Ergotamine Stimulates Human 5-HT4-Serotonin Receptors and Human H2-Histamine Receptors in the Heart.

Ergotamine (2'-methyl-5'α-benzyl-12'-hydroxy-3',6',18-trioxoergotaman) is a tryptamine-related alkaloid from the fungus Claviceps purpurea. Ergotamine is used to treat migraine. Ergotamine can bind to and activate several types of 5-HT1-serotonin receptors. Based on the structural formula of ergotamine, we hypothesized that ergotamine might stimulate 5-HT4-serotonin receptors or H2-histamine receptors in the human heart. We observed that ergotamine exerted concentration- and time-dependent positive inotropic effects in isolated left atrial preparations in H2-TG (mouse which exhibits cardiac-specific overexpression of the human H2-histamine receptor). Similarly, ergotamine increased force of contraction in left atrial preparations from 5-HT4-TG (mouse which exhibits cardiac-specific overexpression of the human 5-HT4-serotonin receptor). An amount of 10 µM ergotamine increased the left ventricular force of contraction in isolated retrogradely perfused spontaneously beating heart preparations of both 5-HT4-TG and H2-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergotamine 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, that were attenuated by 10 µM of the H2-histamine receptor antagonist cimetidine, but not by 10 µM of the 5-HT4-serotonin receptor antagonist tropisetron. These data suggest that ergotamine is in principle an agonist at human 5-HT4-serotonin receptors as well at human H2-histamine receptors. Ergotamine acts as an agonist on H2-histamine receptors in the human atrium.

Prednisone Ameliorates Atrial Inflammation and Fibrosis in Atrial Tachypacing Dogs.

Atrial inflammation and fibrosis have long been considered culprits in the development of atrial fibrillation (AF). Prior clinical studies showed that corticosteroid therapy is beneficial in patients with AF. Here we sought to determine whether prednisone treatment prevents atrial tachypacing (ATP) induced atrial fibrosis.Dogs were randomized into the sham, ATP, ATP + low-dose prednisone (ALP), and ATP + high-dose prednisone (AHP) groups. After 6 days of recovery from surgery, dogs were subjected to ATP at 400 beats per minute for 4 weeks while being treated with prednisone (15 or 40 mg/day) or a placebo. Pacemakers were not activated in the sham group.Compared with the ATP group, the expression of collagen I, collagen III, α-smooth muscle actin, transforming growth factor-ß1 and connective tissue growth factor were significantly reduced in the ALP and AHP groups. Fluorescence assays showed that reactive oxygen species formation in the right atrium was suppressed in the ALP and AHP groups compared with the ATP group. The protein level of NADPH oxidase 2 was reduced in the ALP and AHP groups' versus ATP group, while NOX4 and NOX5 were unchanged. ATP-induced downregulation of BH4 and eNOS uncoupling in the atria was partially restored in the prednisone-treated groups.Our study demonstrated that atrial fibrosis induced by ATP were suppressed by prednisone. Low-dose prednisone was also effective in suppressing the development of atrial fibrosis.

Percutaneous intravenous catheter forceps biopsy in right atrial mass: two case reports and literature review.

BACKGROUND: Primary malignant tumors of the heart are rare. Although preoperative histological diagnosis is difficult, it has paramount value in therapeutic strategy development and prognostic estimation. Herein, we reported 2 cases of intracardiac tumors. CASES PRESENTATION: Both patients presented to the hospital with heart-related symptoms. Echocardiography showed massive masses in the atrium and positron emission tomography-computed tomography (PET/CT) revealed hypermetabolism and invasiveness. One patient cannot take surgery due to extensive metastasis and poor condition. The other patient was primarily diagnosed with lymphoma, and surgery was not recommended. They successfully underwent intravenous atrial biopsy, and histological samples confirmed intimal sarcoma and diffuse large B cell lymphoma. Based on immunohistochemical and molecular assessments, targeted chemotherapy was administered, resulting in clinical and imaging remission at discharge. CONCLUSIONS: Percutaneous intravenous catheter biopsy as a safe invasive test provides an accurate pathological diagnosis after imaging evaluation, and offers a therapeutic direction. Nonmalignant masses and some chemo-radiosensitive malignant tumors in the atrium could have good prognosis after targeted therapy.

Lemon balm (Melissa officinalis L.) essential oil and citronellal modulate anxiety-related symptoms - In vitro and in vivo studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Besides psyche-related symptoms, patients with anxiety disorders can have a large number of somatic symptoms as well. Although the treatment of these disorders is mainly focused on resolving their mental component, one cannot neglect the need for the treatment of accompanying somatic symptoms. Melissa officinalis L. (lemon balm), in various formulations, has been extensively used as an ethnomedicinal remedy for the treatment of different psyche-related symptoms, and its use is considered relatively safe. AIM OF THE STUDY: In the present study, the activity of M. officinalis (MO) essential oil was evaluated in several in vitro and in vivo models mimicking or involving anxiety-related somatic symptoms. MATERIALS AND METHODS: To address the effect of MO essential oil on the gastrointestinal and heart-related symptoms accompanying anxiety disorders, in vitro models were utilized that follow the function of the isolated mouse ileum and atria tissues, respectively, after exposure to MO essential oil. Effects of MO essential oil on BALB/c mice motor activity was estimated using the open field, rota-rod, and horizontal wire tests. Additionally, the essential oil was assayed for its potential in inhibiting acetylcholinesterase activity. RESULTS: The performance of mice treated with 25 mg/kg of the oil showed a statistically significant decrease in the motor impairment arising from acute anxiety (open field test), while there was a prolonged latency and a reduction of the frequency of falling from a rotating rod and/or a horizontal wire (signs of muscle weakness/spasms). Concentrations of the essential oil higher than 1 µg/mL were found to inhibit both spontaneous and induced ileum contractions. Moreover, the essential oil and citronellal were found to decrease isolated mouse atria contraction frequency, as well as contraction force. However, the oil was found to be a very weak acetylcholinesterase inhibitor. CONCLUSION: The modulation of anxiety-related symptoms by the oil was found not to be mediated through the inhibition of the acetylcholinesterase, nonetheless, the mechanistic studies involving the ileum and cardiac tissues, revealed that the activity of MO and citronellal might be related to the modification of either voltage-gated Ca2+ channels or muscarinic receptors. Mice locomotion, balance, and muscle strength were not impacted by the essential oil; however, its main constituent, citronellal, was found to exert a certain degree of muscle function inhibition. All these results suggest that the activity of MO essential oil arises from synergistic and/or antagonistic interactions of its constituents, and is not completely dependent on the oil's main constituent.

Atrial nitroso-redox balance and refractoriness following on-pump cardiac surgery: a randomized trial of atorvastatin.

AIMS: Systemic inflammation and increased activity of atrial NOX2-containing NADPH oxidases have been associated with the new onset of atrial fibrillation (AF) after cardiac surgery. In addition to lowering LDL-cholesterol, statins exert rapid anti-inflammatory and antioxidant effects, the clinical significance of which remains controversial. METHODS AND RESULTS: We first assessed the impact of cardiac surgery and cardiopulmonary bypass (CPB) on atrial nitroso-redox balance by measuring NO synthase (NOS) and GTP cyclohydrolase-1 (GCH-1) activity, biopterin content, and superoxide production in paired samples of the right atrial appendage obtained before (PRE) and after CPB and reperfusion (POST) in 116 patients. The effect of perioperative treatment with atorvastatin (80 mg once daily) on these parameters, blood biomarkers, and the post-operative atrial effective refractory period (AERP) was then evaluated in a randomized, double-blind, placebo-controlled study in 80 patients undergoing cardiac surgery on CPB. CPB and reperfusion led to a significant increase in atrial superoxide production (74% CI 71-76%, n = 46 paired samples, P < 0.0001) and a reduction in atrial tetrahydrobiopterin (BH4) (34% CI 33-35%, n = 36 paired samples, P < 0.01), and in GCH-1 (56% CI 55-58%, n = 26 paired samples, P < 0.001) and NOS activity (58% CI 52-67%, n = 20 paired samples, P < 0.001). Perioperative atorvastatin treatment prevented the effect of CPB and reperfusion on all parameters but had no significant effect on the postoperative right AERP, troponin release, or NT-proBNP after cardiac surgery. CONCLUSION: Perioperative statin therapy prevents post-reperfusion atrial nitroso-redox imbalance in patients undergoing on-pump cardiac surgery but has no significant impact on postoperative atrial refractoriness, perioperative myocardial injury, or markers of postoperative LV function. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01780740.

Connexin 43 participates in atrial electrical remodelling through colocalization with calcium channels in atrial myocytes.

Atrial fibrillation (AF) is associated with atrial conduction disturbances caused by electrical and/or structural remodelling. In the present study, we hypothesized that connexin might interact with the calcium channel through forming a protein complex and, then, participates in the pathogenesis of AF. Western blot and whole-cell patch clamp showed that protein levels of Cav1.2 and connexin 43 (Cx43) and basal ICa,L were decreased in AF subjects compared to sinus rhythm (SR) controls. In cultured atrium-derived myocytes (HL-1 cells), knocking-down of Cx43 or incubation with 30 mmol/L glycyrrhetinic acid significantly inhibited protein levels of Cav1.2 and Cav3.1 and the current density of ICa,L and ICa,T . Incubation with nifedipine or mibefradil decreased the protein level of Cx43 in HL-1 cells. Moreover, Cx43 was colocalized with Cav1.2 and Cav3.1 in atrial myocytes. Therefore, Cx43 might regulate the ICa,L and ICa,T through colocalization with calcium channel subunits in atrial myocytes, representing a potential pathogenic mechanism in AF.

Pharmacological basis for the antihypertensive activity of Grewia asiatica fruit extract.

In the management of cardiovascular disorders, medicines from herbal sources have played a vital role through centuries. The following study was commenced in order to lay possible pharmacological foundation associated with medicinal uses of edible fruit of Grewia asiatica in hypertension through in-vitro method. In this study isolated atrial preparation of Guinea pig was used where crude ethanolic extract of Grewia asiatica fruit (Ga.Cr) decreased the force and rate of spontaneous atrial contractions (0.03-10mg/kg). In isolated rat aortic ring preparations previously vasoconstricted by phenylephrine and High K+, it also resulted in dose dependent vasodilation (0.01-10 mg/kg).In the presence of L-NAME, the relaxation curve of Ga.Cr was partially inhibited showing involvement of Nitric oxide (NO) mediated pathway. The speculative analysis contemplated that Ga.Cr has blood pressure reducing potentials through inhibition of Ca++ influx via Ca++ channels, its release from intracellular stores and through other means like NO mediated pathways.

Characterization and functional role of rapid- and slow-activating delayed rectifier K+ currents in atrioventricular node cells of guinea pigs.

The atrioventricular (AV) node is the only conduction pathway where electrical impulse can pass from atria to ventricles and exhibits spontaneous automaticity. This study examined the function of the rapid- and slow-activating delayed rectifier K+ currents (IKr and IKs) in the regulation of AV node automaticity. Isolated AV node cells from guinea pigs were current- and voltage-clamped to record the action potentials and the IKr and IKs current. The expression of IKr or IKs was confirmed in the AV node cells by immunocytochemistry, and the positive signals of both channels were localized mainly on the cell membrane. The basal spontaneous automaticity was equally reduced by E4031 and HMR-1556, selective blockers of IKr and IKs, respectively. The nonselective ß-adrenoceptor agonist isoproterenol markedly increased the firing rate of action potentials. In the presence of isoproterenol, the firing rate of action potentials was more effectively reduced by the IKs inhibitor HMR-1556 than by the IKr inhibitor E4031. Both E4031 and HMR-1556 prolonged the action potential duration and depolarized the maximum diastolic potential under basal and ß-adrenoceptor-stimulated conditions. IKr was not significantly influenced by ß-adrenoceptor stimulation, but IKs was concentration-dependently enhanced by isoproterenol (EC50: 15 nM), with a significant negative voltage shift in the channel activation. These findings suggest that both the IKr and IKs channels might exert similar effects on regulating the repolarization process of AV node action potentials under basal conditions; however, when the ß-adrenoceptor is activated, IKs modulation may become more important.

Comparison of the effects of left atrial appendage closure and oral anticoagulants in preventing stroke in patients with non-valvular atrial fibrillation: A protocol for systematic review and meta-analysis.

BACKGROUND: This study aims to analyze and evaluate the difference in efficacy between left atrial appendage closure (LAAC) and oral anticoagulants (OA) in preventing stroke in patients with non-valvular atrial fibrillation (NVAF) through the method of meta-analysis. The purpose is to provide for the prevention of stroke in patients with NVAF valuable treatment guidance. METHODS: This study is a comprehensive collection of randomized controlled studies of LAAC and OA in the prevention of stroke in patients with NVAF, and searches PubMed, Embase, the Cochrane Library, Web of Science, CNKI, SinoMed, VIP Database, WANFANG Database, and other Chinese and English databases by combining subject words with free words, and the retrieval time is from the establishment of each database to June 1, 2021. At the same time, searching the included literature and literature of related reviews by manual. Two researchers independently conduct literature screening and quality evaluation. Statistical software RevMan 5.3 and Stata 12.0 were used for meta-analysis. RESULTS: This study evaluating the difference in efficacy between LAAC and OA in preventing stroke in patients with NVAF will be published in high-quality medical academic journals. CONCLUSION: This study will give the best treatment strategy to prevent stroke in patients with NVAF, and provide some reference for clinical medical staff.OSF registration number: DOI 10.17605/OSF.IO/2UXPA (https://osf.io/2uxpa).

Cardiac Effects of Novel Histamine H2 Receptor Agonists.

In an integrative approach, we studied cardiac effects of recently published novel H2 receptor agonists in the heart of mice that overexpress the human H2 receptor (H2-TG mice) and littermate wild type (WT) control mice and in isolated electrically driven muscle preparations from patients undergoing cardiac surgery. Under our experimental conditions, the H2 receptor agonists UR-Po563, UR-MB-158, and UR-MB-159 increased force of contraction in left atrium from H2-TG mice with pEC50 values of 8.27, 9.38, and 8.28, respectively, but not in WT mice. Likewise, UR-Po563, UR-MB-158, and UR-MB-159 increased the beating rate in right atrium from H2-TG mice with pEC50 values of 9.01, 9.24, and 7.91, respectively, but not from WT mice. These effects could be antagonized by famotidine, a H2 receptor antagonist. UR-Po563 (1 µM) increased force of contraction in Langendorff-perfused hearts from H2-TG but not WT mice. Similarly, UR-Po563, UR-MB-158, or UR-MB-159 increased the left ventricular ejection fraction in echocardiography of H2-TG mice. Finally, UR-Po563 increased force of contraction in isolated human right atrial muscle strips. The contractile effects of UR-Po563 in H2-TG mice were accompanied by an increase in the phosphorylation state of phospholamban. In summary, we report here three recently developed agonists functionally stimulating human cardiac H2 receptors in vitro and in vivo. We speculate that these compounds might be of some merit to treat neurologic disorders if their cardiac effects are blocked by concomitantly applied receptor antagonists that cannot pass through the blood-brain barrier or might be useful to treat congestive heart failure in patients. SIGNIFICANCE STATEMENT: Recently, a new generation of histamine H2 receptor (H2R) agonists has been developed as possible treatment option for Alzheimer's disease. Here, possible cardiac (side) effects of these novel H2R agonists have been evaluated.

CXCL12/CXCR4 axis as a key mediator in atrial fibrillation via bioinformatics analysis and functional identification.

Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well understood. In this study, we sought to identify hub genes involved in AF, and explored their functions and underlying mechanisms based on bioinformatics analysis. Five microarray datasets in GEO were used to identify the differentially expressed genes (DEGs) by Robust Rank Aggregation (RRA), and hub genes were screened out using protein-protein interaction (PPI) network. AF model was established using a mixture of acetylcholine and calcium chloride (Ach-CaCl2) by tail vein injection. We totally got 35 robust DEGs that mainly involve in extracellular matrix formation, leukocyte transendothelial migration, and chemokine signaling pathway. Among these DEGs, we identified three hub genes involved in AF, of which CXCL12/CXCR4 axis significantly upregulated in AF patients stands out as one of the most potent targets for AF prevention, and its effect on AF pathogenesis and underlying mechanisms were investigated in vivo subsequently with the specific CXCR4 antagonist AMD3100 (6 mg/kg). Our results demonstrated an elevated transcription and translation of CXCL12/CXCR4 axis in AF patients and mice, accompanied with the anabatic atrial inflammation and fibrosis, thereby providing the substrate for AF maintenance. Blocking its signaling via AMD3100 administration in AF model mice reduced AF inducibility and duration, partly ascribed to decreased atrial inflammation and structural remodeling. Mechanistically, these effects were achieved by reducing the recruitment of CD3+ T lymphocytes and F4/80+ macrophages, and suppressing the hyperactivation of ERK1/2 and AKT/mTOR signaling in atria of AF model mice. In conclusion, this study provides new evidence that antagonizing CXCR4 prevents the development of AF, and suggests that CXCL12/CXCR4 axis may be a potential therapeutic target for AF.

Electrophysiological Response to Acehytisine Was Modulated by Aldosterone in Rats with Aorto-Venocaval Shunts.

Aldosterone induces cardiac electrical and structural remodeling, which leads to the development of heart failure and/or atrial fibrillation (AF). However, it remains unknown whether aldosterone-induced remodeling may modulate the efficacy of anti-AF drugs. In this study, we aimed to jeopardize the structural and functional remodeling by aldosterone in rats with aorto-venocaval shunts (AVS rats) and evaluate the effect of acehytisine in this model. An AVS operation was performed on rats (n = 6, male) and it was accompanied by the intraperitoneal infusion of aldosterone (AVS + Ald) at 2.0 µg/h for 28 d. The cardiopathy was characterized by echocardiography, electrophysiologic and hemodynamic testing, and morphometric examination in comparison with sham-operated rats (n = 3), sham + Ald (n = 6), and AVS (n = 5). Aldosterone accelerated the progression from asymptomatic heart failure to overt heart failure and induced sustained AF resistant to electrical fibrillation in one out of six rats. In addition, it prolonged PR, QT interval and Wenckebach cycle length. Acehytisine failed to suppress AF in the AVS + Ald rats. In conclusion, aldosterone jeopardized electrical remodeling and blunted the electrophysiological response to acehytisine on AF.

Long-chain acylcarnitine 18:1 acutely increases human atrial myocardial contractility and arrhythmia susceptibility.

Long-chain acylcarnitines (LCACs) are known to directly alter cardiac contractility and electrophysiology. However, the acute effect of LCACs on human cardiac function is unknown. We aimed to determine the effect of LCAC 18:1, which has been associated with cardiovascular disease, on the contractility and arrhythmia susceptibility of human atrial myocardium. Additionally, we aimed to assess how LCAC 18:1 alters Ca2+ influx and spontaneous Ca2+ release in vitro. Human right atrial trabeculae (n = 32) stimulated at 1 Hz were treated with LCAC 18:1 at a range of concentrations (1-25 µM) for a 45-min period. Exposure to the LCAC induced a dose-dependent positive inotropic effect on myocardial contractility (maximal 1.5-fold increase vs. control). At the 25 µM dose (n = 8), this was paralleled by an enhanced propensity for spontaneous contractions (50% increase). Furthermore, all LCAC 18:1 effects on myocardial function were reversed following LCAC 18:1 washout. In fluo-4-AM-loaded HEK293 cells, LCAC 18:1 dose dependently increased cytosolic Ca2+ influx relative to vehicle controls and the short-chain acylcarnitine C3. In HEK293 cells expressing ryanodine receptor (RyR2), this increased Ca2+ influx was linked to an increased propensity for RyR2-mediated spontaneous Ca2+ release events. Our study is the first to show that LCAC 18:1 directly and acutely alters human myocardial function and in vitro Ca2+ handling. The metabolite promotes proarrhythmic muscle contractions and increases contractility. The exploratory findings in vitro suggest that LCAC 18:1 increases proarrhythmic RyR2-mediated spontaneous Ca2+ release propensity. The direct effects of metabolites on human myocardial function are essential to understand cardiometabolic dysfunction.NEW & NOTEWORTHY For the first time, the fatty acid metabolite, long-chain acylcarnitine 18:1, is shown to acutely increase the arrhythmia susceptibility and contractility of human atrial myocardium. In vitro, this was linked to an influx of Ca2+ and an enhanced propensity for spontaneous RyR2-mediated Ca2+ release.

Quercetin prevents isoprenaline-induced myocardial fibrosis by promoting autophagy via regulating miR-223-3p/FOXO3.

Atrial fibrillation (AF) is the common arrhythmias. Myocardial fibrosis (MF) is closely related to atrial remodeling and leads to AF. MF is the main cause of cardiovascular diseases and a pathological basis of AF. Thus, the underlying mechanism in MF and AF development should be fully elucidated for AF therapeutic innovation. Autophagy is a highly conserved lysosomal degradation pathway, and the relationship between autophagy and MF has been previously shown. Moreover, research reported that quercetin (Que) could ameliorate MF. The current study aimed to explore the mechanism of Que in MF. The results in this study showed that in clinical AF patients and in aged rats, miR-223-3p was high-expressed, while FOXO3 and autophagy pathway related proteins, such as ATG7, p62/SQSTM1 and the ratio of LC3B-II/LC3B-I were significantly inhibited. In vivo and in vitro studies, we found that Que can effectively inhibit the expression of miR-223-3p in AF model cells and rats myocardial tissues, and meanwhile enhance the expression of FOXO3 and activate the autophagy pathway, and significantly inhibit myocardial fibrosis, and improve myocardial remodeling in atrial fibrillation. All in all, in this study, we found that Que prevents isoprenaline-induced MF by increasing autophagy via regulating miR-223-3p/FOXO3.

A detailed characterization of the hyperpolarization-activated "funny" current (If) in human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes with pacemaker activity.

Properties of the funny current (If) have been studied in several animal and cellular models, but so far little is known concerning its properties in human pacemaker cells. This work provides a detailed characterization of If in human-induced pluripotent stem cell (iPSC)-derived pacemaker cardiomyocytes (pCMs), at different time points. Patch-clamp analysis showed that If density did not change during differentiation; however, after day 30, it activates at more negative potential and with slower time constants. These changes are accompanied by a slowing in beating rate. If displayed the voltage-dependent block by caesium and reversed (Erev) at - 22 mV, compatibly with the 3:1 K+/Na+ permeability ratio. Lowering [Na+]o (30 mM) shifted the Erev to - 39 mV without affecting conductance. Increasing [K+]o (30 mM) shifted the Erev to - 15 mV with a fourfold increase in conductance. pCMs express mainly HCN4 and HCN1 together with the accessory subunits CAV3, KCR1, MiRP1, and SAP97 that contribute to the context-dependence of If. Autonomic agonists modulated the diastolic depolarization, and thus rate, of pCMs. The adrenergic agonist isoproterenol induced rate acceleration and a positive shift of If voltage-dependence (EC50 73.4 nM). The muscarinic agonists had opposite effects (Carbachol EC50, 11,6 nM). Carbachol effect was however small but it could be increased by pre-stimulation with isoproterenol, indicating low cAMP levels in pCMs. In conclusion, we demonstrated that pCMs display an If with the physiological properties expected by pacemaker cells and may thus represent a suitable model for studying human If-related sinus arrhythmias.

Treatment-Related Changes in Left Atrial Structure in Atrial Fibrillation: Findings From the CABANA Imaging Substudy.

[Figure: see text].

Effects of the L/N-Type Ca2+ Channel Blocker Cilnidipine on the Cardiac Histological Remodelling and Inducibility of Atrial Fibrillation in High-Salt-Fed Rats.

High salt intake has been shown to induce hypertrophy and fibrosis in the atria and ventricles, which could result in the development of atrial fibrillation (AF). Whereas the development of AF is suggested to be prevented by renin-angiotensin system (RAS) inhibitors, recent findings have indicated that this prevention is closely associated with their antihypertensive effects. In this study, we investigated whether the L/N-type Ca2+ channel blocker cilnidipine counteracts salt-induced atrial and ventricular remodelling and the inducibility of AF. Cilnidipine was orally administered to Dahl salt-sensitive rats fed with an 8% NaCl diet at 10 mg/kg for 5 weeks, and then electrophysiological evaluation and histological analyses were performed. The effects were compared with those of the L-type Ca2+ channel blocker amlodipine at 3 mg/kg. Following the intake of the 8% NaCl diet, the blood pressure (BP) increased, and fibrosis was induced in the atria and ventricles. Cilnidipine decreased BP, and the extent of the decrease in the cilnidipine group was similar to those in the amlodipine group. Cilnidipine produced a greater decrease in the fibrotic area in the atria and ventricles than amlodipine. The cilnidipine group shortened the AF duration from 7.43 ± 3.16 to 2.95 ± 1.73 s, which had been increased by NaCl intake. Plasma noradrenaline levels in the cilnidipine group were lower than those in the amlodipine group. Thus, the suppressive effects of cilnidipine on the salt-induced atrial and ventricular remodelling, fibrosis, and AF sustainability might be closely associated with its N-type Ca2+ channel-blocking actions.

Insights into sinus arrhythmia of the dog: Acetylcholine perfusion of canine right atrium results in beat-to-beat patterns that mimic sinus arrhythmia supporting exit block in the sinoatrial conduction pathways.

Sinus arrhythmia of the dog is unique because of the pronounced alternating beat-to-beat intervals. The clustering of these short (faster rates) and long (slower rates) intervals is not just influenced by autonomic input from breathing; sinus arrhythmia can persist in the panting or apneic dog. The multiplicity of central and peripheral influences on the sinus node complicates the unraveling of the mechanisms of sinus arrhythmia. Studies of the sinus node suggest that acetylcholine can slow cellular depolarization and block sinoatrial conduction. Electrocardiographic monitoring of the dog supports this notion in that abrupt bifurcation into short and long intervals develop at lower heart rates. We sought to determine whether this phenomenon could be recapitulated in canine atrial preparations perfused with acetylcholine and whether selective pharmacologic blockade of the voltage and calcium clocks could provide insight into its mechanism. Spontaneous beat to beat (A-A) intervals were obtained from monophasic action potential recordings of perfused canine right atrial preparations before and during perfusion with acetylcholine (2-5 µM). The calcium clock was blocked with ryanodine (2-3 µM). The membrane clock was blocked with diltiazem hydrochloride (ICa,L blocker; 0.25 µM) and ZD7288 (If blocker; 3 µM). Hyperpolarization was hindered by blockade of IK,Ado/IK,Ach with tertiapin Q (100 nM) before and during acetylcholine perfusion. Acetylcholine resulted in beat clusters similar to those seen in sinus arrhythmia of the dog. Beat clusters were consistent with intermittent 2:1 and 3:1 sinoatrial conduction block. Tertiapin Q abolished this patterning suggesting a role of IK,Ado/IK,ACh in the mechanism of these acetylcholine-induced beat-to-beat patterns.

In vivo characterization of anti-atrial fibrillatory potential and pharmacological safety profile of INa,L plus IKr inhibitor ranolazine using the halothane-anesthetized dogs.

To characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine having INa,L plus IKr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil and dl-sotalol in our previous studies, ranolazine dihydrochloride in sub-therapeutic (0.3 mg/kg) and supra-therapeutic (3 mg/kg) doses was intravenously infused over 10 min to the halothane-anesthetized dogs (n = 5). The low dose increased the heart rate, cardiac output and atrioventricular conduction velocity possibly via vasodilator action-induced, reflex-mediated increase of adrenergic tone. Meanwhile, the high dose decreased the heart rate, ventricular contraction, cardiac output and mean blood pressure, indicating that drug-induced direct actions may exceed the reflex-mediated compensation. In addition, it prolonged the atrial and ventricular effective refractory periods, of which potency and selectivity for the former were less great compared with those of the clinically-available drugs. Moreover, it did not alter the ventricular early repolarization period in vivo, but prolonged the late repolarization with minimal risk for re-entrant arrhythmias. These in vivo findings of ranolazine suggest that INa,L suppression may attenuate IKr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less promising as an anti-atrial fibrillatory drug, but its potential risk for inducing torsade de pointes will be small. These information can be used as a guide to predict the utility and adverse effects of anti-atrial fibrillatory drugs having multi-channel modulatory action.

New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation.

Hormones are potent endo-, para-, and autocrine endogenous regulators of the function of multiple organs, including the heart. Endocrine dysfunction promotes a number of cardiovascular diseases, including atrial fibrillation (AF). While the heart is a target for endocrine regulation, it is also an active endocrine organ itself, secreting a number of important bioactive hormones that convey significant endocrine effects, but also through para-/autocrine actions, actively participate in cardiac self-regulation. The hormones regulating heart-function work in concert to support myocardial performance. AF is a serious clinical problem associated with increased morbidity and mortality, mainly due to stroke and heart failure. Current therapies for AF remain inadequate. AF is characterized by altered atrial function and structure, including electrical and profibrotic remodelling in the atria and ventricles, which facilitates AF progression and hampers its treatment. Although features of this remodelling are well-established and its mechanisms are partly understood, important pathways pertinent to AF arrhythmogenesis are still unidentified. The discovery of these missing pathways has the potential to lead to therapeutic breakthroughs. Endocrine dysfunction is well-recognized to lead to AF. In this review, we discuss endocrine and cardiocrine signalling systems that directly, or as a consequence of an underlying cardiac pathology, contribute to AF pathogenesis. More specifically, we consider the roles of products from the hypothalamic-pituitary axis, the adrenal glands, adipose tissue, the renin-angiotensin system, atrial cardiomyocytes, and the thyroid gland in controlling atrial electrical and structural properties. The influence of endocrine/paracrine dysfunction on AF risk and mechanisms is evaluated and discussed. We focus on the most recent findings and reflect on the potential of translating them into clinical application.