalling pathway to promote cardiac inotropy in the heart, indicating that this signalling paradigm may be targeted in therapy of heart diseases with reduced ejection fraction.

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Cardiotonic Agents; Carvedilol; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Heart Diseases; Male; Mice, Inbred C57BL; Mice, Knockout; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Rats; Receptors, Adrenergic, beta-1; Second Messenger Systems

Topics: Animals; Cardiovascular Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Heart Diseases; Humans; Myocardium; Second Messenger Systems

Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity.. Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN-/-) mice were assigned to PLN-/-/Control (N/S-0.9%), PLN-/-/DXR (18 mg/kg), and PLN-/-/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan's cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN-/- mice. Levosimendan's cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload.. Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.

Topics: Animals; Antibiotics, Antineoplastic; Calcium Signaling; Calcium-Binding Proteins; Cardiotoxicity; Cardiovascular Agents; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Doxorubicin; Female; Heart Diseases; Male; Mammary Neoplasms, Experimental; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-akt; Rats, Wistar; Simendan; Time Factors

In different pathological situations, cardiac cells undergo hyperosmotic stress (HS) and cell shrinkage. This change in cellular volume has been associated with contractile dysfunction and cell death. Given that nitric oxide (NO) is a well-recognized modulator of cardiac contractility and cell survival, we evaluated whether HS increases NO production and its impact on the negative inotropic effect observed during this type of stress. Superfusing cardiac myocytes with a hypertonic solution (HS: 440 mOsm) decreased cell volume and increased NO-sensitive DAF-FM fluorescence compared with myocytes superfused with an isotonic solution (IS: 309 mOsm). When cells were exposed to HS in addition to different inhibitors: L-NAME (NO synthase inhibitor), nitroguanidine (nNOS inhibitor), and Wortmannin (eNOS inhibitor) cell shrinkage occurred in the absence of NO release, suggesting that HS activates nNOS and eNOS. Consistently, western blot analysis demonstrated that maintaining cardiac myocytes in HS promotes phosphorylation and thus, activation of nNOS and eNOS compared to myocytes maintained in IS. HS-induced nNOS and eNOS activation and NO production were also prevented by AMPK inhibition with Dorsomorphin (DORSO). In addition, the HS-induced negative inotropic effect was exacerbated in the presence of either L-NAME, DORSO, ODQ (guanylate cyclase inhibitor), or KT5823 (PKG inhibitor), suggesting that NO provides contractile support via a cGMP/PKG-dependent mechanism. Our findings suggest a novel mechanism of AMPK-dependent NO release in cardiac myocytes with putative pathophysiological relevance determined, at least in part, by its capability to reduce the extent of contractile dysfunction associated with hyperosmotic stress.

Topics: Adaptation, Physiological; AMP-Activated Protein Kinases; Animals; Cell Size; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Enzyme Activation; Guanylate Cyclase; Heart Diseases; Male; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Osmotic Pressure; Phosphorylation; Rats, Wistar; Signal Transduction

MicroRNAs (miRs) posttranscriptionally regulate mRNA and its translation into protein, and are considered master controllers of genes modulating normal physiology and disease. There is growing interest in how miRs change with drug treatment, and leveraging this for precision guided therapy. Here we contrast 2 closely related therapies, inhibitors of phosphodiesterase type 5 or type 9 (PDE5-I, PDE9-I), given to mice subjected to sustained cardiac pressure overload (PO). Both inhibitors augment cyclic guanosine monophosphate (cGMP) to activate protein kinase G, with PDE5-I regulating nitric oxide (NO) and PDE9-I natriuretic peptide-dependent signaling. While both produced strong phenotypic improvement of PO pathobiology, they surprisingly showed binary differences in miR profiles; PDE5-I broadly reduces more than 120 miRs, including nearly half those increased by PO, whereas PDE9-I has minimal impact on any miR (P < 0.0001). The disparity evolves after pre-miR processing and is organ specific. Lastly, even enhancing NO-coupled cGMP by different methods leads to altered miR regulation. Thus, seemingly similar therapeutic interventions can be barcoded by profound differences in miR signatures, and reversing disease-associated miR changes is not required for therapy success.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Heart Diseases; Humans; Male; Mice; MicroRNAs; Natriuretic Peptides; Nitric Oxide; Phosphodiesterase 5 Inhibitors; RNA Processing, Post-Transcriptional; Signal Transduction

Lipopolysaccharide induces rapid deterioration of cardiac function in rats with pulmonary arterial hypertension. It was desired to investigate if this cardiac dysfunction could be treated by C-type natriuretic peptide. Rat pulmonary arterial hypertension was induced by intraperitoneal injection of monocrotaline. Hemodynamics and cardiac function were measured by pressure-volume (P-V) catheter before and after the rats were treated with lipopolysaccharide and C-type natriuretic peptide. Cyclic guanosine 3',5'-monophosphate (cGMP) level was determined by enzyme-linked immunosorbent assay analysis. After the rats were injected with low-dose lipopolysaccharide, they experienced left ventricle systolic function deterioration. Administration of C-type natriuretic peptide improved hemodynamics and left ventricle systolic function. cGMP level was elevated after C-type natriuretic peptide treatment. C-type natriuretic peptide could ameliorate lipopolysaccharide-induced cardiac dysfunction and restore hemodynamic deterioration in rats with pulmonary arterial hypertension.

Topics: Animals; Cyclic GMP; Heart Diseases; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Lipopolysaccharides; Male; Monocrotaline; Natriuretic Peptide, C-Type; Pulmonary Artery; Rats; Rats, Sprague-Dawley

Although the Nobel Prize for the discovery of nitric oxide (NO) dates back almost 20 years now, the knowledge about cGMP signaling is still constantly increasing. It looks even so that our understanding of the role of the soluble guanylyl cyclase (sGC) and particulate guanylyl cyclase (pGC) in health and disease is in many aspects at the beginning and far from being understood. This holds even true for the therapeutic impact of innovative drugs acting on both the NO/sGC and the pGC pathways. Since cGMP, as second messenger, is involved in the pathogenesis of numerous diseases within the cardiovascular, pulmonary, renal, and endocrine systems and also plays a role in neuronal, sensory, and tumor processes, drug applications might be quite broad. On the 8th International Conference on cGMP, held in Bamberg, Germany, world leading experts came together to discuss these topics. All aspects of cGMP research from the basic understanding of cGMP signaling to clinical applicability were discussed in depth. In addition, present and future therapeutic applications of cGMP-modulating pharmacotherapy were presented ( http://www.cyclicgmp.net/index.html ).

Topics: Animals; Cyclic GMP; Guanylate Cyclase; Heart Diseases; Humans; Nervous System Physiological Phenomena; Nitric Oxide

Inhibition of cGMP-specific phosphodiesterase 5 (PDE5) ameliorates pathological cardiac remodeling and has been gaining attention as a potential therapy for heart failure. Despite promising results in males, the efficacy of the PDE5 inhibitor sildenafil in female cardiac pathologies has not been determined and might be affected by estrogen levels, given the hormone's involvement in cGMP synthesis. Here, we determined that the heart-protective effect of sildenafil in female mice depends on the presence of estrogen via a mechanism that involves myocyte eNOS-dependent cGMP synthesis and the cGMP-dependent protein kinase Iα (PKGIα). Sildenafil treatment failed to exert antiremodeling properties in female pathological hearts from Gαq-overexpressing or pressure-overloaded mice after ovary removal; however, estrogen replacement restored the effectiveness of sildenafil in these animals. In females, sildenafil-elicited myocardial PKG activity required estrogen, which stimulated tonic cardiomyocyte cGMP synthesis via an eNOS/soluble guanylate cyclase pathway. In contrast, eNOS activation, cGMP synthesis, and sildenafil efficacy were not estrogen dependent in male hearts. Estrogen and sildenafil had no impact on pressure-overloaded hearts from animals expressing dysfunctional PKGIα, indicating that PKGIα mediates antiremodeling effects. These results support the importance of sex differences in the use of PDE5 inhibitors for treating heart disease and the critical role of estrogen status when these agents are used in females.

Topics: Animals; Cardiotonic Agents; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Disease Models, Animal; Estradiol; Estrogens; Female; GTP-Binding Protein alpha Subunits, Gq-G11; Guanylate Cyclase; Heart Diseases; Heart Failure; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Ovariectomy; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Receptors, Atrial Natriuretic Factor; Sex Characteristics; Sildenafil Citrate; Sulfones; Treatment Outcome

Nitroalkene derivatives of nitro-oleic acid (OA-NO2) are endogenous lipid products with potent anti-inflammatory properties in vitro. The present study was undertaken to evaluate the in vivo anti-inflammatory effect of OA-NO2 in mice given LPS. Two days before LPS administration, C57BL/6J mice were chronically infused with vehicle (LPS vehicle) or OA-NO2 (LPS OA-NO2) at 200 microg x kg(-1) x day(-1) via osmotic minipumps; LPS was administered via a single intraperitoneal (ip) injection (10 mg/kg in saline). A third group received an ip injection of saline without LPS or OA-NO2 and served as controls. At 18 h of LPS administration, LPS vehicle mice displayed multiorgan dysfunction as evidenced by elevated plasma urea and creatinine (kidney), aspartate aminotransferase (AST) and alanine aminotransferase (ALT; liver), and lactate dehydrogenase (LDH) and reduced ejection fraction (heart). In contrast, the severity of multiorgan dysfunction was less in LPS OA-NO2 animals. The levels of circulating TNF-alpha and renal TNF-alpha mRNA expression, together with renal mRNA expression of monocyte chemoattractant protein-1, ICAM-1, and VCAM-1, and with renal mRNA and protein expression of inducible nitric oxide synthase and cyclooxygenase 2, and renal cGMP and PGE2 contents, were greater in LPS vehicle vs. control mice, but were attenuated in LPS OA-NO2 animals. Similar patterns of changes in the expression of inflammatory mediators were observed in the liver. Together, pretreatment with OA-NO2 ameliorated the inflammatory response and multiorgan injury in endotoxin-induced endotoxemia in mice.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Blood Urea Nitrogen; Body Temperature; Cell Adhesion Molecules; Chemokines; Creatinine; Cyclic GMP; Cyclooxygenase 2; Cytokines; Dinoprostone; Disease Models, Animal; Drug Administration Schedule; Endotoxemia; Heart Diseases; Hematocrit; Inflammation Mediators; Infusion Pumps, Implantable; Kidney; Kidney Diseases; Lipopolysaccharides; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Myocardium; Nitric Oxide Synthase Type II; Oleic Acids; Stroke Volume; Time Factors

Topics: Atrial Natriuretic Factor; Cyclic GMP; Heart Diseases; Humans; Receptors, Atrial Natriuretic Factor

Topics: Atrial Natriuretic Factor; Cyclic GMP; Heart Diseases; Humans

The concentration of atrial natriuretic peptide was measured in order to evaluate its importance in patients suffering from a variety of cardiac diseases. There was a correlation between plasma concentrations of atrial natriuretic peptide and its "second messenger" cyclic guanosine monophosphate (cGMP) in all of the cases examined. We investigated the relationship between atrial natriuretic peptide and cGMP plasma concentrations during rest and exercise in comparison with the scintigraphically assessed left- and right-ventricular ejection fraction in patients with chronic heart disease (n = 20), and after orthotopic heart transplantation (n = 16); plasma concentrations were also measured in healthy controls (n = 14). Atrial natriuretic peptide and cGMP concentrations showed a similar correlation during rest and exercise with r = 0.74 and r = 0.81, respectively. With the exception of patients after heart transplantation, a significant negative correlation was seen between the left ventricular ejection fraction and atrial natriuretic peptide or cGMP plasma concentrations during rest conditions (r = 0.76 or 0.58, respectively). No correlation was apparent between plasma concentrations of atrial natriuretic peptide or cGMP and the left- or right ventricular ejection fraction during exercise. The concentrations of atrial natriuretic peptide and cGMP in plasma differed significantly between healthy controls and patients during rest and exercise. It is noteworthy that atrial natriuretic peptide and cGMP concentrations were markedly higher in patients after heart transplantation than in patients suffering from chronic heart disease. Our results indicate that plasma atrial natriuretic peptide and cGMP concentrations are sensitive markers of cardiac impairment.

Topics: Atrial Natriuretic Factor; Biomarkers; Cyclic GMP; Exercise; Heart Diseases; Heart Transplantation; Humans; Stroke Volume; Ventricular Function, Left; Ventricular Function, Right

1. The pericardial fluid of 20 open heart surgery patients with acquired heart disease was analysed for atrial natriuretic peptide by radioimmunoassay. 2. The concentration of atrial natriuretic peptide in the pericardial fluid was significantly higher than in the corresponding plasma (316.8 +/- 50.0 versus 121.7 +/- 29.1 pg/ml; P < 0.01) and was higher in patients with congestive heart failure than in those without heart failure (469.3 +/- 78.6 versus 181.8 +/- 26.7 pg/ml; P < 0.001). Pericardial and plasma atrial natriuretic peptide concentrations showed a significant positive correlation. Pericardial fluid and plasma samples were fractionated using both reverse-phase high-performance liquid chromatography and gel permeation chromatography. Each fraction was assayed for atrial natriuretic peptide by radioimmunoassay, revealing the presence of beta-atrial natriuretic peptide as well as alpha- and gamma-atrial natriuretic peptide. 3. The pericardial fluid concentration of cyclic GMP, the intracellular second messenger for atrial natriuretic peptide, was significantly higher in patients with congestive heart failure than in patients without heart failure.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cyclic GMP; Female; Heart Diseases; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Pericardium

We studied the role of tissue cyclic AMP levels in the chronotropic effects of theophylline on automatic human atrial fibers obtained from the hearts of 17 patients undergoing corrective open-heart surgery. Atrial fibers were perfused with Tyrode solution and transmembrane action potentials were recorded with a conventional microelectrode technique. In normal Tyrode solution, theophylline (0.1-1 mM) often decreased the late diastolic slope and the spontaneous rate. In the presence of 0.3-1 microM epinephrine, however, theophylline dose-dependently increased the diastolic slope, the rate of spontaneous discharges and the force of contraction. The increase in tissue level of cyclic AMP (+288 +/- 69%) induced by 0.3 mM theophylline in the presence of epinephrine was much greater than the increase (+73 +/- 19%) in the absence of epinephrine. It is concluded that pacemaker activity in human atrial fibers is modulated by tissue levels of cyclic AMP and theophylline may induce atrial tachycardia through an increase in the diastolic slope and the rate of discharges of automatic atrial fibers.

Topics: Action Potentials; Adult; Atrial Function; Child, Preschool; Cyclic AMP; Cyclic GMP; Epinephrine; Female; Heart Atria; Heart Conduction System; Heart Defects, Congenital; Heart Diseases; Heart Rate; Humans; In Vitro Techniques; Male; Middle Aged; Theophylline

The relation of plasma levels of atrial natriuretic peptide (ANP) to those of cyclic 3', 5'-guanosine monophosphate (cGMP) was studied in 43 patients with various heart diseases. Plasma levels of both ANP and cGMP were significantly (p less than 0.001) elevated in 34 patients with chronic heart diseases, and a significant positive correlation was observed between the two variables (r = 0.706, p less than 0.01). Clinical improvement of congestive heart failure resulted in a concomitant decrease in plasma ANP and cGMP levels in 6 patients. In 3 patients with paroxysmal atrial fibrillation, plasma levels of ANP and cGMP increased markedly during arrhythmia. These results indicate that increased circulating ANP may stimulate cGMP production in target cells, which in turn raises plasma levels of cGMP in humans.

Topics: Aged; Atrial Natriuretic Factor; Cyclic GMP; Female; Heart Diseases; Heart Failure; Humans; Male; Middle Aged

Simultaneous measurements of plasma atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (GMP) concentrations were performed in children with various forms of cardiac diseases (n = 22) and in control children (n = 29). In healthy children, plasma ANP and cyclic GMP levels ranged between 2.4 and 98.0 (mean 45.8) pg/mL and 0.2 to 2.8 (mean 1.40) pmol/mL, respectively. In children with cardiac diseases, plasma ANP (26.0 to 499.7 [mean 188.7] pg/mL) and cyclic GMP (0.2 to 6.0 [mean 2.9] pmol/mL) levels were significantly higher than in control children (both P less than .0001). There was a linear correlation between the two values in children with cardiac diseases (P less than .01). Because the effects of ANP to target tissues are mediated by cyclic GMP, cyclic GMP appears to be a marker for the cellular responses to ANP. The increased cyclic GMP levels in children with cardiac diseases indicate that ANP exerts its effects on target organs also in states of chronically enhanced ANP levels.

Topics: Adolescent; Atrial Natriuretic Factor; Child; Child, Preschool; Cyclic GMP; Heart Defects, Congenital; Heart Diseases; Humans; Infant; Reference Values

In children with various forms of cardiac diseases (aged 2 months to 16 years) significantly higher plasma atrial natriuretic peptide (ANP; range 36-680, median 247 pg/ml) and cyclic 3'5'-guanosine monophosphate (cGMP; range 0.2-46, median 8.2 pmol/ml) levels were found than in control children (p less than 0.0001). In control children (aged 4 months to 17 years) plasma ANP and cGMP levels were measured in the range of 2.4-98 pg/ml and of 0.2-2.8 pmol/ml, respectively. There was a linear correlation between the two parameters in children with cardiac diseases (r = 0.62, p less than 0.01). Children with elevated mean right atrial pressure (i.e., greater than 6 mm Hg) showed significantly higher plasma ANP levels than children with normal atrial pressure (p less than 0.01). However, there was only a weak linear correlation between mean right atrial pressure and plasma ANP levels (r = 0.48, p less than 0.01). Plasma ANP levels from right atrium, pulmonary artery, left atrium and left ventricle were significantly higher than those from vena cava (p less than 0.05). Analysis of ANP-like immunoreactive material by high performance liquid chromatography suggested that alpha-ANP is the major form of circulating ANP in blood of children with cardiac diseases.

Topics: Adolescent; Atrial Function; Atrial Natriuretic Factor; Child; Child, Preschool; Chromatography, High Pressure Liquid; Cyclic GMP; Heart Defects, Congenital; Heart Diseases; Hemodynamics; Humans; Infant; Pressure

Atrial natriuretic factor (ANF) acts through specific receptors at its target tissues. Receptor-occupancy by ANF induces activation of particulate guanylate cyclase, increased cyclic GMP formation and also inhibition of adenylate cyclase which results in a decrease of cyclic AMP formation. These second messenger systems appear to mediate the effects of ANF in target tissues. Following receptor-mediated activation of particulate guanylate cyclase, cyclic GMP is extruded from the cells, which leads to elevated cyclic GMP levels in plasma and urine in man, whereas cyclic AMP levels remain unchanged. Since cyclic GMP has a much longer half-life than ANF, it is more sensitive as a marker for ANF release than ANF itself, which has a half-life of just a few minutes. Since cyclic GMP is excreted into urine, determinations of urine cyclic GMP can also allow conclusions about the ANF system when blood sampling is impractical. Thus, cyclic GMP and not cyclic AMP is a sensitive biological marker for ANF.

Topics: Adenylyl Cyclases; Animals; Atrial Natriuretic Factor; Cyclic GMP; Enzyme Activation; Guanylate Cyclase; Heart Diseases; Humans; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

Plasma concentrations of cyclic nucleotides (adenosine monophosphate (AMP) and guanosine monophosphate (GMP) were measured by an ultrasensitive radioimmunoassay in 138 patients with heart failure due to various causes. Measurements were related to the New York Heart Association classification of symptoms, plasma noradrenaline concentrations, and mean pulmonary artery pressures. Serial concentrations of cyclic AMP and GMP were also measured daily in four patients treated for acute left ventricular failure. Plasma concentrations of cycle AMP were related to the severity of the heart failure, plasma noradrenaline concentrations, and pulmonary artery pressures. Cyclic AMP concentrations fell rapidly after treatment of acute left ventricular failure. Plasma concentrations of cyclic GMP also depended on the severity of heart failure and the pulmonary artery pressure, and decreased sharply with treatment although remaining at a high value. The cyclic GMP concentrations were significantly higher in patients with mitral stenosis than in those with other types of heart failure.

Topics: Adult; Aged; Blood Pressure; Cyclic AMP; Cyclic GMP; Female; Heart Diseases; Heart Failure; Humans; Male; Middle Aged; Mitral Valve Stenosis; Norepinephrine; Pulmonary Artery; Time Factors

Topics: Animals; Calcium; Cats; Coronary Disease; Cyclic AMP; Cyclic GMP; Haplorhini; Heart Diseases; Hypoxia; Myocardial Contraction; Myocardium; Papio; Rats; Swine