Negative Chronotropic Effects Research Articles

Effects of plant extracts and derivatives on cardiac K+, Nav, and Cav channels: a review.

Natural products (NPs) are endless sources of compounds for fighting against several pathologies. Many dysfunctions, including cardiovascular disorders, such as cardiac arrhythmias have their modes of action regulation of the concentration of electrolytes inside and outside the cell targeting ion channels. Here, we highlight plant extracts and secondary metabolites' effects on the treatment of related cardiac pathologies on hERG, Nav, and Cav of cardiomyocytes. The natural product's pharmacology of expressed receptors like alpha-adrenergic receptors causes an influx of Ca2+ ions through receptor-operated Ca2+ ion channels. We also examine the NPs associated with cardiac contractions such as myocardial contractility by reducing the L-type calcium current and decreasing the intracellular calcium transient, inhibiting the K+ induced contractions, decreasing amplitude of myocyte shortening and showed negative ionotropic and chronotropic effects due to decreasing cytosolic Ca2+. We examine whether the NPs block potassium channels, particular the hERG channel and regulatory effects on Nav1.7.

An Overview of the Pharmacokinetics and Pharmacodynamics of Landiolol (an Ultra-Short Acting β1 Selective Antagonist) in Atrial Fibrillation.

Landiolol is an ultra-short-acting, selective β1-adrenergic receptor blocker that was originally approved in Japan for the treatment of intraoperative tachyarrhythmias. It has gained attention for its use in the management of tachyarrhythmias and perioperative tachycardia, especially atrial fibrillation for both cardiac and non-cardiac surgeries. It can be the ideal agent for heart rate control due to its high β1-selectivity, potent negative chronotropic effect, a limited negative inotropic potential, and an ultrashort elimination half-life (around 4 min); moreover, it may have a potential therapeutic effects for sepsis and pediatric patients. Landiolol seems to be superior to other short-acting and selective beta-blockers such as esmolol. This review aims to provide a comprehensive overview of landiolol, a new ultra-short-acting β1 selective antagonist, including its pharmacology, clinical applications, efficacy, safety profile, and future directions in research and clinical data.

Initial Characterization of a Transgenic Mouse with Overexpression of the Human H1-Histamine Receptor on the Heart.

There is a debate on whether H1-histamine receptors can alter contractility in the mammalian heart. We studied here a new transgenic mouse model where we increased genetically the cardiac level of the H1-histamine receptor. We wanted to know if histamine could augment or decrease contractile parameters in mice with cardiac-specific overexpression of human H1-histamine receptors (H1-TG) and compared these findings with those in littermate wild-type mice (WT). In H1-TG mice, we studied the presence of H1-histamine receptors by autoradiography of the atrium and ventricle using [3H]mepyramine. The messenger RNA for human H1-histamine receptors was present in the heart from H1-TG and absent from WT. Using in situ hybridization, we noted mRNA for the human H1-histamine receptor in cardiac cells from H1-TG. We noted that histamine (1 nM-10 µM) in paced (1 Hz) left atrial preparations from H1-TG, exerted at each concentration of histamine initially reduced force of contraction and then raised contractile force. Likewise, in spontaneously beating left atrial preparations from H1-TG, we noted that histamine led to a transient reduction in the spontaneous beating rate followed by an augmentation in the beating rate. The negative inotropic and chronotropic and the positive inotropic effects on histamine in isolated atrial muscle strips from H1-TG were attenuated by the H1-histamine receptor antagonist mepyramine. Histamine failed to exert an increased force or reduce the heartbeat in atrial preparations from WT. We concluded that stimulation of H1-histamine-receptors can decrease and then augment contractile force in the mammalian heart and stimulation of H1-histamine receptors exerts a negative chronotropic effect. SIGNIFICANCE STATEMENT: We made novel transgenic mice with cardiomyocyte-specific high expressional levels of the human H1-histamine receptor to contribute to the clarification of the controversy on whether H1-histamine receptors increase or decrease contractility and beating rate in the mammalian heart. From our data, we conclude that stimulation of H1-histamine receptors first decrease and then raise contractile force in the mammalian heart but exert solely negative chronotropic effects.

Cardiac and neurobehavioral impairments in three phylogenetically distant aquatic model organisms exposed to environmentally relevant concentrations of boscalid

Boscalid (2-Chloro-N-(4′-chlorobiphenyl-2-yl) nicotinamide), a pyridine carboxamide fungicide, is an inhibitor of the complex II of the respiration chain in fungal mitochondria. As boscalid is only moderately toxic for aquatic organisms (LC50 > 1–10 mg/L), current environmental levels of this compound in aquatic ecosystems, in the range of ng/L-μg/L, are considered safe for aquatic organisms. In this study, we have exposed zebrafish (Danio rerio), Japanese medaka (Oryzias latipes) and Daphnia magna to a range of concentrations of boscalid (1–1000 μg/L) for 24 h, and the effects on heart rate (HR), basal locomotor activity (BLA), visual motor response (VMR), startle response (SR), and habituation (HB) to a series of vibrational or light stimuli have been evaluated. Moreover, changes in the profile of the main neurotransmitters have been determined. Boscalid altered HR in a concentration-dependent manner, leading to a positive or negative chronotropic effect in fish and D. magna, respectively. While boscalid decreased BLA and increased VMR in Daphnia, these behaviors were not altered in fish. For SR and HB, the response was more species- and concentration-specific, with Daphnia exhibiting the highest sensitivity. At the neurotransmission level, boscalid exposure decreased the levels of L-aspartic acid in fish larvae and increased the levels of dopaminergic metabolites in D. magna. Our study demonstrates that exposure to environmental levels of boscalid alters cardiac activity, impairs ecologically relevant behaviors, and leads to changes in different neurotransmitter systems in phylogenetically distinct vertebrate and invertebrate models. Thus, the results presented emphasize the need to review the current regulation of this fungicide.

Ictal Asystole During Focal Seizures Due to Left Occipital Glioneuronal Tumor: A Report of Case Treated With Cardiac Neuromodulation.

Ictal asystole (IA) is a rare but potentially life-threatening complication of focal epilepsy. The sudden onset of loss of consciousness and drop attacks in a patient with chronic epilepsy should suggest the possibility of this complication. Once the diagnosis is established, rapid management should be considered, especially in high-risk cases. The approach does not differ between temporal and extratemporal lobe epilepsies. Strategies can be aimed at preventing the emergence of cortical epileptic activity from the beginning (surgery, antiseizure therapy), neutralizing negative chronotropic effects on the heart (cardiac neuromodulation), or restarting the heart rhythm with a pacemaker. Pacemaker implantation is not a completely complication-free treatment, and living with a device that requires care and follow-up throughout life makes alternative treatment methods more valid for young patients with many years to live or cases that could benefit from surgery. In this article, we present a patient with a left occipital glioneuronal tumor and drug-resistant occipital lobe epilepsy. IA was documented by long-term video EEG monitoring (VEM). During about 2 years of follow-up after a cardiac neuromodulation procedure, there were no drop attacks or asystole with seizures, confirmed by long-term VEM.

Cholinesterase inhibitors are associated with large reductions in hospitalization for cardiovascular events and mortality in patients with Alzheimer’s dementia and heart failure

AbstractIntroductionCholinesterase inhibitors (ChEIs) are approved for treatment of Alzheimer’s dementia (AD). ChEIs inhibit the enzyme acetylcholinesterase, increasing the duration of action of acetylcholine in the central and peripheral nervous systems. ChEIs are known to be anti‐inflammatory and to have negative chronotropic effects. Observational studies by us and other groups have indeed shown an association with use of ChEIs in AD with lower risk of death and cardiovascular events (CVD) including myocardial infarction, heart failure (HF), and stroke. We next wanted to investigate whether ChEI treatment in AD patients with HF is associated with reduced risk for mortality and for hospitalization due to CVD.MethodsData from the Swedish registry for dementia disorders, SveDem,was linked to the Patient‐, Prescribed Drug‐ and Cause of death registries. In a propensity score (PS) matched cohort of patients with AD and HF, the association between ChEI use and all‐cause death or hospitalization due to CVD was examined with Cox proportional hazards models.ResultsThe PS matched cohort included 455 patients with HF prior to the AD diagnosis with ChEI and 455 non‐ChEI users. During a median follow‐up time of 2.14 years, 549 deaths occurred. Compared to non‐users, ChEI use was associated with 21% lower risk of death (adjusted HR 0.79; 0.66‐0.96). Galantamine and donepezil (0.64; CI 0.47‐0.87 and 0.80; CI 0.64‐0.98) but not rivastigmine (0.96; CI 0.73‐1.28) were associated with lower risk of death. Any ChEI use was associated with a 47% (CI 0.38‐0.75) reduction in risk of hospitalization due to HF and a 52% reduction (CI 0.32‐072) among donepezil‐users.ConclusionsThis study supports previous reports that treatment with ChEIs in AD is associated with reduced mortality risk. We here show that this association is also found in patients with HF and AD but with differential effects among the ChEIs. Further studies are needed to elucidate the mechanisms. The study also showed a substantial reduction in hospitalization due to CVD. Our results highlight the impact of cardiovascular comorbidities in AD which need to be considered in clinical trials as would the impact of the baseline treatment with ChEIs in new anti‐dementia drug trials.

Features of α2-Adrenergic Regulation of Isolated Rat Heart after Hypokinesia.

We studied the effect of the α2-adrenergic receptor agonist clonidine hydrochloride (10-9-10-6 M) on the isolated heart of adult rats after 30-day restriction of motor activity. In hypokinetic rats, in comparison with control animals, clonidine caused a positive inotropic effect; the dynamics of coronary flow was changed after stimulation of α2-adrenergic receptors by clonidine in the minimum and maximum concentrations. Moreover, clonidine in concentrations of 10-8 and 10-7 M reduced coronary flow both in the control group and against the background of hypokinesia. Clonidine (10-8-10-6 M) had a negative chronotropic effect in control and hypokinetic animals, while the dynamics of HR was multidirectional, i.e. either an increase or decrease in the effects was observed depending of the agonist concentration. Overall, the data obtained indicate the participation of α2-adrenergic receptors in adaptive processes after motor activity limitation.

Influence of experimental heart failure therapy with different generations of β-adrenergic blockers on Cardiac Electrical Activity (ECG) and Autonomic Regulation of Heart Rhythm (ARHR)

Abstract: In the complex treatment of chronic heart failure (CHF) β-adrenoblockers (carvedilol, nebivolol, bisoprolol, metoprolol) are used, which due to their pharmacological properties increase the survival rate of patients, improve cardio- and haemodynamic parameters, metabolism. However, modern realities in medicine require creation of new more effective and safe β-adrenoblockers. In this regard, the potential drug Hypertirl is of interest. The aim was to evaluate the cardioprotective effect of 1-(b-phenylethyl)-4-amino-1,2,4-triazolium bromide (Hypertril) on cardiac electrical activity and autonomic regulation of heart rhythm in a model of CHF in comparison with β-adrenoblockers of different generations (Nebivolol, Carvedilol, Bisoprolol, Metoprolol). Materials and methods: Chronic heart failure was induced by 14-day administration of doxorubicin in a cumulative dose of 15 mg/kg to white mongrel rats weighing 190–220g (total 85). The investigated drugs were administered after doxorubicin course for 30 days: Hypertril at an experimentally substantiated dose of 3.5 mg/kg, Metoprolol succinate 15 mg/kg, Nebivolol 10 mg/kg, Carvedilol 50 mg/kg, Bisoprolol 10 mg/kg. At the end of drug administration under thiopental anaesthesia (40 mg/kg), electrocardiogram (ECG) and autonomic regulation of heart rhythm (ARHR) were analysed using a computer analyser CardioCom-2000plus (KAI-Medica, Ukraine). The results of the study were calculated using a standard statistical package “STATISTICA for Windows 6.0” (StatSoftInc., №AXXR712D833214FAN5), “SPSS 16.0” and “Microsoft Office Excell 2003”. Results and discussion: Hypertril administration resulted in a negative chronotropic effect, normalisation of atrial (P) and ventricular (R) spike amplitude, ST segment inversion below isoline, increased amplitude of ventricular myocardial repolarisation T. Myocardial repolarisation spike were observed, as well as normalised the duration of atrial (P) and ventricular depolarisation phase (QRS complex) to the intact value and restored the duration of electrical diastole (TR interval). Hypertril reduced systolic and diastolic myocardial dysfunction in animals with CHF. Hypertril restored autonomic mechanisms of heart rhythm regulation and balanced activity of sympathetic and parasympathetic parts of autonomic nervous system in the control of cardiac function. Conclusion: The obtained results demonstrated the undoubted advantage of the new original molecule (Hypertril) over basic β-adrenoblockers (Metoprolol, Nebivolol, Carvedilol and Bisoprolol) and experimentally justify further in-depth study to create on its basis a drug for the treatment of CHF.

Animals Experimentally Infected with SARS-CoV-2 Generate Functional Autoantibodies against G-Protein-Coupled Receptors.

(1) Background: SARS-CoV-2 infection has been linked to diverse clinical manifestations in humans, including cardiovascular complications. Functional autoantibodies targeting G-protein-coupled receptors have emerged as potential contributors to these effects. This study sought to investigate the production and activity of functional autoantibodies targeting G-protein-coupled receptors after SARS-CoV-2 infection of selected animal species. (2) Methods: The presence of functional autoantibodies such as 2-adrenoceptor, angiotensin II AT1 receptor, muscarinic M2 receptor, and angiotensin 1-7 MAS receptor was assessed in cattle and ferrets experimentally infected with SARS-CoV-2. Bioassays were conducted to evaluate the positive or negative chronotropic responses induced by these autoantibodies. Further experiments identified the extracellular domains to which the functional autoantibodies bind, and receptor antagonists were employed to block the induced responses. (3) Results: Only two out of six cattle that were inoculated with SARS-CoV-2 displayed viral replication and tested positive for functional autoantibodies against G-protein-coupled receptors. These functional autoantibodies specifically recognized β2-adrenoceptor, angiotensin II AT1 receptor, muscarinic M2 receptor, and angiotensin 1-7 MAS receptor and induced distinct positive and negative chronotropic effects in the bioassay. Infected ferrets generated functional autoantibodies against β2-adrenoceptor and muscarinic M2 receptor and presented bioactivity similar to that in cattle. (4) Conclusions: This study uncovers functional autoantibodies targeting G-protein-coupled receptors in cattle and ferrets post-SARS-CoV-2 infection, with implications for cardiovascular function.

7-Hydroxy Frullanolide Ameliorates Isoproterenol-Induced Myocardial Injury through Modification of iNOS and Nrf2 Genes.

Myocardial infarction (MI) is the principal cause of premature death. Protecting myocardium from ischemia is the main focus of intense research. 7-hydroxy frullanolide (7-HF) is a potent anti-inflammatory agent, showing its efficacy in different acute and chronic inflammatory disorders such as atherosclerosis, suggesting it can be a potential cardioprotective agent. For the induction of MI, Sprague-Dawley rats (n = 5) were administered isoproterenol (ISO) 85 mg/kg s.c at 24 h intervals for two days. The potential cardioprotective effect of 7-HF and its mechanisms were explored by in vivo and in vitro methods. 7-HF significantly prevented the extent of myocardial injury by decreasing the infarct size, preserving the histology of myocardial tissue, and reducing the release of cardiac biomarkers. Further, 7-HF increased the mRNA expression of cardioprotective gene Nrf2 and reduced the mRNA expression of iNOS. 7-HF also improved cardiac function by decreasing the cardiac workload through its negative chronotropic and negative ionotropic effect, as well as by reducing peripheral vascular resistance due to the inhibition of voltage-dependent calcium channels and the release of calcium from intracellular calcium stores. In conclusion, 7-HF showed cardioprotective effects in the MI model, which might be due to modulating the expression of iNOS and Nrf2 genes as well as improving cardiac functions.

Determinants of cardiopulmonary exercise test responses in hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Exercise capacity and ventilatory efficiency are often altered in hypertrophic cardiomyopathy (HCM) and several factors have been advocated as possible causes. Aim This study investigates the determinants of cardiopulmonary exercise test (CPET) prognostic markers for HCM (VO2Peak, VE/VCO2 Slope and PETCO2 apex), by considering echocardiographic and cardiac magnetic resonance (CMR) parameters. Secondly, it scopes if myocardial fibrosis at CMR leads to clinical and functional differences. Methods 64 patients with HCM underwent a clinical assessment, including maximal CPET, echocardiography, and CMR. Exclusion criteria were the corrective surgery for cardiac hypertrophy and heart failure stage. Results The study included 66% males, age 40±17 years, NYHA class I or II 91%. Mean left ventricle (LV) ejection fraction was 63,8±7,7%, with a mean LV maximal wall thickness (MVT) of 20,2±5,6 mm; LVOT gradient was >30mmHg in 14% of patients. Late gadolinium enhancement (LGE) was described in 70,3% of cases with a mean LGE extension on bullseye plot of 11%. 39% of patients had a VO2 peak <80% of predicted, 35% a reduced PETCO2 apex and 26% an increased VE/VCO2 Slope. At the stepwise multivariate analysis, age (β=-0,33; p=0,00), BMI (β=-0,80; p=0,002), systolic blood pressure increase (β=0,22; p=0,02), left atrial volume (β=-0,15; p=0,02) and BB therapy (β=-0,45; p=0,00) were independently associated with VO2 peak (R2-adjusted index 0,95). Concerning ventilatory efficiency, sex (β=-0,41; p=0,03), left atrial volume (β=0,46; p=0,01) and LGE extension (β=0,33; p=0,01) were independently associated with VE/VCO2 Slope (R2-adjusted index 0,46). Similar data, with reversed correlations, emerged for PETCO2 apex. Patients with LGE had a LV mass index (mean 104,6 vs 82,7 g/m2, p=0,04), MWT (mean 21,8 vs 16,2 mm, p=0,00) and diastolic function (mean E/e’ 13,4 vs 10,0, p=0,01) worse that the counterpart. No differences were found in sex, age, therapy, CPET parameters and arrhythmic burden. BB+ patients were older, had more LV hypertrophy, worse diastolic parameters, and functional capacity while ventilatory efficiency was similar. Conclusions This study supports previous data about VO2 peak determinants. The correlation between the extension of the LGE and ventilatory efficiency in patients with HCM is an original finding. It confirms the pathophysiological explanation of a lung ventilation/perfusion mismatch due to the increased left atrium pressure that is secondary to a more severe LV diastolic disfunction in patients with LGE. The reduced VO2 in BB+ compared to BB- patients is not inferable given the different age and severity of disease. Moreover, the negative chronotropic effect of BB during exercise prolongs the diastolic filling time, thus, improving stroke volume and alleviating the LV filling pressures, thus normalising, in the less advanced stages of pathology, the ventilatory efficiency in HCM patients.

O068 Magnesium, the anaesthetists’ friend during carotid endarterectomy (CEA)

Abstract Introduction Magnesium can be used as an antihypertensive for CEA patients, with the added benefit of anti-arrhythmic and anti-convulsive effects without the negative chronotropic effect of classic antihypertensives. It however causes vasodilation and increased diuresis, possibly increasing post-operative vasopressor requirements. This study determines the postoperative haemodynamic impact of magnesium therapy on CEA patients. Methods A retrospective review of CEA patients’ medical records between April 2020 and December 2021 was undertaken. In our unit, the postoperative trigger for commencing vasopressors (metaraminol or noradrenaline) is a systolic blood pressure <110 mmHg. A comparison of the postoperative vasopressor requirements in patients given intraoperative magnesium {5g IV infusion over 20 min if SBP >170mmHg} with those not given magnesium therapy was made (using Chi-square test). A secondary outcome was to assess the development of new acute postoperative kidney injury (AKI) (eGFR <60 ml/min/1.73m2). Results Of the 89 CEA patients; 8 had incomplete data and 65% were over 70 years old. The Surgical Outcome Risk Tool (SORT) score identified 44 (53%) patients as high risk (>5% risk of perioperative mortality). There was no difference between the magnesium vs non-magnesium therapy groups postoperatively in vasopressor requirement. (p=0.38, X2=0.74) or AKI rates (n=14, 16.8%). Conclusion Organ perfusion and cardiac stability can be achieved perioperatively in CEA patients with magnesium therapy without increasing vasopressors requirement or renal impairment; making it a good first-line therapy for intraoperative hypertension.

Effectiveness of the repurposed drug isotretinoin in an experimental murine model of Chagas disease

Benznidazole and nifurtimox are the drugs currently used for the treatment of Chagas disease, however its side effects may affect patient adherence. In the search for new alternative therapies, we previously identified isotretinoin (ISO), an FDA-approved drug widely used for the treatment of severe acne through a drug repurposing strategy. ISO shows a strong activity against Trypanosoma cruzi parasites in the nanomolar range, and its mechanism of action is through the inhibition of T. cruzi polyamine and amino acid transporters from the Amino Acid/Auxin Permeases (AAAP) family. In this work, a murine model of chronic Chagas disease (C57BL/6 J mice), intraperitoneally infected with T. cruzi Nicaragua isolate (DTU TcI), were treated with different oral administrations of ISO: daily doses of 5 mg/kg/day for 30 days and weekly doses of 10 mg/kg during 13 weeks. The efficacy of the treatments was evaluated by monitoring blood parasitemia by qPCR, anti-T. cruzi antibodies by ELISA, and cardiac abnormalities by electrocardiography. No parasites were detected in blood after any of the ISO treatments. The electrocardiographic study of the untreated chronic mice showed a significant decrease in heart rate, while in the treated mice this negative chronotropic effect was not observed. Atrioventricular nodal conduction time in untreated mice was significantly longer than in treated animals. Mice treated even with ISO 10 mg/kg dose every 7 days, showed a significant reduction in anti-T. cruzi IgG levels. In conclusion, the intermittent administration of ISO 10 mg/kg would improve myocardial compromise during the chronic stage.

Negative Chronotropic Effects of Class I Antiarrhythmic Drugs on Guinea Pig Right Atria: Correlation with L-Type Ca2+ Channel Blockade

The negative chronotropic effects of eight Vaughan Williams Class I antiarrhythmic drugs were examined in guinea pig right atrial tissue preparations. The drugs decreased the spontaneous beating rate at concentrations overlapping with their therapeutic blood levels. Cibenzoline, aprindine, flecainide, and propafenone showed stronger effects; 10 µM of each drug decreased the beating rate to about 75% of initial values. Disopyramide, mexiletine, pilsicainide, and ranolazine showed weaker effects; 10 µM of each drug decreased the beating rate to about 90% of initial values. The potency of drugs correlated with the reported IC50 values to block the L-type Ca2+ channel current rather than the Na+ and K+ channel currents. The reported IC50 values for the blockade of the hyperpolarization-activated inward current (If) and the Na+-Ca2+ exchanger current were much higher than those for the blockade of the L-type Ca2+ channel current. These results indicate that the negative chronotropic effects of Class I antiarrhythmic drugs can be largely explained by their blockade of the L-type Ca2+ channel.

A comprehensive pharmacological analysis of fenoterol and its derivatives to unravel the role of β2-adrenergic receptor in zebrafish

β-adrenergic receptors (βARs) belong to a key molecular targets that regulate the most important processes occurring in the human organism. Although over the last decades a zebrafish model has been developed as a model complementary to rodents in biomedical research, the role of β2AR in regulation of pathological and toxicological effects remains to elucidate. Therefore, the study aimed to clarify the role of β2AR with a particular emphasis on the distinct role of subtypes A and B of zebrafish β2AR. As model compounds selective β2AR agonists – (R,R)-fenoterol ((R,R)-Fen) and its new derivatives: (R,R)-4’-methoxyfenoterol ((R,R)-MFen) and (R,R)-4'-methoxy-1-naphtylfenoterol ((R,R)-MNFen) – were tested. We described dose-dependent changes observed after fenoterols exposure in terms of general toxicity, cardiotoxicity and neurobehavioural responses. Subsequently, to better characterise the role of β2-adrenergic stimulation in zebrafish, we have performed a series of molecular docking simulations. Our results indicate that (R,R)-Fen displays the highest affinity for subtype A of zebrafish β2AR and β2AAR might be involved in pigment depletion. (R,R)-MFen shows the lowest affinity for zebrafish β2ARs out of the tested fenoterols and this might be associated with its cardiotoxic and anxiogenic effects. (R,R)-MNFen displays the highest affinity for subtype B of zebrafish β2AR and modulation of this receptor might be associated with the development of malformations, increases locomotor activity and induces a negative chronotropic effect. Taken together, the presented data offer insights into the functional responses of the zebrafish β2ARs confirming their intraspecies conservation, and support the translation of the zebrafish model in pharmacological and toxicological research.

Sophoridine manifests as a leading compound for anti-arrhythmia with multiple ion-channel blocking effects

BackgroundSophoridine (SR) has shown the potential to be an antiarrhythmic agent. However, SR's electrophysiological properties and druggability research are relatively inadequate, which limits the development of SR as an antiarrhythmic candidate. PurposeTo facilitate the development process of SR as an antiarrhythmic candidate, we performed integrated studies on the electrophysiological properties of SR in vitro and ex vivo to gain more comprehensive insights into the multi-ion channel blocking effects of SR, which provided the foundation for the further drugability studies in antiarrhythmic and safety studies. Firstly, SR's electrophysiological properties and antiarrhythmic potentials were recorded and assessed at the cell and tissue levels by comprehensively integrating the patch clamp with the Electrical and Optical Mapping systems. Subsequently, the antiarrhythmic effects of SR were validated by aconitine and ouabain-induced arrhythmia in vivo. Finally, the safety of SR as an antiarrhythmic candidate compound was evaluated based on the guidelines of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). Study designThe antiarrhythmic effect of SR was evaluated at the in vitro, ex vivo, and in vivo levels. MethodsIsolated primary cardiomyocytes and stable cell lines were prepared to explore the electrophysiologic properties of being a multiple ion-channel blocker in vitro by whole-cell patch clamp. Using electrical and optical mapping, the negative chronotropic effect of SR was determined in langendorff-perfused rat or guinea-pig hearts.The antiarrhythmic activity of SR was assessed by the ex vivo tachyarrhythmia models induced by left coronary artery ligation (LCAL) and isoproterenol (ISO). Canonical models of aconitine and ouabain-induced arrhythmia were used to verify the antiarrhythmic effects in vivo. Finally, the pro-arrhythmic risk of SR was detected in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hSCCMs) using a Microelectrode array (MEA). ResultsSingle-cell patch assay validated the multiple ion-channel blockers of SR in transient outward current potassium currents (Ito), l-type calcium currents (ICa-l), and rapid activation delayed rectifier potassium currents (IKr). SR ex vivo depressed heart rates (HR) and ventricular conduction velocity (CV) and prolonged Q-T intervals in a concentration-dependent manner. Consistent with the changes in HRs, SR extended the active time of hearts and increased the action potential duration measured at 90% repolarization (APD90). SR could also significantly lengthen the onset time and curtail the duration of spontaneous ventricular tachycardia (VT) in the ex vivo arrhythmic model induced by LCAL. Meanwhile, SR could also significantly upregulate the programmed electrical stimulation (PES) frequency after the ISO challenge in forming electrical alternans and re-entrant excitation. Furthermore, SR exerted antiarrhythmic effects in the tachyarrhythmia models induced by aconitine and ouabain in vivo. Notably, the pro-arrhythmic risk of SR was shallow for a moderate inhibition of the human ether-à-go-go-related gene (hERG) channel. Moreover, SR prolonged field potential duration (FPDc) of hSCCMs in a concentration-dependent manner without early after depolarization (EAD) and arrhythmia occurrence. ConclusionOur results indicated that SR manifested as a multiple ion-channel blocker in the electrophysiological properties and exerts antiarrhythmic effects ex vivo and in vivo. Meanwhile, due to the low pro-arrhythmic risk in the hERG inhibition assay and the induction of EAD, SR has great potential as a leading candidate in the treatment of ventricular tachyarrhythmia.

Pharmacokinetic-Pharmacodynamic Modeling of the Ponesimod Effect on Heart Rate in Patients With Multiple Sclerosis.

The purpose of this study was to characterize the ponesimod effect on the heart rate (HR) in patients with multiple sclerosis (MS). A previous pharmacokinetic (PK) and pharmacodynamic model developed in healthy participants was updated using data from phase II and III trials conducted in patients with MS. Clinically relevant covariates were assessed. Simulations were conducted to evaluate the impact of the lack of adherence to ponesimod treatment and provide guidance in cases of treatment re-initiation. The maximal effect parameter of the PK/HR model was lower in patients with MS (23.5% decrease) compared with healthy volunteers (43.2%). The effect of patient covariates on PK/HR was similar to those identified in healthy participants and not clinically relevant in patients with MS. The population PK/HR model well characterized the effect of ponesimod on the time course of HR in patients with MS. After 2 weeks of treatment with 10 mg or higher doses, the model indicated full tolerance development. After repeated dosing at 20 mg, tolerance was maintained > 60% of the steady-state tolerance for up to 4 days after the last dose. Re-initiating with gradual uptitration is recommended if drug discontinuation lasts ≥ 4 days. This managed the negative chronotropic effects of ponesimod. No bradycardia events were observed within the first 2 weeks of treatment in patients with relapsing MS with a baseline HR > 55 bpm. This justifies the recommendation included in the human prescription drug labeling to monitor HR after the first ponesimod dose in these patients.

The Effects of Curcumin on Mechanical Functions and Cardiac Contractility in Isolated Rat Hearts.

Curcumin is a bioactive compound that has well-known pharmacological activities. Numerous studies have shown that curcumin provides potential cardiovascular benefits through a variety of mechanisms.The present study aims to discuss different concentrations of curcumin's impact on mechanical functions and cardiac contractility in isolated perfused rat hearts. The hearts were isolated under sodium thiopental (50 mg/kg) anesthesia and perfused with a modified Krebs-Henseleit solution (mK-Hs). After stabilization, curcumin was applied in concentrations of 0.1, 1, and 10 µM. In isolated rat hearts, indexes of + dP / dt max, LVDP, MAP, and LVEDP were evaluated for cardiac contractility and ventricular function. All curcumin concentrations reduced +dP/dtmax and LVDP. Ten µM curcumin also significantly decreased heart rate. Curcumin (1 and 10 µM) increased LVEDP and reduced MAP amplitude with a concomitant increase in MAP duration. Curcumin at all concentrations did not affect dMAPdtmax and dMAPdtmin. Our results might suggest that curcumin at higher concentrations (≥ 1 µM) increases LVEDP with a negative chronotropic effect and decreases MAP amplitude with an increase in MAP duration. There is sufficient evidence from this study that Curcumin possesses an adverse inotropic action. Different disease models should support the pathophysiological role of Curcumin on cardiac contraction.

Феназепам® и Дексмедетомидин при плановых чрескожных коронарных вмешательствах. Сравнительный анализ

INTRODUCTION: Intraprocedural analgosedation in planned percutaneous coronary interventions is a priority method of anesthesia, since it provides comfort for patient in comparison with when it is absent; it leads to a fast recovery of patients and reduction of the incidence of complications in comparison with the general anesthesia. The question of the optimal sedation method is still open. AIM: To carry out a comparative analysis of sedation with Phenazepam® and Dexmedetomidine in planned percutaneous coronary interventions in patients with stable coronary heart disease. MATERIALS AND METHODS: A prospective randomized study was conducted from September 2021 to January 2022. The study included patients with stable ischemic heart disease (serum troponin T level less than 0.32 ng/ml; absence of anginous pain at the beginning of X-ray endovascular intervention), who had planned percutaneous coronary intervention. The Phenazepam® sedation group included 40 patients, including 30.0% (n = 12) women and 70.0% (n = 28) men. 40 patients were included in the Dexmedetomidine sedation group: 30.0% (n = 12) women, 70.0% (n = 28) men. RESULTS: There was a statistically significant (p < 0.001) reduction of blood pressure and heart rate in patients in the group of sedation with Dexmedetomidine at the stage of stenting of the coronary artery, compared with analogous parameters in the group of sedation with Phenazepam®. Patients in the group of sedation with Dexmedetomidine developed chest pain at the stage of coronary artery stenting reliably 3.13 times less often (p = 0.024) than patients of the group of sedation with Phenazepam® (OR: 0.32; 95% CI: 0.13–0.80). With use of Dexmedetomidine, relief of anginal pain with narcotic analgesics was required 20 times less often (p < 0.001) than with Phenazepam® (OR: 0.05; 95% CI: 0.01–0.38). One can confidently speak about the superiority and safety of analgosedation with Dexmedetomidine in planned percutaneous coronary interventions over sedation with Phenazepam®. CONCLUSIONS: Dexmedetomidine provides deeper sedation and sufficient pain relief in patients in planned percutaneous coronary interventions than Phenazepam®. At the same time, Dexmedetomidine has a more pronounced hypotensive and a negative chronotropic effect.

Cardiovascular Effects of Nigella Sativa on Isolated Rabbit Heart and its Impact on Cardiac Remodeling

Background: Black Cumin/Nigella sativa (NS) which belongs to the botanical family of Ranunculaceae commonly grows in Eastern Europe, the Middle East, and Western Asia. Its prolonged use can produce physiological changes with or without affecting the architecture of different organs like the heart (cardiac remodeling). The data for the cardiovascular benefits of black cumin are not well-established scientifically. Objectives: To determine the direct cardiovascular effects of Nigella Sativa extract on heart rate, cardiac contractility (apical force), ECG, and coronary flow in the normal heart with and without cardiac remodeling. Methods: This experimental study was conducted on forty-two (42) rabbits. These rabbits were divided into seven groups, each comprising six animals (Group I-VI without cardiac remodeling and Group VII with cardiac remodeling). NS was given to these groups in different doses i.e., Group I (NS=10ug), Group II (NS=30ug), Group III (NS=100ug), Group IV (NS=300ug), Group V (NS=3000ug), Group VI (NS=10000ug) and VII (NS=300ug). Radnoti's working heart system was used to determine the effects of NS on heart rate, cardiac contractility (apical Force), ECG, and coronary flow in a normal heart with and without cardiac remodeling. The results were analyzed using SPSS version 28. Results: Results of this study revealed negative chronotropic and positive inotropic effects without ECG changes in the normal heart and with ECG changes in the remodeled heart. Conclusions: Prolonged use of Nigella sativa can lead to disturbed ECG by affecting the conducting tissue.