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Background: Hypoxia is one of the most significant pathogenic factors in cardiovascular diseases. Preclinical studies suggest that nonpsychoactive cannabidiol (CBD) and β-adrenoceptor stimulation might possess cardioprotective potential against ischemia-reperfusion injury. The current study evaluates the influence of hypoxia-reoxygenation (H/R) on the function of atria and ventricular papillary muscles in the presence of CBD and the nonselective β-adrenoceptor agonist isoprenaline (ISO). Methods: The concentration curves for ISO were constructed in the presence of CBD (1 µM) before or after H/R. In chronic experiments (CBD 10 mg/kg, 14 days), the left atria isolated from spontaneously hypertensive (SHR) and their normotensive control (WKY) rats were subjected to H/R following ISO administration. Results: Hypoxia decreased the rate and force of contractions in all compartments. The right atria were the most resistant to hypoxia regardless of prior β-adrenergic stimulation. Previous β-adrenergic stimulation improved recovery in isolated left atria and right (but not left) papillary muscles. Acute (but not chronic) CBD administration increased the effects of ISO in left atria and right (but not left) papillary muscles. Hypertension accelerates left atrial recovery during reoxygenation. Conclusions: H/R directly modifies the function of particular cardiac compartments in a manner dependent on cardiac region and β-adrenergic prestimulation. The moderate direct cardioprotective potential of CBD and β-adrenergic stimulation against H/R is dependent on the cardiac region, and it is less than in the whole heart with preserved coronary flow. In clinical terms, our research expands the existing knowledge about the impact of cannabidiol on cardiac ischemia, the world′s leading cause of death.

Objectives : To determine the effects of β -adrenoceptor and muscarinic agonists on the contractile rate of isolated right atria of rats fed a high fructose diet with or without rosiglitazone (RSG). Materials and Methods : Male Sprague Dawley rats were assigned to four groups and given ad libitum access to one of the following diets: standard chow, standard chow supplemented with 4 mg/kg/day RSG, a high fructose diet and a high fructose diet with 4 mg/kg/day RSG. All the groups were maintained on these regimens for three weeks with weekly measurements of systolic blood pressure and body weight. At the end of the three weeks, the rats were exsanguinated and the hearts were rapidly removed following which blood glucose, insulin and lipid profiles were estimated. The right atria were isolated from the heart and their responsiveness to sympathetic and parasympathetic agonists was studied. Results : Basal, spontaneous, isolated atrial pacemaker rate was diminished in fructose-fed rats. The maximum pacemaker rate to isoproterenol or norepinephrine was unchanged in fructose-fed rats. Further, the increase in atrial rate and half maximal effective concentration values for each agent were also unaffected. The sensitivity to negative chronotropic action of acetylcholine was enhanced in fructose fed rats, whereas the response to carbachol was unchanged. The increased sensitivity to acetylcholine was restored by RSG treatment. Conclusion : High fructose diet induced insulin resistance and hypertension with alterations in basal spontaneous pacemaker, enhanced sensitivity to cholinergic agonist without any changes in the response to adrenergic and cholinergic receptor activation. Treatment with insulin sensitizer rosiglitazone was able to prevent all these changes. The present study suggests that rosiglitazone may have effect on the cardiovascular system in addition to the insulin sensitising action.

Four phenylcarbamic acid derivatives, (1-(4-fluorophenyl)- 4-[3-(4-methoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride (1), (1-(2-methylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (2), (1-(2-methylphenyl)-4-[3-(4-ethoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (3) and (1-(3-trifluoromethylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (4) were investigated for their ability to affect various cardiovascular functions and to establish their chemical structure-biological activity relationship. The compounds were evaluated for their antiarrhythmic efficacy using ouabain-induced rhythm disturbances and the ability to inhibit the positive chronotropic effect of isoproterenol in isolated atria of Wistar rats. Electrocardiogram (ECG) parameters in isolated hearts of spontaneously hypertensive rats (SHR) perfused according to the Langendorff method and ability to decrease phenylephrine- -induced contraction of the aortic strips after repeated administration of the compounds were also analyzed. Only compound 3 delayed significantly the evaluated parameter of arrhythmogenicity and was able to antagonize the isoproterenol- induced positive chronotropic effect in normotensive rats’ atria. Similarly, in SHR rats, only compound 3 was able to decrease heart frequency significantly without influencing the duration of QT (time between the start of the Q wave and the end of the T wave) and QTc (frequency corrected QT) intervals. The evaluated endothelial function was improved after administration of compound 2. Fluorine-containing structures (1 and 4) were less effective compared to 2´-methylphenylpiperazine derivatives (2 and 3). The latter two compounds showed suitable efficacy, which supported their use for futher pharmacological research.

Cardiovascular effects of an essential oil from the aerial parts of Mentha x villosa (OEMV) were tested in rats using a combined in vivo and in vitro approach. In non-anesthetized normotensive rats, OEMV (1, 5, 10, 20, 30 mg kg −1 body wt., i.v.) induced a significant and dose-dependent hypotension (−3±1.8%; −6±0.7%; −40±6.7%; −58±3.8%; −57±2.1%, respectively) associated with decreases in heart rate (−1±0.3%; −9±0.9%; −17±3.2%; −72±3.1%; −82±1.4%, respectively). The hypotensive and bradycardic responses evoked by OEMV were attenuated and blocked by pre-treatment of the animals with atropine (2 mg kg −1body wt., i.v.). In isolated rat atrial preparations, OEMV (10, 100, 300, 500 μg ml −1) produced concentration-related negative chronotropic and inotropic effects (IC 50 value=229±17 and 120±13 μg ml −1, respectively). In isolated rat aortic rings, increasing concentrations of OEMV (10, 100, 300, 500 μg ml −1) were able to antagonize the effects of phenylephrine (1 μM), prostaglandin F 2 α (10 μM) and KCl (80 mM)-induced contractions (IC 50 value=255±9, 174±4 and 165±14 μg ml −1, respectively). The vasorelaxant activity induced by OEMV was attenuated significantly by either endothelium removal (IC 50 value=304±9 μg ml −1), N G-nitro l-arginine methyl ester ( l-NAME) 100 μM (IC 50 value=359±18 μg ml −1), l-NAME 300 μM (IC 50 value=488±20 μg ml −1) or indomethacin 10 μM (IC 50 value=334±18 μg ml −1). However, it was not affected by atropine 1 μM (IC 50 value=247±12 μg ml −1). Furthermore, the hypotensive response induced by OEMV was attenuated significantly after nitric oxide (NO) synthase blockade ( l-NAME, 20 mg kg −1 body wt., i.v.), while bradycardia was not altered. The results suggest that the hypotensive effect induced by OEMV is probably due to its direct cardiodepressant action and peripheral vasodilation, which can be attributed to both endothelium-dependent (via EDRFs, at least NO and prostacyclin) and endothelium-independent mechanisms (such as Ca 2+ channel blockade).

Aim： To investigate the effects of deferiprone on doxorubicin-induced cardiotoxicity and determine its protection on cardiac contractility in vivo at tissue level. Methods： Spontaneously-beating isolated atria from rats were pretreated with deferiprone for 10 min at 1.2 mmol/L or 0.3 mmol/L, respectively before co-incubation with doxorubicin （DOX） at 0.03 mmol/L for 60 min. Contractility （dF/dt） was assessed every 10 min during the incubation. After that, the tissues around the sinuatrial nodes were fixed for ultrastructural study; succinate dehydrogenase （SDH） and Cu, Zn superoxide dismutase （Cu, Zn-SOD） activity, as well as malondialdehyde （MDA） level of the atria were assayed. Results： Treatment with DOX alone resulted in a 49.34% reduction of the contractility, mitochondria swelling, disruption of mitochondrial crista and decreased electron density of the matrices. Conversely, with the presence of deferiprone, the negative inotropic effect and lesions in the cardiac mitochondria structure induced by DOX were attenuated. Cu, Zn-SOD activity increased by 12.97%-12.11%, the MDA level decreased by 29.12%-39.82% and succinate dehydrogenase （SDH） activity was ameliorated by 25.15%-34.76%. Conclusion ： Deferiprone can efficiently preserve cardiac contractility. Moreover, the results of this study indicate that deferiprone is able to protect mitochondrial function and structure form damage induced by DOX. This cardiac protective potential of deferiprone could be due to its defense capability against oxidative damage.

β-Adrenoreceptor antagonistic activity of a newly synthesized compound was evaluated in vivo by measuring the mean arterial blood pressure and heart rate of urethane-anesthetized rats treated with isoprenaline. In vitro β 1 -, β 2 - and β 3 -antagonism was studied using isolated rat right atria, isolated rat uterus and isolated rat colon preparations, respectively, in comparison to isoprenaline response. DPJ 904 (1, 3 and 10 mg/kg, i.v.) produced dose-dependent hypotensive and bradycardia response in anesthetized rat. DPJ 904 (1, 3 and 10 mg/kg, i.v.) significantly inhibited both the tachycardial effects and hypotensive response induced by isoprenaline. DPJ 904-antagonized isoprenaline induced positive chronotropic effects of isolated rat right atria and a uterine relaxant effect indicating β 1 - and β 2 -blockade. The parallel shift to the right of the concentration-response curve of isoprenaline in the presence of DPJ 904 in KCl (30 mmol/l) induced contraction of the rat colon suggesting that DPJ 904 also possessed β 3 -adrenoreceptor antagonistic activity. The selectivity to β 1 -adrenoreceptor was nearly 20.5 times greater than to β 2 -adrenoreceptor. The present study indicates that DPJ 904 possesses β-adrenoreceptor antagonistic activity with slightly more affinity to the β 1 -adrenoreceptor subtype.

Four phenylcarbamic acid derivatives, 1 (1-(4-fluorophenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride, 2 (1-(2-methylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride), 3 (1-(2-methylphenyl)-4-[3-(4-ethoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride) and 4 (1-(3-trifluoromethylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride) were investigated for their ability to affect various cardiovascular functions and to establish their chemical structure-biological activity relationship. The compounds were evaluated for their antiarrhythmic efficacy using ouabain-induced rhythm disturbances and the ability to inhibit the positive chronotropic effect of isoproterenol in isolated atria of Wistar rats. Electrocardiogram (ECG) parameters in isolated hearts of spontaneously hypertensive rats (SHR) perfused according to the Langendorff method and ability to decrease phenylephrine-induced contraction of the aortic strips after repeated administration of the compounds were also analyzed. Only compound 3 delayed significantly the evaluated parameter of arrhythmogenicity and was able to antagonize the isoproterenol-induced positive chronotropic effect in normotensive rats’ atria. Similarly, in SHR rats, only compound 3 was able to decrease heart frequency significantly without influencing the duration of QT (time between the start of the Q wave and the end of the T wave) and QTc (frequency corrected QT) intervals. The evaluated endothelial function was improved after administration of compound 2. Fluorine-containing structures (1 and 4) were less effective compared to 2´-methylphenylpiperazine derivatives (2 and 3). The latter two compounds showed suitable efficacy, which supported their use for futher pharmacological research.

The positive chronotropic effect of a high concentration of 5-hydroxytryptamine (5-HT) in rat isolated atria results mainly from a tyramine-like mechanism and is linked to an increase in cAMP production by an indirect stimulation of beta-adrenoceptors. Using this preparation, we have compared the action of tyramine and 5-HT. The tyramine (0.15 microM)-induced increase in atrial rate was suppressed by atenolol (a beta 1-blocking drug) and by nadolol (a beta 1 beta 2-blocker), while the positive chronotropic effect of 5-HT was reduced by atenolol and suppressed by nadolol. The 5-HT-induced elevation in cAMP was unchanged in the presence of atenolol and abolished by nadolol. The involvement of beta 2-adrenoceptors in the effects of 5-HT could result from competition between 5-HT and noradrenaline at the beta 1-adrenoceptors that results in a fixation of noradrenaline on beta 2-adrenoceptors.

Objectives Right atrial (RA) strain is increasingly recognized as a significant predictor of adverse events in patients with various cardiovascular conditions. However, the prognostic value of RA strain in patients with left ventricular noncompaction (LVNC) is unclear. The objective of this study was to evaluate the prognostic significance of RA strain derived from cardiac magnetic resonance feature tracking (CMR-FT) in patients with LVNC. Methods 394 LVNC patients who underwent CMR at 4 Chinese medical facilities from September 2014 to July 2023 were retrospectively and consecutively included in total. RA strain parameters were obtained using CMR-FT. Major adverse cardiac events (MACEs) were assessed, and all patients were followed up. Results 156 patients (39.6%) experienced MACEs during a median follow-up of 34 months. At univariable analysis, RA conduit strain was associated with MACE (hazard ratio [HR] 0.88 [95% CI 0.85–0.91]; P  < 0.001). RA conduit strain maintained an independent predictor of MACE in a multivariate model that included left ventricular ejection fraction (LVEF) and late gadolinium enhancement (LGE) (HR 0.89 [95% CI 0.85–0.93]; p  < 0.001). Furthermore, adding RA conduit strain to the multivariate model greatly enhanced the prognostic role of endpoint events (C-statistic improvement: 0.766–0.871, Delong test: p  < 0.001). Net reclassification index (NRI) (0.201, p  < 0.05) and integrated discrimination improvement (IDI) (0.038, p  < 0.05) also showed the same trend. Conclusion CMR-FT derived RA conduit strain is a potent independent indicator of major adverse cardiac events in left ventricular noncompaction patients. In addition, RA conduit strain can provide additional prognostic value over the multivariable baseline clinical model. Graphical abstract