cyclic-gmp and Arrhythmias--Cardiac

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: Adenylyl Cyclases; Animals; Arrhythmias, Cardiac; Calcium; Calcium-Transporting ATPases; Cholinergic Fibers; Coronary Disease; Cyclic AMP; Cyclic GMP; Heart Rate; Hormones; Humans; Myocardial Contraction; Myocardium; Myosins; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Phosphorylation; Phosphotransferases; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta

Anoxia has been compared with ischaemia. The abrupt restoration of either oxygen of flow may accelerate cardiac damage. Anoxic stimulation of glycolysis (Pasteur effect) is inhibited during ischaemia by lactate and proton accumulation at the levels of phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase. Anaerobic glycolysis provides lactate and ATP; breakdown of the latter provides protons. During partial respiration thought to occur in partial ischaemia, continued production of CO2 is a factor contributing to intracellular acidosis; mitochondrial ATP when formed by continued respiration also yields protons when ultimately broken down. The endoproducts of aerobic glycolysis (pyruvate and NADH) are transported into the mitochondria by the malate-aspartate cycle and by pyruvate dehydrogenase activity. Adenine nucleotide transferase activity normally transfers the mitochondrially-made ATP to the cytoplasm, but acyl CoA accumulates in ischaemia (or during perfusions with high circulating free fatty acids) to inhibit the transferase. The mitochondrial creatine kinase is thought to transform ATP transported outwards into creatine phosphate which can permeate the outer mitochondrial membrane. Further compartmentation of ATP may be by other creatine kinase isoenzymes or in relation to the cell membrane. The glycogenolytic-sarcoplasmic reticulum complex links a glycogen pool to the sarcoplasmic reticulum. Cyclic AMP may regulate admission of calcium to the cell during the plateau of the action potential and promote calcium uptake by the sarcoplasmic reticulum by phosphorylation of phospholamban. The latter promotes the activity of the calcium-transport ATPase. Calcium and cyclic AMP may also interact at the level of the contractile proteins where cyclic AMP phosphrylates troponin. Cyclic GMP generally has opposite effects to cyclic AMP and undergoes opposite changes in the frog cardiac cycle to those of cyclic AMP. A present it is reasonable to suppose that physiological effects of adrenaline or of cholinergic agents on the myocardium are mediated by cyclic AMP or cyclic GMP, respectively, but this hypothesis still lacks firm support. There is an association between tissue cyclic AMP and ventricular fibrillation after coronary ligation, and direct evidence for a role of cyclic AMP in promoting arrhythmias has been obtained by studies on the ventricular fibrillation threshold in the rat heart. However, there are other mechanisms, involving first the ef

Topics: Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Calcium; Cyclic AMP; Cyclic GMP; Energy Metabolism; Fatty Acids, Nonesterified; Glucose; Glycolysis; Humans; Hydrogen-Ion Concentration; Hypoxia; Lactates; Mitochondria, Heart; Myocardial Infarction; Myocardium; Oxygen Consumption; Pyruvate Kinase; Pyruvates; Rats

We studied low-dose human atrial natriuretic peptide (hANP) infusion therapy during cardiac surgery and reported the cardiac and renal protective effects. The efficacy of a bolus injection of hANP (the "hANP shot") simultaneously with induction of cardioplegia has been proven in animal experiments. In the present study the clinical effects of this "hANP shot" were examined.. The subjects were 67 patients undergoing Coronary artery bypass grafting. At the time of inducing cardioplegia, 1 group received a simultaneous bolus injection of 100 μg of hANP (hANP group) and the other group received an injection of physiological saline (placebo group). The primary endpoints were (1) operative mortality and complications, and (2) the creatine kinase isoenzyme MB (CPK-MB), troponin-I, and human heart fatty acid binding protein (H-FABP) levels. The secondary endpoints were (1) the incidence of arrhythmia, and levels of (2) atrial and B-type natriuretic peptides, and cyclic guanosine monophosphate (cGMP), and (3) renin, angiotensin II, and aldosterone. Postoperative CPK-MB, troponin-I, and H-FABP levels were significantly lower in the hANP group than in the placebo group. Postoperative arrhythmia was significantly less frequent in the hANP group than in the placebo group.. It is possible to achieve cardioprotective effects based on the safety of the "hANP shot", as well as from biomarkers of ischemia and results related to arrhythmia. The "hANP shot" should also be evaluated as a safer and new cardioprotective method for cardiac surgery.

Topics: Aged; Aldosterone; Angiotensin II; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Cardiotonic Agents; Coronary Artery Bypass; Creatine Kinase, MB Form; Cyclic GMP; Dose-Response Relationship, Drug; Fatty Acid Binding Protein 3; Fatty Acid-Binding Proteins; Female; Heart Arrest, Induced; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Postoperative Complications; Renin; Troponin I

Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways.. To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes.. In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in I. CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Catecholamines; Cyclic GMP; Humans; Mice; Myocytes, Cardiac; Natriuretic Peptide, C-Type; Phosphoric Diester Hydrolases; Signal Transduction

The cardiac natriuretic peptides [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] are important regulators of cardiovascular physiology, with reduced natriuretic peptide (NP) activity linked to multiple human cardiovascular diseases. We hypothesized that deficiency of either ANP or BNP would lead to similar changes in left ventricular structure and function given their shared receptor affinities.. We directly compared murine models deficient of ANP or BNP in the same genetic backgrounds (C57BL6/J) and environments. We evaluated control, ANP-deficient (Nppa-/-) or BNP-deficient (Nppb-/-) mice under unstressed conditions and multiple forms of pathological myocardial stress. Survival, myocardial structure, function and electrophysiology, tissue histology, and biochemical analyses were evaluated in the groups. In vitro validation of our findings was performed using human-derived induced pluripotent stem cell cardiomyocytes (iPS-CMs). In the unstressed state, both ANP- and BNP-deficient mice displayed mild ventricular hypertrophy which did not increase up to 1 year of life. NP-deficient mice exposed to acute myocardial stress secondary to thoracic aortic constriction (TAC) had similar pathological myocardial remodelling but a significant increase in sudden death. We discovered that the NP-deficient mice are more susceptible to stress-induced ventricular arrhythmias using both in vivo and ex vivo models. Mechanistically, deficiency of either ANP or BNP led to reduced myocardial cGMP levels and reduced phosphorylation of the cAMP response element-binding protein (CREBS133) transcriptional regulator. Selective CREB inhibition sensitized wild-type hearts to stress-induced ventricular arrhythmias. ANP and BNP regulate cardiomyocyte CREBS133 phosphorylation through a cGMP-dependent protein kinase 1 (PKG1) and p38 mitogen-activated protein kinase (p38 MAPK) signalling cascade.. Our data show that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels to regulate cardiomyocyte p38 MAPK and CREB activity. Cardiac natriuretic peptide deficiency leads to a reduction in CREB signalling which sensitizes the heart to stress-induced ventricular arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Cyclic GMP; Mice; Myocytes, Cardiac; Natriuretic Peptide, Brain; Natriuretic Peptides; p38 Mitogen-Activated Protein Kinases; Vasodilator Agents

Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias.. Cellular arrhythmia, ion currents, and Ca. Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in I. Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Gene Expression Regulation; Guanine Nucleotide Exchange Factors; Heart; Humans; Isoproterenol; Mice; Myocytes, Cardiac

Elevated levels of brain natriuretic peptide (BNP) are regarded as an early compensatory response to cardiac myocyte hypertrophy, although exogenously administered BNP shows poor clinical efficacy in heart failure and hypertension. We tested whether phosphodiesterase 2A (PDE2A), which regulates the action of BNP-activated cyclic guanosine monophosphate (cGMP), was directly involved in modulating Ca2+ handling from stellate ganglia (SG) neurons and cardiac norepinephrine (NE) release in rats and humans with an enhanced sympathetic phenotype. SG were also isolated from patients with sympathetic hyperactivity and healthy donor patients. PDE2A activity of the SG was greater in both spontaneously hypertensive rats (SHRs) and patients compared with their respective controls, whereas PDE2A mRNA was only high in SHR SG. BNP significantly reduced the magnitude of the calcium transients and ICaN in normal Wistar Kyoto (WKY) SG neurons, but not in the SHRs. cGMP levels stimulated by BNP were also attenuated in SHR SG neurons. Overexpression of PDE2A in WKY neurons recapitulated the calcium phenotype seen in SHR neurons. Functionally, BNP significantly reduced [3H]-NE release in the WKY rats, but not in the SHRs. Blockade of overexpressed PDE2A with Bay 60-7550 or overexpression of catalytically inactive PDE2A reestablished the modulatory action of BNP in SHR SG neurons. This suggests that PDE2A may be a key target in modulating the action of BNP to reduce sympathetic hyperactivity.

Topics: Adult; Aged; Animals; Arrhythmias, Cardiac; Autonomic Nervous System Diseases; Calcium; Case-Control Studies; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Electromagnetic Fields; Female; Heart; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neurons; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Stellate Ganglion; Synaptic Transmission; Ventricular Function; Young Adult

This study investigated the effects and associated underlying mechanisms of molsidomine, a nitric oxide (NO) donor, on cardiac electrical remodeling and ventricular tachycardias (VTs) induced by chronic isoprenaline (ISO) stimulation in rats. The rats were randomly divided into groups that were treated with saline (control group), ISO (ISO group), ISO + molsidomine (ISO + M group), and ISO + molsidomine + the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, ISO + M + O group) for 14 days. An electrophysiological study was performed to assess cardiac repolarization, action potential duration restitution, and the induction of action potential duration alternans and VTs in vitro. The properties of the Ca transients, Ca handling-related proteins, and NO/guanosine 3'5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) pathway were examined. Compared with the control group, chronic ISO stimulation prolonged the cardiac repolarization, decreased the Ca transient alternans and action potential duration alternans thresholds, and increased the maximum slope (Smax) of the action potential duration restitution curve and incidence of VTs in vitro. All these effects were attenuated by molsidomine treatment (P < 0.05). Moreover, molsidomine activated cGMP/PKG signaling and stabilized the expression of calcium handling-related proteins compared with the ISO group. However, the protective effects of molsidomine were partially inhibited by ODQ. Our results suggest that molsidomine stabilizes calcium handling and attenuates cardiac electrical remodeling and arrhythmogenesis in rats with chronic β-adrenergic receptor activation. These effects are at least partially mediated by the activation of NO/cGMP/PKG pathway.

Topics: Adrenergic beta-Agonists; Animals; Arrhythmias, Cardiac; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Electrocardiography; Male; Molsidomine; Nitric Oxide; Nitric Oxide Donors; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Signal Transduction; Ventricular Remodeling

Sonic hedgehog (SHH) is a conserved protein involved in embryonic tissue patterning and development. SHH signaling has been reported as a cardio-protective pathway via muscle repair-associated angiogenesis. The goal of this study was to investigate the role of SHH signaling pathway in the adult myocardium in physiological situation and after ischemia-reperfusion. We show in a rat model of ischemia-reperfusion that stimulation of SHH pathway, either by a recombinant peptide or shed membranes microparticles harboring SHH ligand, prior to reperfusion reduces both infarct size and subsequent arrhythmias by preventing ventricular repolarization abnormalities. We further demonstrate in healthy animals a reduction of QTc interval mediated by NO/cGMP pathway leading to the shortening of ventricular cardiomyocytes action potential duration due to the activation of an inward rectifying potassium current sharing pharmacological and electrophysiological properties with ATP-dependent potassium current. Besides its effect on both angiogenesis and endothelial dysfunction we demonstrate here a novel cardio-protective effect of SHH acting directly on the cardiomyocytes. This emphasizes the pleotropic effect of SHH pathway as a potential cardiac therapeutic target.

Topics: Animals; Arrhythmias, Cardiac; Cyclic GMP; Hedgehog Proteins; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Nitric Oxide; Rats; Rats, Inbred WKY; Signal Transduction

High-fat diet and consequent metabolic syndrome (MS) can lead to elevated risk for cardiac arrhythmias. This preclinical study was to investigate if cicletanine (CIC) could produce cardioprotective effects in conscious rabbits exhibiting the main symptoms of MS.. NZW rabbits that had undergone an 8-week-long cholesterol-enriched diet (1.5%) were instrumented with a pacemaker electrode and randomly assigned into 3 groups according to the oral treatment of either CIC (50 mg·kg) or sotalol (25 mg·kg) and their placebo b.i.d. over 5 days. Study groups were subjected to either "arrhythmia challenge" by programmed electrical stimulation in the "Arrhythmogenesis" study (N = 54) or global myocardial ischemia by rapid pacing in the "Ventricular Overdrive Pacing-induced Myocardial Ischemia" study (N = 18). The antiarrhythmic effect was evaluated by the establishment of the incidence of programmed electrical stimulation-induced arrhythmias. Proarrhythmia indicators (eg, QTc, Tpeak-Tend) were also measured to assess the cardiac safety profile of CIC. To evaluate the background of antiarrhythmic effect, cardiac cyclic nucleotide (cyclic 3',5'-guanosine monophosphate [cGMP], cyclic 3',5'-adenosine monophosphate [cAMP]) and nitric oxide content were determined. The antiischemic effect was characterized by change of intracavital ST segment.. Cicletanine treatment significantly decreased the incidence of ventricular arrhythmias, increased cardiac cGMP and nitric oxide content and reduced cardiac cAMP level. Cicletanine did not modify significantly QTc and Tpeak-Tend interval. The ST-segment change in response to rapid pacing was reduced significantly by CIC. (P < 0.05).. Cicletanine exerts beneficial cardiac effects in rabbits with symptoms of MS, which may be of influence with regard to the clinical application of the drug.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Cardiac Pacing, Artificial; Cholesterol, Dietary; Consciousness; Cyclic AMP; Cyclic GMP; Diet, High-Fat; Disease Models, Animal; Electrocardiography; Heart Rate; Lipids; Male; Metabolic Syndrome; Myocardium; Nitric Oxide; Pyridines; Rabbits; Sotalol; Time Factors

Role of G-protein coupled pathways in modulating the cardiotoxic effects produced by Indian red scorpion (Mesobuthus tamulus) venom were examined. The isometric contractions of spontaneously beating or paced (3.5 Hz) rat right atrial preparations in vitro were recorded. The cumulative concentration (0.01-3.0 microg/ml)-response of venom on spontaneously beating atria exhibited a marked decrease in rate (by 55%) and an increase in force (by 92%) only at a higher concentration (3.0 microg/ml). The venom-induced decrease in rate and increase in force were sensitive to atropine, N-omega-nitro-L-arginine methylester (NO synthase inhibitor) and methylene blue (guanylyl cyclase inhibitor). Further, nifedipine, a Ca(2+) channel antagonist, blocked the force changes but not the rate changes induced by venom. In the paced atrium, on the other hand, a concentration-dependent decrease in force was observed, and at 3 microg/ml, the decrease was 50%. Pretreatment with nifedipine, but not with methylene blue, significantly attenuated the venom-induced force changes in paced atrium. The observations of this study demonstrate that the venom-induced atrial dysrhythmia is mediated through the muscarinic receptor-dependent NO-G-cyclase cell-signaling pathways.

Topics: Animals; Arrhythmias, Cardiac; Cyclic GMP; Guanylate Cyclase; Heart Atria; In Vitro Techniques; Male; Myocardial Contraction; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Inbred Strains; Scorpion Venoms; Scorpions; Signal Transduction

We sought to determine the physiologic actions and potential therapeutic applications of mutant atrial natriuretic peptide (mANP).. The cardiac hormone atrial natriuretic peptide (ANP) is a 28-amino acid (AA) peptide that consists of a 17-AA ring structure together with a 6-AA N-terminus and a 5-AA C-terminus. In a targeted scan for sequence variants within the human ANP gene, a mutation was identified that results in a 40-AA peptide consisting of native ANP((1-28)) and a C-terminal extension of 12 AA. We have termed this peptide mutant ANP.. In vitro 3',5'-cyclic guanosine monophosphate (cGMP) activation in response to mANP was studied in cultured human cardiac fibroblasts known to express natriuretic peptide receptor A. The cardiorenal and neurohumoral properties of mANP compared with ANP were assessed in vivo in normal dogs.. We observed an incremental in vitro cGMP dose response with increasing concentrations of mANP. In vivo with high-dose mANP (33 pmol/kg/min), we observed significantly greater plasma cGMP activation, diuretic, natriuretic, glomerular filtration rate enhancing, renin-angiotensin-aldosterone system inhibiting, cardiac unloading, and blood pressure lowering properties when compared with native ANP. Low-dose mANP (2 pmol/kg/min) has natriuretic and diuretic properties without altering systemic hemodynamics compared with no natriuretic or diuretic response with low-dose native ANP.. These studies establish that mANP activates cGMP in vitro and exerts greater and more sustained natriuretic, diuretic, glomerular filtration rate, and renal blood flow enhancing actions than native ANP in vivo.

Topics: Animals; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Blood Pressure; Cell Culture Techniques; Cyclic GMP; Dogs; Fibroblasts; Glomerular Filtration Rate; Humans; Mutant Proteins; Mutation; Myocardium; Renin-Angiotensin System

Isolated rat hearts were perfused for 10 min with oxygenated buffer and equilibrated with carbon monoxide (CO) of 0.001% and 0.01% before the induction of 30 min global ischemia followed by 120 min of reperfusion. These concentrations of CO significantly improved the post-ischemic recovery of coronary flow (CF), aortic flow (AF), and left ventricular developed pressure (LVDP). The improvement in recovery reflected in the reduction of infarct size and the incidence of reperfusion-induced ventricular fibrillation (VF). Thus, hearts subjected to 0.001% and 0.01% of CO exposure via the perfusion buffer, infarct size was reduced from the CO-free control value of 39% +/- 5% to 21% +/- 3% (*p<0.05) and 18% +/- 4% (*p<0.05), respectively. In the presence of 0.001% and 0.01% CO, the incidence of VF was also reduced from its control value of 92% to 17% (*p<0.05) and 17% (*p<0.05), respectively. Increasing the CO exposure to 0.1% in the buffer, all hearts showed VF combined with ventricular tachycardia or bradycardia and various rhythm disturbances indicating the direct toxic effects of CO on the myocardium. The results show that cardioprotective concentrations (0.01% and 0.001%) of exogenous CO related to an increase in cGMP levels and guanylate cyclase activities.

Topics: Animals; Arrhythmias, Cardiac; Carbon Monoxide; Cardiotonic Agents; Cyclic GMP; Dose-Response Relationship, Drug; Guanylate Cyclase; Heart; In Vitro Techniques; Male; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Regional Blood Flow

This study was designed to compare the haemodynamic, electrophysiological and pharmacodynamic effects of three selective inhibitors of the different isoenzyme forms of phosphodiesterase (PDE) on ischaemia-induced dysrhythmias in the anaesthetized rat. The drugs used were pimobendan, a selective PDE III inhibitor, rolipram, a selective PDE IV inhibitor, and zaprinast, a selective PDE V inhibitor.. The coronary artery was occluded 15 min after commencing drug administration, and myocardial ischaemia was maintained for 30 min during which the heart rate and mean arterial pressure were recorded. cAMP and cGMP were determined by radioimmunoassay.. Pretreatment with rolipram decreased the duration of ventricular tachycardia without any change in the incidences of dysrhythmias or the mortality rate. This drug did not modify ventricular content of adenosine 3',5'-cyclic monophosphate (cAMP) or guanosine 3',5'-cyclic monophosphate (cGMP). Pimobendan (1 mg kg(-1) + 0.1 mg kg(-1) min) decreased the duration of ventricular tachycardia. This dose of pimobendan and zaprinast (1 mg kg(-1) + 0.1 mg kg(-1) min(-1)) increased the incidence rate of ventricular fibrillation following coronary artery ligation and the mortality rate. Moreover, both drugs increased cGMP in the ventricle.. The results demonstrated that pimobendan and zaprinast increased the incidence of dysrhythmias and the mortality rate, which was accompanied by an increase in the ventricular content of cGMP. Rolipram decreased the duration of ventricular tachycardia without a change in the cyclic nucleotide content or in the mortality rate.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Anesthesia; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Vessels; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Rate; Heart Ventricles; Ligation; Male; Myocardial Ischemia; Myocardium; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Purinones; Pyridazines; Rats; Rats, Sprague-Dawley; Rolipram

Adrenomedullin (AM) has been shown to protect against cardiac remodeling. In this study, we investigated the potential role of AM in myocardial ischemia-reperfusion (I/R) injury through adenovirus-mediated gene delivery. One week after AM gene delivery, rats were subjected to 30-min coronary occlusion, followed by 2-h reperfusion. AM gene transfer significantly reduced the ratio of infarct size to ischemic area at risk and the occurrence of sustained ventricular fibrillation compared with control rats. AM gene delivery also attenuated apoptosis, assessed by both terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and DNA laddering. The effect of AM gene transfer on infarct size, arrhythmia, and apoptosis was abolished by an AM antagonist, calcitonin gene-related peptide [CGRP(8-37)]. Expression of human AM significantly increased cardiac cGMP levels and reduced superoxide production, superoxide density, NAD(P)H oxidase activity, p38 MAPK activation, and Bax levels. Moreover, AM increased Akt and Bad phosphorylation and Bcl-2 levels, but decreased caspase-3 activation. These results indicate that AM protects against myocardial infarction, arrhythmia, and apoptosis in I/R injury via suppression of oxidative stress-induced Bax and p38 MAPK phosphorylation and activation of the Akt-Bad-Bcl-2 signaling pathway. Successful application of this technology may have a protective effect in coronary artery diseases.

Topics: Adrenomedullin; Animals; Apoptosis; Arrhythmias, Cardiac; Blotting, Western; Cyclic AMP; Cyclic GMP; Gene Transfer Techniques; Hemodynamics; Humans; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; NADPH Oxidases; Peptides; Proteins; Rats; Rats, Wistar; Superoxides

Human brain natriuretic peptide (hBNP) is a new therapeutic agent, nesiritide, indicated in patients with decompensated congestive heart failure, a group at significant risk of developing cardiac arrhythmias. Whether hBNP has cardiac electrophysiologic effects has not been reported.. In 9 healthy, chronically instrumented, conscious dogs, hemodynamic and electrophysiologic parameters were assessed at baseline and during recombinant hBNP (nesiritide) infusion at 0.03 and 0.09 microg/kg/min after 1 hour at each dose. Infusion of hBNP produced dose-related increases (P <.001) in hBNP and cyclic GMP plasma levels and reductions (P <.05) in mean arterial pressure. Mean central venous pressure and sinus cycle length did not change significantly. Infusion of hBNP produced no significant changes in any of the electrophysiologic parameters including no change in surface ECG variables (P wave duration, PR interval, QRS duration, and QTc interval), corrected sinus node recovery time, atrioventricular nodal Wenckebach cycle length, and atrial and ventricular effective refractory periods measured at a 400 ms cycle length. Spontaneous or induced arrhythmias were not observed during hBNP infusion.. In conscious, healthy dogs, short-term infusion of recombinant hBNP has no significant effects on atrial or ventricular electrophysiologic parameters.

Topics: Animals; Arrhythmias, Cardiac; Consciousness; Cyclic GMP; Dogs; Dose-Response Relationship, Drug; Electric Stimulation; Electrocardiography; Electrophysiologic Techniques, Cardiac; Heart Atria; Heart Conduction System; Heart Ventricles; Hemodynamics; Infusions, Intravenous; Models, Animal; Models, Cardiovascular; Natriuretic Agents; Natriuretic Peptide, Brain; Reference Values; Treatment Outcome; Ventricular Function

NCX 4016, a nitro-ester of aspirin endowed with antithrombotic activity, appears to have clinical potential in treating cardiac complications related to coronary insufficiency. This compound has been shown to improve postischemic ventricular dysfunction and to reduce myocardial infarct size in the rabbit. The cardioprotection conferred by NCX 4016 (10, 30, and 100 mg/kg) and aspirin (ASA, 54 mg/kg) was evaluated in anesthetized rats subjected to 30 min of myocardial ischemia followed by 120 min of reperfusion (MI/R). Drugs were given orally for 5 consecutive days. NCX 4016 displayed remarkable cardioprotection in rats subjected to MI/R as was evident in the reduction of ventricular premature beats and in the incidence of ventricular tachycardia and fibrillation; they were reduced dose dependently and correlated with survival of all rats treated with the higher dose of NCX 4016. In these animals, infarct size was restricted proportionally to the dose of NCX 4016 associated with diminution of both plasma creatine phosphokinase and cardiac myeloperoxidase activities. ASA showed only a minor degree of protection against MI/R damage. Rats treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) demonstrated aggravated myocardial damage in terms of arrhythmias, mortality, and infarct size. Supplementation of nitric oxide (NO) with NCX 4016 (100 mg/kg) greatly reduced the worsening effect caused by L-NAME. The beneficial effects of NCX 4016 appear to derive in large part from the NO moiety, which modulates a number of cellular events leading to inflammation, obstruction of the coronary microcirculation, arrhythmias, and myocardial necrosis.

Topics: Animals; Arrhythmias, Cardiac; Aspirin; Creatine Kinase; Cyclic GMP; Fibrinolytic Agents; Hemodynamics; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; NG-Nitroarginine Methyl Ester; Peroxidase; Platelet Aggregation Inhibitors; Rats; Rats, Wistar

The tissue kallikrein-kinin system is present in the heart, and kinin has been shown to have cardioprotective effects. In this study, we investigated the potential role of tissue kallikrein in myocardial ischemia/reperfusion injury through adenovirus-mediated human kallikrein gene delivery. One week after gene delivery, the rats were subjected to a 30-minute coronary occlusion followed by a 2-hour reperfusion. Kallikrein gene delivery caused significant decreases in the ratio of infarct size to ischemic area at risk (from 69.6% to 44.5%, n=10 and 8, P<0.01) and in the incidence of ventricular fibrillation (from 64.3% to 16.7%, n=14 and 24, P<0.01) compared with the group injected with control adenovirus. Kallikrein gene delivery also attenuated programmed cell death in the ischemic area compared with the control area as assessed with the terminal deoxynucleotidyl transferase-mediated nick end labeling assay (n=6, P<0.01). Icatibant, a specific bradykinin B(2) receptor antagonist, abolished these kallikrein-mediated beneficial effects. The expression of human tissue kallikrein mRNA was identified in rat heart, kidney, lung, liver, and adrenal gland. After kallikrein gene delivery, cardiac kinin and cGMP levels were significantly elevated compared with the control (29.6+/-12.7 versus 6.1+/-2.1 pg/mg protein, n=7, P<0.01; 1.30+/-0.06 versus 0.86+/-0.09 pmol/mg protein, n=5, P<0.05). These results indicate that kallikrein gene delivery protects against myocardial infarction, ventricular arrhythmias, and apoptosis in ischemia/reperfusion injury via kinin-cGMP signal pathway. The successful application of this technology may have potential therapeutic value in the treatment of coronary artery diseases.

Topics: Animals; Animals, Genetically Modified; Apoptosis; Arrhythmias, Cardiac; Base Sequence; Cyclic GMP; DNA Primers; Gene Expression; Hemodynamics; Humans; Kallikreins; Kinins; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Wistar; RNA, Messenger

Nitric oxide generated by cardiac myocytes or delivered by drugs has been shown to regulate cardiac contractile function and has been implicated in suppressing some cardiac arrhythmias, although this remains controversial. We examined the ability of the soluble cardiac glycoside, ouabain, to trigger arrhythmic contractions in ventricular myocytes isolated from mice lacking a functional endothelial nitric oxide synthase gene (eNOS(null)). Arrhythmic activity, defined as aftercontractions, was induced with ouabain (50 micromol/L) and recorded using a video-motion detector in isolated, electrically driven single ventricular myocytes from adult eNOS(null)or from their wild-type (WT) littermates. The rate of ouabain-induced arrhythmic contractions was significantly higher in eNOS(null)myocytes than in WT myocytes. Application of the NO donor S-nitroso-acetylcysteine (SNAC) significantly diminished the frequency of arrhythmic contractions in eNOS(null)myocytes. The antiarrhythmic effect of NO, whether generated by eNOS in WT cells or by SNAC, could be partially reversed by 1H-[1,2,4]oxadiazolo-[4, 3-a]- quinoxalin-1-one (ODQ), a specific soluble guanylyl cyclase inhibitor. Ouabain significantly increased intracellular cGMP in WT but not eNOS(null)hearts, and this cGMP response was blocked by ODQ. Since cardiac glycoside- induced aftercontractions are activated by the transient inward current (I(ti)), the role of NO in ouabain (100 micromol/L)- induced I(ti)was examined using the nystatin-perforated patch-clamp technique. The frequency of ouabain-induced I(ti)was significantly higher in eNOS(null)myocytes than in WT myocytes, and this could be suppressed by SNAC. These data demonstrate that NO derived from myocyte eNOS activation suppresses ouabain-induced arrhythmic contractions by a mechanism that might involve activation of guanylyl cyclase and elevation of cGMP.

Topics: Acetylcysteine; Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Cells, Cultured; Cyclic GMP; Electrophysiology; Endothelium, Vascular; Mice; Mice, Transgenic; Myocardial Contraction; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Ouabain; Time Factors

Carperitide, a recombinant form of alpha-hANP, possesses potent diuretic, natriuretic, and vasodilatory activity, and inhibits the renin-aldosterone system and sympathetic nervous activity. However, its beneficial effects on ischemic myocardium have not been studied fully. We examined carperitide's effects on infarct size, hemodynamics, and arrhythmia frequency in anesthetized dogs (n = 20) subjected to a 90-min coronary artery occlusion/6-h reperfusion protocol. Intravenous infusion of carperitide (0.2 microg/kg/min) commenced 15 min after occlusion and continued during occlusion/reperfusion. Ventricular fibrillation developed in two of 10 control versus three of 10 treated dogs (p = NS). Hemodynamics, collateral blood flow to the ischemic wall measured 10 min after occlusion, and extent of area at risk were comparable for the two groups. Infarct size/area at risk was smaller in treated than in control dogs (4.5 +/- 2.1% vs. 27.8 +/- 7.8%, respectively; p < 0.05). During occlusion, carperitide tended to increase collateral blood flow (+39%) and significantly decreased left ventricular systolic pressure (-13%) and end-diastolic pressure (-40%) compared with baseline. In control dogs, collateral blood flow tended to decrease (-8.3%), whereas most hemodynamic parameters did not change significantly with respect to baseline. The number of arrhythmias recorded during occlusion/reperfusion was similar in the two groups. Intravenous administration of carperitide limited infarct size, but did not reduce incidence of ventricular arrhythmias after 90-min coronary occlusion/6-h reperfusion in anesthetized dogs. Although the beneficial effects of carperitide may be attributable to concomitant changes in hemodynamics and collateral blood flow, the precise mechanisms require further investigation.

Topics: Animals; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Cardiotonic Agents; Collateral Circulation; Coronary Disease; Cyclic GMP; Dogs; Female; Humans; Male; Myocardial Infarction; Myocardial Reperfusion; Peptide Fragments

The majority of clinically used inotropes act by increasing cytosolic calcium levels, which may hypothetically worsen reperfusion stunning and provoke arrhythmias. We tested the hypothesis that the calcium sensitizer levosimendan (levo) given during ischemia alone or ischemia and reperfusion would improve reperfusion function without promoting arrhythmias. The Langendorff-perfused guinea pig heart, subjected to 40-min low-flow ischemia (0.4 ml/min) with or without levo (10-300 nM) given during ischemia or ischemia/reperfusion was used. Left ventricular developed pressure (LVDP) was used as an index of mechanical function. The effect of levo (300 nM) or dobutamine (0.1 microM) on the incidence of ischemia/reperfusion arrhythmias was also investigated. Control hearts (vehicle-perfused) had LVDPs of 69.4 +/- 2.1 mm Hg whereas hearts treated with levo during ischemia and reperfusion (300 nM) had LVDPs of 104.5 +/- 2.7 mm Hg (p <.05). Hearts treated with levo during ischemia alone (10 nM) had reperfusion LVDPs of 95.8 +/- 4.2 mm Hg (p <.05) after 30-min reperfusion. Hearts treated with both levo and 10 microM glibenclamide (K(ATP) channel blocker) during ischemia had reperfusion LVDPs of 73.4 +/- 4.3 mm Hg after 30-min reperfusion. Of control hearts, 25% developed reperfusion ventricular tachycardia but not ventricular fibrillation. Levo-treated hearts had no ischemia/reperfusion arrhythmias whereas 83% (p <.05 versus control) of dobutamine-treated hearts developed ventricular tachycardia and 33% (p <.05 versus levo) developed reperfusion ventricular fibrillation. Levo improved reperfusion function without promoting arrhythmias in this model. This was possibly achieved by opening the K(ATP) channels during ischemia and sensitizing myocardial contractile apparatus instead of elevating cytosolic calcium levels in reperfused hearts.

Topics: Adenosine Triphosphate; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channel Agonists; Calcium Channel Blockers; Cyclic AMP; Cyclic GMP; Dobutamine; Glyburide; Guinea Pigs; Heart; Hydrazones; In Vitro Techniques; L-Lactate Dehydrogenase; Lactic Acid; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nucleotides, Cyclic; Phosphocreatine; Pyridazines; Simendan; Stereoisomerism

The effect of a nitric oxide (NO) donor and the influence of endogenous NO in modulating ischaemia-induced arrhythmias was assessed in anaesthetised rats. The nitric oxide donor C87-3754 (1 mg/kg) caused a significant reduction in arterial blood pressure before coronary artery ligation but did not influence the incidence or severity of ventricular arrhythmias during a 30-min period of myocardial ischaemia [60 and 58% incidence of ventricular fibrillation (VF) in control and treated rats, respectively]. When the hearts were preconditioned by a short (3 min) coronary artery occlusion before the 30-min period of ischaemia, there was a marked reduction in both the number of ventricular ectopic beats (260 +/- 65 vs. 812 +/- 256 beats/min in controls; p < 0.05) and the incidence of ventricular fibrillation (9 vs. 67% in controls; p < 0.05). Neither NG-nitro-L-arginine methyl ester (L-NAME; 10-100 mg/kg) nor methylene blue (1-50 mg/kg) attenuated this marked antiarrhythmic effect of preconditioning. L-NAME caused a significant increase in blood pressure with all doses used, whereas methylene blue did not increase blood pressure. Both L-NAME and methylene blue attenuated ventricular arrhythmias in non-preconditioned hearts. L-NAME reduced the number of ventricular ectopic beats (from 812 +/- 256 to 318 +/- 81 beats/min at 10 mg/kg; p < 0.05), whereas methylene blue decreased the incidence of VF from 67 to 20% at a dose of 50 mg/kg (p < 0.05). These findings suggest that neither endogenous nor exogenously administered NO reduces ischaemic arrhythmias in anaesthetised rats. Furthermore, the antiarrhythmic effect of preconditioning in this species appears to be independent of NO. The antiarrhythmic effects seen with both methylene blue and L-NAME may be the result of actions other than inhibition of the production or actions of NO.

Topics: Analysis of Variance; Animals; Arrhythmias, Cardiac; Blood Pressure; Cyclic GMP; Disease Models, Animal; Enzyme Inhibitors; Ischemic Preconditioning, Myocardial; Male; Methylene Blue; Myocardial Ischemia; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Sprague-Dawley; Sydnones; Vasodilator Agents; Ventricular Fibrillation

We have reported that chronic treatment of patients with beta 1-adrenoceptor blockers sensitises isolated atrial preparations to adrenaline, noradrenaline and 5-Ht. We have now examined the effect of chronic treatment with beta-adrenoceptor blockers on responses to histamine of human right atrial appendages. We compared the effects of histamine on contractile force, cyclic AMP and cyclic GMP levels as well as cyclic AMP-dependent protein kinase (PKA) activity and explored the arrhythmogenic effects of histamine in preparations obtained from patients chronically treated or not treated with beta-adrenoceptor blockers. Histamine increased contractile force in paced preparations; the effects were blocked by the H2 receptor antagonist famotidine (0.1-30 mumol/l). The maximum inotropic response to histamine was doubled and the inotropic potency of histamine 0.4 log units greater in atria from beta-adrenoceptor blocker-treated compared to non beta-adrenoceptor blocker-treated patients. Histamine elicited frequency-dependent arrhythmias that were blocked by famotidine (30 mumol/l) but not by mepyramine (1 mumol/l). The incidence of arrhythmias was higher in atria from beta-adrenoceptor blocker-treated compared to untreated patients. Histamine increased both cyclic AMP and cyclic GMP levels, as well as PKA activity, significantly more in atria from beta-adrenoceptor blocker-treated compared to those from untreated patients. Mepyramine 1 mumol/l prevented the histamine-evoked increase in cyclic GMP levels, reduced the inotropic hyperresponsiveness and abolished the hyperresponsiveness in cyclic AMP levels and PKA activity observed in patients chronically treated with beta blockers. Sodium nitroprusside 10 mumol/l caused smaller increase of cyclic GMP levels than histamine and restored the contracile force depressed by mepyramine to its original level in atria from beta-adrenoceptor blocker-treated patients. The evidence is consistent with sensitisation of both the histamine H1 and histamine H2 receptor systems by chronic beta 1-adrenoceptor blockade. H1 receptor-mediated increases in cyclic GMP, enhanced through an as yet unknown mechanism by chronic beta 1-adrenoceptor blockade, may inhibit phosphodiesterase 3 activity, thereby causing enhanced histamine-evoked increases in cyclic AMP levels and PKA activity, and accounting partially for the increased inotropic responses to histamine through H2 receptors.

Topics: Adrenergic beta-Antagonists; Arrhythmias, Cardiac; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Dose-Response Relationship, Drug; Famotidine; Female; Heart; Heart Atria; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Male; Middle Aged; Myocardial Contraction; Pyrilamine; Receptors, Histamine H1; Receptors, Histamine H2; Stimulation, Chemical

The aim of this investigation was to test whether the administration of atrial natriuretic peptide (ANP) has cardioprotective effects against ischaemic and reperfusion injury.. Thoracotomized dogs underwent a 30 min left circumflex coronary artery occlusion and 60 min of reperfusion (control group; n = 16). The ANP group (n = 9) received a 20 micrograms bolus injection of synthetic alpha human ANP (SUN 4936) followed by infusion at a dose of 0.1 microgram/kg/min from the beginning of coronary occlusion to the end of the procedure.. Administration of exogenous ANP increased plasma ANP immediately and maintained levels at 3000 pg/ml, resulting in an 8-fold increase in plasma cyclic guanosine monophosphate (cGMP) levels. Plasma ANP and plasma cGMP levels did not change at all in controls. There were no significant differences in haemodynamic parameters during ischaemia and reperfusion between the groups. In the ANP group, the prevalence and frequency of ventricular extrasystoles within 10 min after reperfusion decreased markedly [ANP 22% vs. control 100%, P < 0.01, and ANP 1 (1) vs. control 92 (50), P < 0.05, respectively]. No dog in the ANP group had ventricular fibrillation (VF), but the incidence of VF was not statistically significant between the groups [ANP 0% vs. control 25%]. ATP content in the inner layers of the ischaemic myocardium in the ANP group was higher than in controls (P < 0.05) [1.92 (0.28) vs. 1.18 (0.13) mumol/g wet weight]. There was no significant difference in the content of myocardial tissue angiotensin II between the groups.. These data show that the infusion of ANP has cardioprotective effects on myocardial ischaemia and reperfusion in this model. These beneficial effects are probably due to direct effects through cGMP rather than haemodynamic changes.

Topics: Angiotensin II; Animals; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Cyclic GMP; Dogs; Female; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium

Cardiac anaphylaxis, an acute ischemic dysfunction comprising coronary vasoconstriction and arrhythmias, is a model of clinically recognized immediate hypersensitivity reactions affecting the heart. Bradykinin, a mediator of hypersensitivity, is also a potent coronary vasodilator, acting via nitric oxide and prostacyclin production. Because ischemia increases bradykinin outflow from the heart, we questioned whether bradykinin might mitigate anaphylactic coronary vasoconstriction. Antigen challenge of hearts isolated from presensitized guinea pigs was associated with an approximately 30% increase in bradykinin overflow. Furthermore, (1) when the half-life of bradykinin was prolonged with the kininase II/angiotensin-converting enzyme inhibitors captopril and enalaprilat, anaphylactic coronary vasoconstriction was attenuated and reversed, and arrhythmias were alleviated; (2) the bradykinin B2-receptor antagonist HOE 140 prevented these effects; and (3) HOE 140 exacerbated both anaphylactic coronary vasoconstriction and arrhythmias. During cardiac anaphylaxis, the coronary overflow of cGMP, a marker of nitric oxide production, and 6-ketoprostaglandin F1 alpha, a stable prostacyclin metabolite, increased two-fold and fourfold, respectively. Because neither enalaprilat nor HOE 140 affected these changes, the enhanced overflow of cGMP and 6-ketoprostaglandin F1 alpha is likely to reflect the actions of other hypersensitivity mediators (eg, histamine and leukotrienes). We postulate that bradykinin plays a protective role in cardiac anaphylaxis by accumulating at the luminal surface of the coronary endothelium and promoting, in an autocrine mode, a B2-receptor-mediated production of nitric oxide and prostacyclin in concentrations sufficient to elicit a paracrine effect on coronary vascular smooth muscle, thus opposing the vasoconstricting effects of other anaphylactic mediators.

Topics: Anaphylaxis; Animals; Arrhythmias, Cardiac; Bradykinin; Captopril; Coronary Vessels; Cyclic GMP; Epoprostenol; Guinea Pigs; Male; Nitric Oxide; Vasodilation

1. The aim of the present studies was to examine the effects of nitric oxide donors on arrhythmias induced by coronary artery occlusion and reperfusion, and on cardiac cyclic nucleotides. Experiments were performed in pentobarbitone-anaesthetized rats prepared for occlusion of the left coronary artery. 2. Sodium nitroprusside (0.1, 0.3 and 1 microgram kg-1 min-1) had no significant effects on the incidence of ventricular tachycardia, total ventricular fibrillation or the mortality resulting from 25 min of acute myocardial ischaemia when compared with values in controls. In addition, there was no alteration in the number of ventricular premature beats that occurred in survivors. 3. 3-Morpholinosydnonimine-N-ethylcarbamide (SIN-1, 10, 20 and 40 micrograms kg-1 min-1) caused marked hypotension but did not alter the incidence or severity of ischaemia-induced arrhythmias. In rats subject to abrupt reperfusion after 5 min of myocardial ischaemia, lower doses of SIN-1 (1, 3 and 10 micrograms kg-1 min-1) still caused significant reductions in systolic and diastolic blood pressure but were devoid of antiarrhythmic activity. 4. In separate experiments in sham-operated rats, sodium nitroprusside (1 microgram kg-1 min-1), isosorbide dinitrate (30 and 60 micrograms kg-1 min-1) and SIN-1 (20 and 40 micrograms kg-1 min-1) had no significant effects on cardiac cyclic GMP content. 5. These results indicate that nitric oxide donors do not alter arrhythmias induced by acute coronary artery occlusion or reperfusion in anaesthetized rats. Although increases in total cardiac cyclic GMP could not be detected, the results suggest that, at least in the rat, cyclic GMP does not influence these arrhythmias.

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cyclic AMP; Cyclic GMP; Hemodynamics; Isosorbide Dinitrate; Male; Molsidomine; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitroprusside; Rats; Rats, Wistar; Vasodilator Agents

Topics: Acetylcholinesterase; Adaptation, Physiological; Adrenal Glands; Animals; Arrhythmias, Cardiac; Butyrylcholinesterase; Choline O-Acetyltransferase; Cyclic AMP; Cyclic GMP; Heart; Immobilization; Male; Myocardium; Rats; Rats, Wistar; Receptors, Adrenergic; Receptors, Cholinergic; Stress, Physiological

Topics: Arrhythmias, Cardiac; Cyclic AMP; Cyclic GMP; Exonucleases; Humans; Myocardium; Phosphodiesterase Inhibitors

1. Flosequinan, milrinone, isoprenaline and forskolin given intravenously at similarly hypotensive doses have been evaluated in separate studies for their effect on ischaemia-induced arrhythmias and on ventricular cyclic nucleotide content following coronary artery ligation in the pentobarbitone anaesthetized rat. 2. Flosequinan did not affect mortality or arrhythmias following coronary artery ligation in either study and no change in ventricular cyclic nucleotide content was observed. 3. Isoprenaline caused a significant increase in mortality (P < 0.05) in both studies whereas milrinone and forskolin caused a significant increase in mortality in only one of the two studies conducted. All three agents caused significant increases in cyclic AMP which were associated with increased incidence of arrhythmias. 4. When compared at similarly hypotensive doses, flosequinan, in contrast to milrinone, isoprenaline and forskolin, did not influence ischaemia-induced arrhythmias or raise ventricular cyclic nucleotide levels in the anesthetized rat.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Anesthesia; Animals; Arrhythmias, Cardiac; Blood Pressure; Colforsin; Coronary Vessels; Cyclic AMP; Cyclic GMP; Enzyme Activation; Isoproterenol; Male; Milrinone; Myocardial Ischemia; Myocardium; Phosphodiesterase Inhibitors; Pyridones; Quinolines; Rats; Rats, Wistar; Vasodilator Agents

The role of NO-formation induced by accumulated endogenous bradykinin (BK) via local ACE-inhibition with ramiprilat (RT) or by adding BK exogenously was evaluated in cultured bovine aortic endothelial cells (BAEC) and in isolated rat hearts with post-ischaemic reperfusion injuries. Furthermore we used the n-octyl-ester of ramipril (RA-octil) which was shown to have no ACE-inhibitory action. In BAEC, ACE-inhibition by RT (1 x 10(-8)-1 x 10(-6) mol/l) or addition of BK (1 x 10(-8)-1 x 10(-6) mol/l) stimulated the formation of NO and prostacyclin (PGI2) as assessed by endothelial cyclic GMP- and 6-keto-PGF1a formation. Cyclic GMP and PGI2 synthesis was completely suppressed by the NO synthase inhibitor NG-nitro-L-arginine (L-NNA, 1 x 10(-5) mol/l) and by the B2 kinin receptor antagonist HOE 140 (1 x 10(-7) mol/l). RA-octil (1 x 10(-8)-1 x 10(-4) mol/l) did not affect endothelial cyclic GMP production in BAEC. In isolated working rat hearts subjected to local ischemia with reperfusion both RT (1 x 10(-8) mol/l) and BK (1 x 10(-9) mol/l) reduced the incidence and duration of ventricular fibrillation. In parallel myocardial function (left ventricular pressure, coronary flow) and metabolism (high energy rich phosphates) were improved showing a comparable fingerprint for RT and BK. Addition of L-NNA (1 x 10(-6) mol/l) or HOE 140 (1 x 10(-9) mol/l) abolished these protective effects of RT and BK. As in the BAEC studies RA-octil was without beneficial effects on the isolated ischaemic rat heart. The findings on BAEC show that inhibition of ACE localized on the luminal side of the vascular endothelium results in increased synthesis of NO and prostacyclin by local accumulation of endothelium-derived BK. Similar mechanisms may occur in the ischaemic rat heart leading to cardioprotection.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Bradykinin; Cattle; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Epoprostenol; Female; In Vitro Techniques; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Nitric Oxide; Ramipril; Rats; Rats, Wistar

Short periods of coronary artery occlusion (2 x 5 min) markedly reduce the severity of arrhythmias and the changes in ST-segment elevation and in the degree of inhomogeneity of conduction during a subsequent 25 min occlusion of the left anterior descending coronary artery in anaesthetized dogs. These changes were completely reversed if methylene blue (5 mg min-1) was infused into a side branch of the coronary artery throughout both the preconditioning and prolonged occlusions. These results suggest that the pronounced antiarrhythmic effects of preconditioning result from activation of guanylyl cyclase and result in increased levels of guanosine 3':5'-cyclic monophosphate.

Topics: Animals; Arrhythmias, Cardiac; Coronary Vessels; Cyclic GMP; Dogs; Guanylate Cyclase; Infusions, Intra-Arterial; Methylene Blue; Myocardial Ischemia

Persistent atrial standstill is a very rare pathophysiologic condition whose diagnosis is established when both electrical and mechanical silence of the atria are confirmed. To test the hypothesis that secretion of atrial natriuretic peptide is disturbed in patients with persistent atrial standstill, the response of atrial natriuretic peptide secretion and other neurohormonal factors during exercise was investigated in three patients with a rate-responsive ventricular demand (VVI) pacemaker implanted for confirmed persistent atrial standstill. The results were compared with those observed in eight normal subjects and patients with a rate-responsive VVI (Group A) or atrial demand (AAI) (Group B) pacemaker implanted for confirmed sick sinus syndrome. Patients in Group A displayed significant elevation of alpha-human atrial natriuretic peptide secretion both before and during exercise (122.5 +/- 14.8 and 207.5 +/- 8.3 pg/ml, respectively) compared with those in Group B (55 +/- 14.1 and 116.4 +/- 51.5 pg/ml, respectively) and the normal subjects (18.9 +/- 9.8 and 30.8 +/- 19.2 pg/ml, respectively). This indicated development of a nonphysiologic increase in atrial volume or pressure overload, or both, in rate-responsive VVI pacing because of lack of atrioventricular synchrony. However, patients with persistent atrial standstill had undetectable (less than 10 pg/ml) or almost undetectable secretion of atrial natriuretic peptide as well as lower levels of cyclic guanosine monophosphate in the circulation both before and during exercise. Changes in plasma catecholamines during exercise were similar in patients with persistent atrial standstill compared with the other groups. This study indicates that "endocrinologic silence" accompanies electrical and mechanical silence of the atria, which may constitute a third diagnostic clue to persistent atrial standstill.

Topics: Adult; Aged; Arrhythmias, Cardiac; Atrial Function; Atrial Natriuretic Factor; Cyclic AMP; Cyclic GMP; Electrocardiography; Epinephrine; Exercise; Exercise Test; Female; Heart Atria; Humans; Male; Middle Aged; Norepinephrine; Pacemaker, Artificial; Sick Sinus Syndrome

The effect of antiarrhythmic drugs, ritmilen and allapinin, on endogenic prostanoid and cyclic nucleotide levels was examined in patients with heart rhythm disorders. Intravenous administration of antiarrhythmic agents is shown to be accompanied with increased release of prostacyclin that has antiarrhythmic properties into myocardial outflow. Both ritmilen and allapinin promoted the predominance of prostacyclin over thromboxane, with its intrinsic arrhythmogenic properties. Ritmilen- or allapinin-induced changes in prostaglandins E and F2 alpha consisted in that PGE prevailed, as compared to PGF2 alpha. There were no significant changes in cyclic nucleotide ratios (cAMP/cGMP) in response to treatment.

Topics: Aconitine; Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cyclic AMP; Cyclic GMP; Dinoprost; Disopyramide; Female; Humans; Male; Middle Aged; Nucleotides, Cyclic; Prostaglandins; Prostaglandins E; Prostaglandins F; Stimulation, Chemical

Cardiac toxicity of methylphosphonothiolate (MPT), an organophosphorus compound, has been investigated in the rat. Subcutaneous injection of MPT (12 micrograms/kg body wt) induced cardiac arrhythmias, the occurrence of which was significantly more frequent than in the control group. Death rate among MPT-treated animals appeared to be in relationship with cardiac arrhythmias. Plasma nonesterified fatty acid concentrations increased in MPT-poisoned rats. cAMP and cGMP contents in myocardial tissue were unchanged 150 min after MPT administration, as compared with control. Similarly, no change has occurred in high energy compound levels.

Topics: Animals; Arrhythmias, Cardiac; Cyclic AMP; Cyclic GMP; Electrocardiography; Fatty Acids, Nonesterified; Heart; Lethal Dose 50; Male; Myocardium; Organothiophosphorus Compounds; Rats; Rats, Inbred Strains

In anesthetized rats a 30-min intravenous infusion of adenosine (2.5 mg/kg/min) performed after the coronary artery ligation significantly decreased the incidence and severity of early ischemic arrhythmias. After the infusion of adenosine, there was an increase in cGMP level in the left ventricular myocardium, cAMP content remained unchanged.

Topics: Adenosine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Disease; Cyclic AMP; Cyclic GMP; Drug Evaluation, Preclinical; Heart; Male; Myocardium; Rats; Time Factors

The aims of this study were to determine whether a relationship exists between the occurrence of coronary artery occlusion-induced arrhythmias in the anaesthetized rat and the levels of cyclic AMP and cyclic GMP in both normal and ischaemic myocardium, and to assess whether such arrhythmias were modified by pretreatment with the phosphodiesterase inhibitors, quazodine and isobutyl methylxanthine (IBMX), or with the butyryl derivatives of cyclic AMP and cyclic GMP. At 5 min after coronary artery ligation (when only a few arrhythmias had occurred) both cyclic AMP and cyclic GMP levels were elevated in normal myocardium whereas in ischaemic tissue only cyclic AMP was raised. As the peak of the arrhythmic activity and after cessation of the arrhythmias, i.e. at 10 and 30 min post-ligation respectively, levels of both nucleotides had fallen in ischaemic although not in normal tissue. The severity of these occlusion-induced arrhythmias was exacerbated by pretreatment intravenously with quazodine, IBMX, dibutyryl cyclic AMP and dibutyryl cyclic GMP. Pretreatment with IBMX was also shown to elevate significantly both cyclic AMP and cyclic GMP content of left ventricular tissue before occlusion. None of the drug pretreatments markedly affected mean arterial blood pressure but heart rate was significantly increased following quazodine and IBMX administration. We conclude that in the pentobarbitone-anaesthetized rat the occurrence of occlusion-induced arrhythmias was not accompanied by a rise in cyclic nucleotide content of the ischaemic myocardium but agents which may elevate either myocardial cyclic AMP or cyclic GMP levels exacerbate such arrhythmias.

Topics: 1-Methyl-3-isobutylxanthine; Anesthesia; Animals; Arrhythmias, Cardiac; Bucladesine; Coronary Disease; Cyclic AMP; Cyclic GMP; Dibutyryl Cyclic GMP; Heart; Male; Myocardium; Quinazolines; Rats; Rats, Inbred Strains

Forty-one children with cardiac arrhythmias were examined. It was established that cardiac rhythm disorders in children were accompanied by an increase in the cGMP levels as well as a decrease in the cAMP content, CPK activity and the cAMP/cGMP ratio varying in relation to the form of arrhythmia and the nature of heart damage.

Topics: Adolescent; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Cardiomyopathies; Child; Child, Preschool; Creatine Kinase; Cyclic AMP; Cyclic GMP; Ehlers-Danlos Syndrome; Female; Heart Block; Humans; Male; Mitral Valve Prolapse; Tachycardia, Paroxysmal

Topics: Acidosis; Animals; Arrhythmias, Cardiac; Calcium; Calcium Channel Blockers; Cyclic AMP; Cyclic GMP; Heart; Hydrogen-Ion Concentration; Ion Channels; Kinetics; Myocardium; Phosphorylation

The hypothesis that c GMP and sodium nitroprusside (NP), an activator of guanylate cyclase which elevates levels of c GMP, have antiarrhythmic activity was tested in the barium chloride (BaCl2) model of arrhythmias. Electrocardiograms were recorded continuously on tape in unanesthetized New Zealand white rabbits weighing approximately 2.0 kg. BaCl2, 4 mg/kg i.v. bolus, induced frequent ventricular ectopic beats. These ventricular arrhythmias were abolished by 8-bromo-c GMP, 5 mg/kg, injected into the left ventricle (5/6 rabbits), NP 25.0 microgram/kg/min i.v. (6/6), NP 10 micrograms/kg/min i.v. (3/6), and markedly reduced in frequency by NP 10 micrograms/kg/min (3/6). In temporal association with NP, 4 fold increases in c GMP levels in blood and significant increases in myocardial GMP were found compared to control animals (n = 6). In this model, c GMP and NP have significant antiarrhythmic properties. NP effect may be mediated by alterations in c GMP metabolism.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Barium; Barium Compounds; Chlorides; Cyclic GMP; Electrocardiography; Ferricyanides; Hemodynamics; Nitroprusside; Rabbits

Topics: Aged; Arrhythmias, Cardiac; Catecholamines; Cyclic AMP; Cyclic GMP; Dopamine; Epinephrine; Fatty Acids, Nonesterified; Female; Humans; Male; Middle Aged; Myocardial Infarction; Norepinephrine; Nucleotides, Cyclic

In anaesthetized open-chest dogs, cardiac arrhythmias (CA) were induced by cumulative intravenous doses of aconitine or ouabain. Aconitine in a dose which did not induce CA had no influence on the PGE and PGF2 alpha effluxes into coronary sinus blood (CSB), whereas the PGE efflux into CSB increased after a subtoxic dose of ouabain. However, both PGE and PGF2 alpha effluxes were increased, when CA had developed. During aconitine induced CA, the PGE efflux was 6.5-fold and that of PGF2 alpha had increased by 80%. During ouabain induced CA, the effluxes of both PGs were about 3-fold. Propranolol and lidocaine decreased the PGF2 alpha efflux into CSB by about 50% and the PGE efflux was doubled after lidocaine and decreased after propranolol by about a third. The increased PGE efflux into CSB during CA was normalized after propranolol and quinidine if the CA was abolished or the cardiac rhythm improved. Lidocaine did not modify the increase in PGE efflux, despite the abolishment of CA. The increase in PGF2 alpha efflux was not influenced by antiarrhythmic drugs. The cyclic AMP and cyclic GMP in CSB remained unchanged during ouabain induced arrhythmias or after propranolol. The increased efflux of PGE into CSB during aconitine and ouabain induced CA and its abolishment by propranolol support the hypothesis that PGE participates in the modulation of increased sympathetic tone during CA.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Cyclic AMP; Cyclic GMP; Dinoprost; Dogs; Female; Male; Ouabain; Prostaglandins; Prostaglandins E; Prostaglandins F

Topics: Acetylcholine; Animals; Arrhythmias, Cardiac; Coronary Disease; Cyclic AMP; Cyclic GMP; Dogs; Myocardial Infarction; Myocardium; Propranolol