Isolated Rabbit Hearts Research Articles

Oxytocin does not directly alter cardiac repolarization in rabbit or human cardiac myocytes.

Oxytocin, a nine amino acid peptide, is highly conserved in placental mammals, including humans. Oxytocin has a physiological role in parturition and parenteral administration of the synthetic peptide is used to induce labor and control postpartum hemorrhage. Endogenous levels of oxytocin before labor are ∼20 pg/mL, but pharmacological administration of the peptide can achieve levels of 110 pg/mL (0.1 nmol/L) following intravenous administration. Cardiac arrhythmia and premature ventricular contractions have been associated with oxytocin administration in addition to QTc interval prolongation. In the conscious rabbit model, intravenous oxytocin produced QT and QTc prolongation. The mechanism of oxytocin-induced QTc prolongation is uncertain but could be the result of indirect changes in autonomic nervous tone, or a direct effect on the duration of cardiomyocyte repolarization. The purpose of this study was to examine the ability of oxytocin to alter cardiac repolarization directly. Two conventional models were used: QTc interval evaluation in the isolated rabbit heart (IRH) and assessment of action potential duration (APD) in human ventricular myocytes (HVM). Oxytocin did not prolong QTc intervals in IRH or APD in HVM when tested at suprapharmacological concentrations, for example, up to 1 μmol/L. The results indicate that oxytocin has very low risk for eliciting QTc and APD prolongation directly, and infer that the QTc changes observed in vivo may be attributed to an indirect mechanism.

Cardioprotective effect of saffron extracts against acute doxorubicin toxicity in isolated rabbit hearts submitted to ischemia-reperfusion injury.

Doxorubicin (DOX) is an anthracycline antibiotic routinely used as a chemotherapeutic agent for the treatment of solid tumours. However, DOX possesses an acute and cumulative cardiotoxicity due to free radical production. The present study was designed to investigate the possible protective effects of saffron (Crocus sativus) extracts against DOX-induced acute cardiotoxicity in isolated rabbit hearts submitted to 30 min global ischemia followed by 40 min reperfusion. DOX was delivered during reperfusion, without or with saffron given 5 min before ischemia or at reperfusion. Cardiodynamic, biochemical, and histopathological parameters were determined. In addition, to determine the expression of the AKT/mTOR/4EBP1 pathway, the levels of p38 MAPK and cardiac troponin T in heart homogenates were visualized by Western blotting. DOX administration during 40 min of reperfusion increased ischemic tissue damage, but did not act synergistically. Administration of saffron extracts during the first minutes of reperfusion significantly reduced oxidative myocardial damage, but was less effective when given before ischemia. Subsequent Western blot analysis revealed that saffron administration preserved cardiac troponin T proteins, inhibited the p38 MAPK pathway, and activated the AKT/mTOR/4EBP1 pathway in reperfusion- and DOX-treated rabbit hearts. In conclusion, saffron extracts, acting through antioxidant and antiapoptotic mechanisms, exhibited a protective effect against DOX-induced cardiotoxicity under ischemic condition.

Oxytocin does not prolong repolarization in the isolated rabbit heart

Oxytocin does not prolong repolarization in the isolated rabbit heart

Sex differences in β-adrenergic responsiveness of action potentials and intracellular calcium handling in isolated rabbit hearts.

Cardioprotection in females, as observed in the setting of heart failure, has been attributed to sex differences in intracellular calcium handling and its modulation by β-adrenergic signaling. However, further studies examining sex differences in β-adrenergic responsiveness have yielded inconsistent results and have mostly been limited to studies of contractility, ion channel function, or calcium handling alone. Given the close interaction of the action potential (AP) and intracellular calcium transient (CaT) through the process of excitation-contraction coupling, the need for studies exploring the relationship between agonist-induced AP and calcium handling changes in female and male hearts is evident. Thus, the aim of this study was to use optical mapping to examine sex differences in ventricular APs and CaTs measured simultaneously from Langendorff-perfused hearts isolated from naïve adult rabbits during β-adrenergic stimulation. The non-selective β-agonist isoproterenol (Iso) decreased AP duration (APD90), CaT duration (CaD80), and the decay constant of the CaT (τ) in a dose-dependent manner (1–316.2 nM), with a plateau at doses ≥31.6 nM. The Iso-induced changes in APD90 and τ (but not CaD80) were significantly smaller in female than male hearts. These sex differences were more significant at faster (5.5 Hz) than resting rates (3 Hz). Treatment with Iso led to the development of spontaneous calcium release (SCR) with a dose threshold of 31.6 nM. While SCR occurrence was similar in female (49%) and male (53%) hearts, the associated ectopic beats had a lower frequency of occurrence (16% versus 40%) and higher threshold (100 nM versus 31.6 nM) in female than male hearts (p<0.05). In conclusion, female hearts had a decreased capacity to respond to β-adrenergic stimulation, particularly under conditions of increased demand (i.e. faster pacing rates and “maximal” levels of Iso effects), however this reduced β-adrenergic responsiveness of female hearts was associated with reduced arrhythmic activity.

THE EFFECT OF RYANODINE RECEPTOR-2 STABILIZER, DANTROLENE, ON PHASE SINGULARITIES IN A RABBIT MODEL OF VENTRICULAR FIBRILLATION

We have demonstrated that Dantrolene, a Ryanodine receptor stabilizer facilitates defibrillation and greater organization during in-vivo swine VF. However the effect of dantrolene on phase singularities (PS) is unknown. We hypothesized that dantrolene infusion during VF will decrease the number of PS and their duration in isolated rabbit hearts.

Ultrasound shear wave elasticity imaging quantifies coronary perfusion pressure effect on cardiac compliance.

Diastolic heart failure (DHF) is a major source of cardiac related morbidity and mortality in the world today. A major contributor to, or indicator of DHF is a change in cardiac compliance. Currently, there is no accepted clinical method to evaluate the compliance of cardiac tissue in diastolic dysfunction. Shear wave elasticity imaging (SWEI) is a novel ultrasound-based elastography technique that provides a measure of tissue stiffness. Coronary perfusion pressure affects cardiac stiffness during diastole; we sought to characterize the relationship between these two parameters using the SWEI technique. In this work, we demonstrate how changes in coronary perfusion pressure are reflected in a local SWEI measurement of stiffness during diastole. Eight Langendorff perfused isolated rabbit hearts were used in this study. Coronary perfusion pressure was changed in a randomized order (0-90 mmHg range) and SWEI measurements were recorded during diastole with each change. Coronary perfusion pressure and the SWEI measurement of stiffness had a positive linear correlation with the 95% confidence interval (CI) for the slope of 0.009-0.011 m/s/mmHg ( R(2) = 0.88 ). Furthermore, shear modulus was linearly correlated to the coronary perfusion pressure with the 95% CI of this slope of 0.035-0.042 kPa/mmHg ( R(2) = 0.83). In conclusion, diastolic SWEI measurements of stiffness can be used to characterize factors affecting cardiac compliance specifically the mechanical interaction (cross-talk) between perfusion pressure in the coronary vasculature and cardiac muscle. This relationship was found to be linear over the range of pressures tested.

The role of gap junctions in stretch-induced atrial fibrillation.

AimsThe aim of this study was to investigate the role of gap junctions in atrial fibrillation (AF) by analysing the effects of a gap junction enhancer and blocker on AF vulnerability and electrophysiological properties of isolated hearts.Methods and resultsThe acute atrial stretch model of AF in the isolated rabbit heart was used. Sustained AF (SAF) was induced by a burst of high-frequency stimulation of the Bachmann's bundle. The effective refractory period (ERP) was measured, and the total conduction time (TCT) and the pattern of conduction of the anterior surface of the left atrium were monitored by using an optical mapping system. The effect of enhancing gap junction function by 100–1000 nM rotigaptide (ZP123) and block by 30 μM carbenoxolone on these parameters was measured. SAF inducibility was increased with an elevation of intra-atrial pressure. Enhanced gap junction conductance induced by treatment with 100–1000 nM rotigaptide reduced SAF inducibility, and the gap junction blocker carbenoxolone increased SAF inducibility. In the absence of gap junction enhancer or blocker, normal conduction was observed at 0 cmH2O. When intra-atrial pressure was raised to 12 cmH2O, the conduction pattern was changed to a heterogeneous zig-zag pattern and TCT was prolonged. Conduction pattern was not affected by either agent. Rotigaptide shortened TCT, whereas carbenoxolone prolonged TCT. ERP was significantly shortened with an increase in intra-atrial pressure, but ERP was unaffected by either agent.ConclusionGap junction modulators changed AF inducibility through their effects on atrial conduction, not by altering ERP.

Assessment of efficacy of proarrhythmia biomarkers in isolated rabbit hearts with attenuated repolarization reserve.

Isolated hearts with reduced repolarization reserve would be suitable for assessing the proarrhythmic liability of drugs. However, it is not known which proarrhythmia biomarkers indicate the increased susceptibility to torsades de pointes arrhythmia (TdP) in such experimental setting. Thus, we estimated the efficacy of proarrhythmia biomarkers in isolated hearts with attenuated repolarization reserve. Langendorff-perfused rabbit hearts were used. Repolarization reserve was reduced by concomitant inhibition of the rapid (IKr) and slow (IKs) delayed rectifier potassium currents by dofetilide and HMR-1556, respectively. Rate corrected QT (QTc) interval and beat-to-beat variability of the QT interval measured in sinus rhythm or irrespective of rhythm even during arrhythmias (sinus and absolute QT variability, respectively) were tested. QTc failed to predict increased proarrhythmic risk. Sinus QT variability indicated proarrhythmic liability when low concentration of dofetilide was used. However, when arrhythmias compromised sinus variability measurement during coperfusion of catecholamines and elevated concentration of dofetilide, only absolute QT variability indicated increased proarrhythmic risk. Absolute QT variability parameters seem to be the most practical and sensitive biomarkers of proarrhythmic liability in rabbit hearts with reduced repolarization reserve. Absolute QT variability parameters could serve as surrogates for torsades de pointes in drug-safety investigations in isolated rabbit hearts with attenuated repolarization reserve.

QT Interval Heterogeneities Induced Through Local Epicardial Warming/Cooling. An Experimental Study

Introduction and objectivesAbnormal QT interval durations and dispersions have been associated with increased risk of ventricular arrhythmias. The present study examines the possible arrhythmogenic effect of inducing QT interval variations through local epicardial cooling and warming. MethodsIn 10 isolated rabbit hearts, the temperatures of epicardial regions of the left ventricle were modified in a stepwise manner (from 22°C to 42°C) with simultaneous electrogram recording in these regions and in others of the same ventricle. QT and activation-recovery intervals were determined during sinus rhythm, whereas conduction velocity and ventricular arrhythmia induction were determined during programmed stimulation. ResultsIn the area modified from baseline temperature (37°C), the QT (standard deviation) was prolonged with maximum hypothermia (195 [47] vs 149 [12] ms; P<.05) and shortened with hyperthermia (143 [18] vs 152 [27] ms; P<.05). The same behavior was displayed for the activation-recovery interval. The conduction velocity decreased with hypothermia and increased with hyperthermia. No changes were seen in the other unmodified area. Repetitive responses were seen in 5 experiments, but no relationship was found between their occurrence and hypothermia or hyperthermia (P>.34). ConclusionsIn the experimental model employed, local variations in the epicardial temperature modulate the QT interval, activation-recovery interval, and conduction velocity. Induction of heterogeneities did not promote ventricular arrhythmia occurrence.

Heterogeneidades inducidas en el intervalo QT mediante enfriamiento/calentamiento epicárdico local. Estudio experimental

Introduction and objectivesAbnormal QT interval durations and dispersions have been associated with increased risk of ventricular arrhythmias. The present study examines the possible arrhythmogenic effect of inducing QT interval variations through local epicardial cooling and warming. MethodsIn 10 isolated rabbit hearts, the temperatures of epicardial regions of the left ventricle were modified in a stepwise manner (from 22°C to 42°C) with simultaneous electrogram recording in these regions and in others of the same ventricle. QT and activation-recovery intervals were determined during sinus rhythm, whereas conduction velocity and ventricular arrhythmia induction were determined during programmed stimulation. ResultsIn the area modified from baseline temperature (37°C), the QT (standard deviation) was prolonged with maximum hypothermia (195 [47] vs 149 [12] ms; P<.05) and shortened with hyperthermia (143 [18] vs 152 [27] ms; P<.05). The same behavior was displayed for the activation-recovery interval. The conduction velocity decreased with hypothermia and increased with hyperthermia. No changes were seen in the other unmodified area. Repetitive responses were seen in 5 experiments, but no relationship was found between their occurrence and hypothermia or hyperthermia (P>.34). ConclusionsIn the experimental model employed, local variations in the epicardial temperature modulate the QT interval, activation-recovery interval, and conduction velocity. Induction of heterogeneities did not promote ventricular arrhythmia occurrence.Full English text available from: www.revespcardiol.org/en

Simultaneous optical mapping system of endocardial and epicardial excitation.

The cardiac excitation propagation during arrhythmia shows a three-dimensional complex excitation behavior. Numerous optical measurements of the propagation and action potentials of the cardiac muscles have been made to elucidate the detailed arrhythmia phenomenon. The conventional optical measurement system mainly observes the action potential signal of the epicardium, and the endocardial signal measurement without incising the heart is difficult. In addition, an incised heart no longer exhibits the natural excitation behavior. Therefore, we constructed a simultaneous measurement system that integrates the conventional epicardial measurement system and the endocardial measurement system by using an endoscope for an intact heart. Then, we proposed a line-laser registration method that can match correspondence between the epicardial and endocardial images for a short period. We demonstrated that this registration method has a sub-millimeter accuracy. Subsequently, we succeeded in simultaneous optical measurement of the excitation propagation of the epicardium and endocardium of the right heart wall by using an isolated rabbit heart.

The effect of acute coronary perfusion change on cardiac function measured by Shear Wave Elasticity Imaging.

The possibility of measuring cardiac function noninvasively has generated wide interest in elastography imaging techniques. Shear Wave Elasticity Imaging (SWEI) is an ultrasound-based elastography technique used to measure stiffness of tissues. While this technique has been studied extensively in static homogenous tissues such as liver, breast or prostate, there is still a significant need to study its capabilities to measure cardiac stiffness and function. In this research, we have studied the potential of SWEI to evaluate the coronary perfusion pressure effect on systolic and diastolic stiffness referred to as elastance and compliance of the heart. Five isolated rabbit hearts were used in this study in a Langendorff preparation. SWEI measurements of stiffness were recorded in two steps. In the first step, coronary perfusion was set to normal and then was reduced to half-normal. After 40 minutes of half-normal perfusion, it was returned to normal perfusion for the second step. SWEI velocity decreased from 6.003 m/s to 4.713 m/s in systole and from 1.948 m/s to 1.507 m/s in diastole in the first step. During the second step raising the perfusion to normal, SWEI stiffness showed an increase from 3.760 m/s to 5.468 m/s in systole and from 1.678 m/s to 2.156 m/s during diastole. Our results show that SWEI measurements of stiffness can characterize the cross talk between coronary perfusion and cardiac stiffness and also has the potential to measure compliance and elastance of the heart in systole and diastole.

Abstract 272: Sex Differences in β-Adrenergic Responsiveness of Excitation-Contraction Coupling in Isolated Rabbit Hearts

Introduction: Sex differences in β-adrenergic receptor (β-AR) responsiveness are associated with female cardioprotection. We hypothesize that female (F) rabbits have reduced responsiveness to β-AR stimulation vs males (M), and that the degree and type of sex differences vary with the β-AR subtypes that are activated. Methods: Ventricular action potentials (AP) and intracellular calcium transients (CaT) were optically mapped from the epicardial surface of rabbit hearts during 3 Hz pacing. Spontaneous calcium release (SCR) and ectopic activity were elicited at 1, 3, and 5.5 Hz. β-responsiveness was assessed with the nonselective β-agonist isoproterenol (Iso, 1-316 nM), or β2-AR selective agonist zinterol (Zin, 10 nM). Results: At baseline, the time constant of CaT decay (τ) was faster in F than M (54.0±1.7 vs 62.1±3.0 ms; n=14, 14; p &lt; 0.05), with no sex difference in CaT duration (CaD80). AP duration (APD90) was shorter in F than M (202.5±5.0 vs 218.2±5.7 ms; p &lt; 0.05). Iso decreased τ, CaD80, and APD90 in a dose-dependent manner in both sexes (n = 5, 5 for F, M). Iso decreased τ to a lesser extent in F than M for 1 and 32-316 nM Iso (F = 11-32 ms, M = 23-48 ms; p &lt; 0.05). The Iso-induced decrease in CaD80 was not significantly different in F than M at any dose. The Iso-induced decrease in APD90 was significantly less in F than M only at 316 nM Iso (75.5±8.7 ms vs 103.9±6.2 ms, p &lt; 0.05). In contrast, there were no sex differences in the response to Zin for τ, CaD80, or APD90 (n = 6, 6 for F, M). Zin decreased τ by 7.2±2.0 ms in F vs 12.7±3.7 ms in M; CaD80 by 18.0±5.3% in F vs 21.1±8.0 ms in M; and APD90 by 24.9±8.5 ms in F vs 21.9±8.9 ms in M. SCR was observed in 50% (6/12) of hearts treated with Zin, whereas Iso elicited SCR in all hearts (10/10) with a dose threshold of 32 nM. No ectopic beats were observed with Zin (0/36 trials in 12 hearts). With Iso, ectopic activity was less frequent in F hearts (16%, 12/75 trials in 5 hearts) than in M hearts (41%, 26/68 trials in 5 hearts, p &lt; 0.05). Conclusions: These results suggest that sex differences in AP and CaT depend on the dose of the agonist used and the β-AR subtypes that are activated. Elucidating nuances of sex differences in β-AR subtype physiology will provide a better understanding of the mechanisms of reduced β-responsiveness in F and its cardioprotective effects.

Effects of ranolazine on torsades de pointes tachycardias in a healthy isolated rabbit heart model.

PurposeTorsades de pointes (TdP) tachycardias are triggered, polymorphic ventricular arrhythmias arising from early afterdepolarizations (EADs) and increased dispersion of repolarization. Ranolazine is a new agent which reduces pathologically elevated late INa but also IKr. Aim of this study was to evaluate the effects of ranolazine in a validated isolated Langendorff-perfused rabbit heart model.MethodsTdP was reproducibly induced with d-sotalol (10−4 mol/L) and low potassium (K) (1.0 mmol/L for 5 min, pacing at CL 1000 ms). In 10 hearts, ECG and 8 epi- and endocardial monophasic action potentials were recorded. Action potential duration (APD) was measured at 90% repolarization and dispersion defined as APD max–min.ResultsD-sotalol prolonged APD90 and increased dispersion of APD90, simultaneously causing EADs and induction of TdP. The combination of d-sotalol and two concentrations of ranolazine did not increase dispersion of ventricular APD90 as compared to vehicle. Ranolazine at 5 μmol/L did not cause additional induction of EADs and/or TdP but also did not significantly suppress arrhythmogenic triggers. The higher concentration of ranolazine (10 μmol/L) in combination with d-sotalol caused further prolongation of APD90, at the same time reduction in APD90 dispersion. In parallel, the incidence of EADs was reduced and an antitorsadogenic effect was seen.ConclusionsIn the healthy isolated rabbit heart (where late INa is not elevated), ranolazine does not cause proarrhythmia but exerts antiarrhythmic effects in a dose-dependent manner against d-sotalol/low K-induced TdP. This finding—despite additional APD prolongation—supports the safety of a combined use of both drugs and merits clinical investigation.

Arrhythmogenic effects by local left ventricular stretch: effects of flecainide and streptomycin.

Mechanical stretch has been shown to provoke arrhythmia. We wanted to analyze ventricular arrhythmia induced by local left ventricular stretch in order to find out, where arrhythmias originate and whether they can be prevented pharmacologically. Isolated rabbit hearts (Langendorff technique) were submitted to increased left ventricular stretch at the left wall by insertion of an additional intraventricular balloon and adjusting the end-diastolic pressure (EDP) to 25 mmHg for 10 min followed by 20 min recovery at normal EDP of 5-8 mmHg. Activation and repolarization processes were investigated by ventricular 256 electrode epicardial mapping. The hearts were treated during the whole procedure either with vehicle, 0.5 μM flecainide (sodium channel blocker) or 100 μM streptomycin (here used as stretch-activated ion-channel blocker). In addition, we performed a series of experiments, in which we enhanced EDP to 30 mmHg (global stretch instead of local stretch) by inflating the left ventricular pressure balloon (strain, 0.148 ± 0.034). Each series was performed with n = 6. Stretch resulted in local strain of 25% at the left wall together with a local slowing of the activation process at the left wall, in a change in the activation pattern, and in ventricular arrhythmia. Coronary flow was not affected. Ventricular arrhythmias originated from the border between the stretched area and the non-stretched region. Flecainide and streptomycin reduced the prolongation of the activation process at the stretched left wall and mitigated the difference in total activation time between left and front wall but only partially prevented arrhythmia. In the additional global stretch experiments relative coronary flow and the other parameters remained unchanged, in particular TAT. Thus, in contrast to the local stretch series, there was no difference in the change in TAT between left and front wall. Only rare single ventricular extrasystoles (<1/min; originating from LV (front and left wall) i.e. from within the stretched region) were seen during stretch (but not at the beginning) and during recovery. Local left ventricular stretch can elicit ventricular arrhythmias. Local slowing of electrical activation seems involved so that the difference in total activation time of the stretched free left wall and the non-stretched increased.

Dystrophin proteolysis: a potential target for MMP-2 and its prevention by ischemic preconditioning.

Dystrophin is responsible for the mechanical stabilization of the sarcolemma, and it has been shown that it is one of the most sensitive proteins to ischemic injury. However, the enzyme responsible for this proteolysis is still unknown. Isolated rabbit hearts were subjected to 30 min of global ischemia with and without reperfusion (180 min) to determine whether dystrophin is cleaved by matrix metalloproteinase (MMP)-2 during acute ischemia and whether ischemic preconditioning (PC) prevents dystrophin breakdown through MMP-2 inhibition. The activity of MMP-2 was evaluated by zymography and using doxycycline as an inhibitor. Also, to stimulate MMP-2 activity without ischemia, SIN-1 was administered in the absence and presence of doxycycline. Finally, we considered the PC effect on MMP-2 activity and dystrophin expression. The dystrophin level decreased during ischemia, reaching 21% of control values (P < 0.05), but the spectrin level remained unchanged. MMP-2 activity increased 71% during ischemia compared with control values (P < 0.05). Doxycycline administration before ischemia prevented dystrophin breakdown. In normoxic hearts, SIN-1 increased thiobarbituric acid-reactive substances by 33% (P < 0.05) and MMP-2 activity by 36% (P < 0.05) and significantly reduced the dystrophin level to 23% of control values (P < 0.05). PC significantly prevented dystrophin breakdown by inhibiting MMP-2 activity, and the dystrophin level reached 89% of control values (P < 0.05). In conclusion, MMP-2 could be responsible for the proteolysis of dystrophin. Thus, dystrophin emerges as a possible novel substrate for MMP-2 in the context of ischemic injury. Furthermore, our results demonstrate that ischemic PC prevents dystrophin breakdown most likely by inhibiting MMP-2 activity.

The Discovery of Asunaprevir (BMS-650032), An Orally Efficacious NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).

Fresh and Decayed Stem Juice of Musa acuminata x balbisiana (Musa paradisiaca) Reduce the Force and Rate of Contractility of an Isolated Perfused Rabbit Heart

Background: Decaying stem juice of Musa acuminata × balbisiana is commonly used by local communities and traditional herbalist in Central Uganda in the management of cardiovascular conditions like hypertension. Aims: The study investigated the ionotropic and chronotropic effect of fresh and decaying stem juice of Musa acuminata × balbisiana on the isolated perfused rabbit heart. Materials and Methods: Methods. Study Design: An experimental study. Place and Duration of Study: Study was done at the Dept of Pharmacology &amp; Therapeutics Pharmacology Lab between December 2012 to March 2013. Experimental Procedure: An experimental study determined the effects of fresh and decayed stem juices of Musa acuminate X balbisiana on the rate and force of contraction of an isolated rabbit heart using Langendorff’s heart perfusion experiment and methods. The heart rate (beats/minute) was determined. The force of contraction of the heart was determined by measuring the height of each peak on the kymogram. Results: The force and rate of contractility of an isolated perfused rabbit decreased with increasing doses of the stem juice from 0.156 mg/mL to 100mg/mL for both the fresh and decayed stem juice of M. acuminata. The decrease could be associated with the high [K+] ions that decrease the membrane potential or cause hyperpolarization the myocardial cell membranes leading to reduced force and rate of heart contractility. The effect of the fresh stem juice was short lived and at very high concentrations, it caused a cardiac arrest while the effect of the decayed stem juice was prolonged. Conclusion: Fresh and decayed stem juice of Musa acuminata × balbisiana have compounds that cause a negative ionotropic and chronotropic effect on an isolated perfused rabbit heart.

Dantrolene Improves Survival After Ventricular Fibrillation by Mitigating Impaired Calcium Handling in Animal Models

Resistant ventricular fibrillation, refibrillation. and diminished myocardial contractility are important factors leading to poor survival after cardiac arrest. We hypothesized that dantrolene improves survival after ventricular fibrillation (VF) by rectifying the calcium dysregulation caused by VF. VF was induced in 26 Yorkshire pigs for 4 minutes. Cardiopulmonary resuscitation was then commenced for 3 minutes, and dantrolene or isotonic saline was infused at the onset of cardiopulmonary resuscitation. Animals were defibrillated and observed for 30 minutes. To study the effect of VF on calcium handling and its modulation by dantrolene, hearts from 14 New Zealand rabbits were Langendorff-perfused. The inducibility of VF after dantrolene administration was documented. Optical mapping was performed to evaluate diastolic spontaneous calcium elevations as a measure of cytosolic calcium leak. The sustained return of spontaneous circulation (systolic blood pressure ≥60 mm Hg) was achieved in 85% of the dantrolene group in comparison with 39% of controls (P=0.02). return of spontaneous circulation was achieved earlier in dantrolene-treated pigs after successful defibrillation (21 ± 6 s versus 181 ± 57 s in controls, P=0.005). The median number of refibrillation episodes was lower in the dantrolene group (0 versus 1, P=0.04). In isolated rabbit hearts, the successful induction of VF was achieved in 83% of attempts in controls versus 41% in dantrolene-treated hearts (P=0.007). VF caused diastolic calcium leaks in the form of spontaneous calcium elevations. Administration of 20 μmol/L dantrolene significantly decreased spontaneous calcium elevation amplitude versus controls. (0.024 ± 0.013 versus 0.12 ± 0.02 arbitrary unit [200-ms cycle length], P=0.001). Dantrolene infusion during cardiopulmonary resuscitation facilitates successful defibrillation, improves hemodynamics postdefibrillation, decreases refibrillation, and thus improves survival after cardiac arrest. The effects are mediated through normalizing VF-induced dysfunctional calcium cycling.

Effects of Resveratrol on Oxidative Stress Injury Induced by Rapid-Pacing in Isolated Rabbit Hearts

Oxidative stress injury plays an important role in the process of atrial remodeling. The mechanisms of oxidative stress injury in atrial by rapid pacing and the protective effects of resveratrol will be explored in this study. Thirty-two isolated rabbit hearts were produced by rapid atrial pacing. They were randomly divided into 4 groups: control group (Ctrl group), Rapid Atrial Pacing group (RAP group), Apocynin Pretreatment group (APO group) and Resveratrol Pretreatment group (RES group); each with 8 rabbits. At the end, the indexs of the oxdise stress were measured take advantage of the techniques of the immunohistochemistry, western blotting and reverse transcription PCR.