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Extracellular purines and pyrimidines have major effects on cardiac rhythm and contraction. ATP/UTP are released during various physiopathological conditions, such as ischemia, and despite degradation by ectonucleotidases, their interstitial concentrations can markedly increase, a fact that is clearly associated with arrhythmia. In the present whole cell patch-clamp analysis on ventricular cardiomyocytes isolated from various mammalian species, ATP and UTP elicited a sustained, nonselective cationic current, [I.sub.ATP]. UDP was ineffective, whereas 2'(3')-O-(4-benzoylbenzoyl)-ATP was active, suggesting that P2[Y.sub.2] receptors are involved. [I.sub.ATP] resulted from the binding of AT[P.sup.4-] to P2[Y.sub.2] purinoceptors. [I.sub.ATP] was maintained after ATP removal in the presence of guanosine 5'-[[gamma]-thio]triphosphate and was inhibited by U-73122, a PLC inhibitor. Single-channel openings are rather infrequent under basal conditions. ATP markedly increased opening probability, an effect prevented by U-73122. Two main conductance levels of 14 and 23 pS were easily distinguished. Similarly, in fura-2-1oaded cardiomyocytes, [Mn.sup.2+] quenching and [Ba.sup.2+] influx were significant only in the presence of ATP or UTP. Adult rat ventricular cardiomyocytes expressed transient receptor potential channel TRPC1, -3, -4, and -7 mRNA and the TRPC3 and TRPC7 proteins that coimmunoprecipitated. Finally, the anti-TRPC3 antibody added to the patch pipette solution inhibited [I.sub.ATP]. In conclusion, activation of P2[Y.sub.2] receptors, via a G protein and stimulation of PLC[beta], induces the opening of heteromeric TRPC3/7 channels, leading to a sustained, nonspecific cationic current. Such a depolarizing current could induce cell automaticity and trigger the arrhythmic events during an early infarct when ATP/UTP release occurs. These results emphasize a new, potentially deleterious role of TRPC channel activation. purinergic receptor; signal transduction; infarction; arrhythmia

OBJECTIVES Open in new tab Download slide Open in new tab Download slide Pulmonary hypertension and heart disease contribute to the high morbidity rate following pneumonectomy (PN). The pathophysiology is still poorly understood. The objective was to investigate the consequences of PN on cardiopulmonary function in rats and to explore in vitro the involved mechanisms. METHODS Sixty Sprague-Dawley male rats randomly underwent either a right PN (PN group) or sham surgery. Ten rats per group were sacrificed on postoperative days 3, 7 and 28. Cardiopulmonary alterations were investigated by echocardiographic, haemodynamic and histological analyses. In vitro , the shear stress was reproduced using a Flexcell Tension™ cyclic stretch on cultured human pulmonary endothelial cells (P-ECs) to investigate the impact on pulmonary artery smooth muscle cell (PA-SMC) growth. Data are expressed as mean ± SD. RESULTS Mean pulmonary arterial pressure gradually increased in the PN group to reach 35 ± 7 mmHg on postoperative day 28 vs 18 ± 4 in sham (P  =   0.001), likewise the proportion of muscularized distal pulmonary arteries, 83 ± 1% vs 5 ± 1%, respectively (P  <   0.001), related to in situ PA-SMC proliferation. The right ventricle area and lateral wall thickness were doubled in the PN group on postoperative day 28. The left ventricle ejection fraction decreased on postoperative days 7 and 28 while the right ventricle function was maintained. In vitro , the human PA-SMC growth was significantly greater when seeded with stretched vs non-stretched P-EC media, highlighting the role of shear stress on the P-EC paracrine function. CONCLUSIONS Right PN led to pulmonary hypertension and proportional right heart remodelling in rats. The shear stress related to high blood flow alters the pulmonary endothelial paracrine control of SMC growth. [ABSTRACT FROM AUTHOR]

Risk of hospital readmission and cardiac mortality increases with atmospheric pollution for patients with heart failure. The underlying mechanisms are unclear. Carbon monoxide (CO) a ubiquitous environmental pollutant could be involved. We explored the effect of daily exposure of CO relevant to urban pollution on post-myocardial infarcted animals. Rats with ischemic heart failure were exposed 4 weeks to daily peaks of CO mimicking urban exposure or to standard filtered air. CO exposure worsened cardiac contractile dysfunction evaluated by echocardiography and at the cardiomyocyte level. In line with clinical reports, the animals exposed to CO also exhibited a severe arrhythmogenic phenotype with numerous sustained ventricular tachycardias as monitored by surface telemetric electrocardiograms. CO did not affect cardiac β-adrenergic responsiveness. Instead, mitochondrial dysfunction was exacerbated leading to additional oxidative stress and Ca 2+ cycling alterations. This was reversed following acute antioxidant treatment of cardiomyocytes with N-acetylcysteine confirming involvement of CO-induced oxidative stress. Exposure to daily peaks of CO pollution aggravated cardiac dysfunction in rats with ischemic heart failure by specifically targeting mitochondria and generating ROS-dependent alterations. This pathway may contribute to the high sensibility and vulnerability of individuals with cardiac disease to environmental outdoor air quality.

Acute myocardial infarction leads to an increase in oxidative stress and lipid peroxidation. 4(RS)-4-F 4t -Neuroprostane (4-F 4t -NeuroP) is a mediator produced by non-enzymatic free radical peroxidation of the cardioprotective polyunsaturated fatty acid, docosahexaenoic acid (DHA). In this study, we investigated whether intra-cardiac delivery of 4-F 4t -NeuroP (0.03mg/kg) prior to occlusion (ischemia) prevents and protects rat myocardium from reperfusion damages. Using a rat model of ischemic-reperfusion (I/R), we showed that intra-cardiac infusion of 4-F 4t -NeuroP significantly decreased infarct size following reperfusion (-27%) and also reduced ventricular arrhythmia score considerably during reperfusion (-41%). Most notably, 4-F 4t -NeuroP decreased ventricular tachycardia and post-reperfusion lengthening of QT interval. The evaluation of the mitochondrial homeostasis indicates a limitation of mitochondrial swelling in response to Ca 2+ by decreasing the mitochondrial permeability transition pore opening and increasing mitochondria membrane potential. On the other hand, mitochondrial respiration measured by oxygraphy, and mitochondrial ROS production measured with MitoSox red® were unchanged. We found decreased cytochrome c release and caspase 3 activity, indicating that 4-F 4t -NeuroP prevented reperfusion damages and reduced apoptosis. In conclusion, 4-F 4t -NeuroP derived from DHA was able to protect I/R cardiac injuries by regulating the mitochondrial homeostasis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Despite its degradation by ectonucleotidases, a low ATP concentration is present in the interstitial space; moreover, its level can markedly increase during various physiopathological conditions. ATP and uridine 5'-triphosphate (UTP) releases correlate with the occurrence of ventricular premature beats and ventricular tachycardia. ATP facilitates several voltage-dependent ionic currents including the L-type Ca(2+) current. More recently, ATP and UTP were also shown to induce a poor voltage-dependent, long-lasting current carried by the heterotetrameric transient receptor potential (TRP) channels TRPC3/7. ATP effects result from its binding to metabotropic P2Y2 receptors that lead to diacylglycerol formation and activation of phospholipase Cβ and inositol-1,4,5-triphosphate production. ATP also favours TRPM4 activation by increasing Ca(2+) release from the sarcoplasmic reticulum. Indeed, TRPM4 current properties match those of the Ca(2+)-activated, nonselective cationic current supporting the delayed afterdepolarizations observed under conditions of Ca(2+) overload. In the present article, it was hypothesized that creatine, at a relatively high concentration, would serve as a buffer for the sudden release of ATP and UTP during the early phase of ischemia in association with previously described arrhythmic events. The potential preventive effect of creatine was tested by analyzing its ability to antagonize the arrhythmia that occurred on inducing a coronary ligature in rats that were or were not preinjected with creatine. Electrocardiogram recordings of creatine-injected rats clearly demonstrated that both ventricular premature beats and, particularly, ventricular tachycardia markedly decreased. The effect of creatine was even more striking in early deaths. However, an injection of beta-guanidinopropionate, a creatine analogue with 1000-fold lower kinetics, had no significant protective effect.

Background: Cardiac hypertrophy underlies arrhythmias and sudden death, for which mineralocorticoid receptor (MR) activity has recently been implicated. We sought to establish the sequence of ionic events that link the initiating insult and MR to hypertrophy development., Methods and Results: Using whole-cell, patch-clamp and quantitative reverse transcription-polymerase chain reaction techniques on right ventricular myocytes of a myocardial infarction (MI) rat model, we examined the cellular response over time. One week after MI, no sign of cellular hypertrophy was found, but action potential duration (APD) was lengthened. Both an increase in Ca2+ current (I(Ca)) and a decrease in K+ transient outward current (I(to)) underlay this effect. Consistently, the relative expression of mRNA coding for the Ca2+ channel alpha1C subunit (Ca(v)1.2) increased, and that of the K+ channel K(v)4.2 subunit decreased. Three weeks after MI, AP prolongation endured, whereas cellular hypertrophy developed. I(Ca) density, Ca(v)1.2, and K(v)4.2 mRNA levels regained control levels, but I(to) density remained reduced. Long-term treatment with RU28318, an MR antagonist, prevented this electrical remodeling. In a different etiologic model of abdominal aortic constriction, we confirmed that APD prolongation and modifications of ionic currents precede cellular hypertrophy., Conclusions: Electrical remodeling, which is triggered at least in part by MR activation, is an initial, early cellular response to hypertrophic insults.