Comparative effects of amiodarone and dronedarone treatments on cardiac function in a rabbit model.

AIM: The objective of the study was to compare the effects of amiodarone (AM) and dronedarone (DR) on heart rate variability (HRV) and cardiac contractility in a rabbit model. MATERIALS AND METHODS: A total of 16 male New Zealand white rabbits were divided into two groups, treated either with AM or DR at incremental dosages of 50 mg/kg/day (AM50 and DR50) and 100 mg/kg/day (AM100 and DR100), orally administrated for 7 days. At the end of each period, electrocardiograms were recorded during consciousness and analyzed using the short-term time and frequency domains of HRV. Standard echocardiography and speckle-tracking echocardiography were studied during immobilization with xylazine and ketamine. RESULTS: The results showed that AM100 and DR100 significantly decreased heart rate, total power, low-frequency component, and low-to-high frequency ratio compared with baselines. Most echocardiogram parameters revealed no significant difference from baselines, except for the global circumferential plane strain rate and time to peak standard deviation of strain, which had statistical significances after treating with AM. CONCLUSION: Both AM and DR possess negative chronotropy and reduce HRV, which may be explained by their sympathetic suppression and calcium channel blocking activities. Theoretically, both antiarrhythmic drugs may also possess negative inotropy, but only AM is shown to have a negative inotropic effect and reduces cardiac dyssynchrony in this model.

Sildenafil improves heart rate variability in dogs with asymptomatic myxomatous mitral valve degeneration.

Myxomatous mitral valve degeneration (MMVD) causes an imbalance of sympathovagal activity resulted in poor cardiac outcomes. Phosphodiesterase-5 inhibitors have been revealed cardioprotective effect in patients with heart diseases. This study aimed to 1) compare the heart rate variability (HRV) between asymptomatic MMVD and healthy dogs and 2) assess long-term effects of sildenafil and enalapril on time- and frequency-domains analyzes. Thirty-four dogs with MMVD stage B1 or B2 and thirteen healthy dogs were recruited into the study. MMVD dogs were divided into 3 subgroups: control (n=13), sildenafil (n=12) and enalapril (n=9). HRV was analyzed from 1-hr Holter recording at baseline (D0) in all dogs and at 30, 90 and 180 days after treatment. The results showed that MMVD dogs had significant higher heart rate (HR), systemic blood pressures, the ratio of low to high frequency (LF/HF) and had significant decreased standard deviation of all normal to normal RR intervals (SDNN) and the percentage of the number of normal-to-normal sinus RR intervals with differences >50 msec computed over the entire recording (pNN50) when compared with healthy dogs (P<0.05). Neither time nor frequency domain parameters were different among subgroups of MMVD dogs at D0. After treatment with sildenafil for 90 days, both time- and frequency-domain parameters were significantly increased when compared with control and enalapril groups. This study demonstrated that sildenafil improves HRV in asymptomatic MMVD dogs suggesting that sildenafil should be used in the MMVD dogs to restore the sympathovagal balance.

Dronedarone attenuates the duration of atrial fibrillation in a dog model of sustained atrial fibrillation.

Atrial fibrillation (AF) is a supraventricular arrhythmia that leads to a decrease in cardiac output and impairs cardiac function and quality of life. Dronedarone has an atrial-selective property and has been used for management of AF in humans, but limited information is available in dogs. This study was designed to evaluate efficacy of dronedarone in attenuating the duration of AF in dog model of sustained AF. Six beagle dogs were anesthetized with isoflurane and instrumented to measure atrial action potential duration (aAPD) and atrial effective refractory period (AERP). Then AF was induced by rapid right atrial pacing (20 V, 40 Hz) simultaneously with infusion of phenylephrine (2 µg/kg/min, intravenously) for 20 min. The duration of sustained AF was recorded, and the animals were allowed to recover. Dronedarone was given at a dose of 20 mg/kg, BID, orally for 7 days. On the last day, the dogs were anesthetized again to record aAPD and AERP, and AF was induced with the same procedure as described above. The results showed that after dronedarone administration the aAPD was lengthened significantly from 76.4 ± 4.2 ms to 91.2 ± 3.9 ms (P<0.05) and AERP was prolonged significantly from 97.5 ± 2.8 ms to 120 ± 4.8 ms (P<0.05). The duration of sustained AF was also significantly attenuated after receipt of dronedarone (P<0.05). It can be suggested that oral dronedarone attenuates the duration of sustained AF in a dog model of AF by extending the AERP more than the aAPD, causing post-repolarization refractoriness. Hence, dronedarone may be useful for management of AF in dogs.

Short-term effects of oral dronedarone administration on cardiac function, blood pressure and electrocardiogram in conscious telemetry dogs.

Dronedarone is a multichannel blocking antiarrhythmic drug that has been used for management of atrial fibrillation in humans, but the data in veterinary medicine are inadequate. The objective of this study was to determine the short-term effects of oral dronedarone on cardiac inotropy and lusitropy, blood pressure and electrocardiogram (ECG) in healthy dogs. A total of 6 beagle dogs were instrumented with telemetry units and sono-micrometry crystals to obtain left ventricular pressure-volume relationship, mean blood pressure (MBP) and ECG. Dogs were given orally dronedarone (20 mg/kg, twice per day) for 7 days. All parameters were obtained hourly at 4-8 hr after the first dose and at 12-, 96- (day 4) and 168-hr (day 7) after dosing. The results showed that dronedarone had no effect on inotropy and lusitropy, while it significantly lengthened PQ interval (P<0.001) and lowered MBP (P<0.05). Dronedarone also tended to reduce cardiac output (P=0.237) and heart rate (P=0.057). These results suggested that short-term effects of oral dronedarone administration at a dose of 20 mg/kg, twice per day, produced negative dromotropy with minimal effect on cardiac function in conscious dogs.

Acute effects of intravenous dronedarone on electrocardiograms, hemodynamics and cardiac functions in anesthetized dogs.

Dronedarone is a class III antiarrhythmic that has been used for management of atrial fibrillation in humans, but limited information was found in dogs. The objective of this study was to determine the acute effects of escalating concentrations of dronedarone on electrocardiograms (ECG), hemodynamics and cardiac mechanics in healthy dogs. A total of 7 beagle dogs were anesthetized with isoflurane and instrumented to obtain lead II ECG, pressures at ascending aorta, right atrium, pulmonary artery and left ventricle, and left ventricular pressure-volume relationship. Five dogs were given vehicle and followed by escalating doses of dronedarone (0.5, 1.0 and 2.5 mg/kg, 15 min for each dose), and two dogs were used as a vehicle-treated control. All parameters were measured at 15 min after the end of each dose. The results showed that all parameters in vehicle-treated dogs were unaltered. Dronedarone at 2.5 mg/kg significantly lengthened PQ interval (P<0.01), reduced cardiac output (P<0.01) and increased systemic vascular resistance (P<0.01). Dronedarone produced negative inotropy assessed by significantly lowered end-systolic pressure-volume relationship, preload recruitable stroke work, contractility index and dP/dtmax. It also impaired diastolic function by significantly increased end-diastolic pressure-volume relationship, tau and dP/dtmin. These results suggested that acute effects of dronedarone produced negative dromotropy, inotropy and lusitropy in anesthetized dogs. Care should be taken when given dronedarone to dogs, especially when the patients have impaired cardiac function.

Test of the usefulness of a paradigm to identify potential cardiovascular liabilities of four test articles with varying pharmacological properties in anesthetized guinea pigs.

The evaluation of proarrhythmic and hemodynamic liabilities for new compounds remains a major concern of preclinical safety assessment paradigms. Contrastingly, albeit functional liabilities can also translate to clinical morbidity and mortality, lesser preclinical efforts are focused on the evaluation of drug-induced changes in inotrope and lusitrope, particularly in the setting of concomitant hemodynamic/arrhythmic liabilities. This study aimed to establish the feasibility of an anesthetized guinea pig preparation to assess functional liabilities in the setting of simultaneous drug-induced electrocardiographic/hemodynamic changes, by evaluating the effects of various compounds with known cardiovascular properties on direct and indirect indices of left ventricular function. In short, twenty nine male guinea pigs were instrumented to measure electrocardiograms, systemic arterial pressure, and left ventricular pressure-volume relationships. After baseline measurement, all animals were given intravenous infusions of vehicle and two escalating concentrations of either chromanol 293B (n = 8), milrinone (n = 6), metoprolol (n = 7), or nicorandil (n = 8) for 10 minutes each. In all cases, these compounds produced the expected changes. The slope of preload-recruitable stroke work (PRSW), a pressure-volume derived load independent index, was the most sensitive marker of drug-induced changes in inotropy. Among the indirect functional indices studied, only the "contractility index" (dP/dtmax normalized by the pressure at its occurrence) and the static myocardial compliance (ratio of end diastolic volume and pressure) appeared to be adequate predictors of drug-induced changes in inotropy/lusitropy. Overall, the data confirms that both electrophysiological and mechanical liabilities can be accurately assessed in an anesthetized guinea pig preparation.

Assessment of QT-prolonging drugs in the isolated normal and failing rabbit hearts.

Lengthening of QTc is the usual signal to indicate torsadogenic potential of a therapeutic agent. The ICH S7B guideline recommends that new chemical entities should be assessed for potential of delayed ventricular repolarization in animal models. The aim of this study was to determine a feasibility of using isolated failing heart rabbit to assess the QT-lengthening drugs in comparison with their effects on isolated normal heart rabbits. Heart failure was induced by ligation of the left anterior descending and descending branch of left circumflex coronary arteries. One month after ligation, all rabbits were anesthetized and the hearts were removed quickly, and they were perfused with the oxygenated Krebs-Henseleit solution to which escalating concentrations of QT-lengthening compounds were added. RR, QT, and QTc(F) were not significantly different, at rest, between failing and normal hearts. During baseline, dP/dtmax was lower and dP/dtmin was higher for failing hearts than for normals. In responses to all three QT-lengthening compounds, RR, QT and QTc(F) lengthened similarly in a dose-response manner in both the failing and normal hearts. Neither the failing nor the normal hearts developed fatal arrhythmias, torsades de pointes. Langendorff preparations of failing hearts are as good as normal isolated hearts and can be use to assess the potential of delayed ventricular repolarization of test articles.

Protective effect of creatine supplementation and estrogen replacement on cardiac reserve function and antioxidant reservation against oxidative stress in exercise-trained ovariectomized hamsters.

The combined effect of creatine (Cr) or estrogen (E(2)) with exercise training on cardiac reserve function and antioxidant reservation against oxidative stress were investigated in ovariectomized female Golden Syrian hamsters. One hundred animals were divided into nonexercise and exercise-trained groups, in which each group was separated into the control and 4 treatments of Cr depletion (Cr-), Cr supplementation (Cr+), E(2) replacement (E(2)), and Cr supplementation combined with E(2) replacement (Cr+E (2)). In the exercise-trained group, wheel-running exercise (10 minutes a day, 5 days a week) was imposed for 9 weeks. After the animals were sacrificed, several indicators of cardiac function, specifically the corrected QT interval, left ventricular developed pressure (LVDP), and maximum rate of rise (dP/dt(max)) against a hydrogen peroxide (H(2)O(2)) stress test were measured in isolated hearts using the Langendorff apparatus. Markers of oxidative stress, in other words, reduced glutathione (GSH), oxidized glutathione (GSSG), and an antioxidant enzyme, glutathione peroxidase (GPx) were determined. Exercise-trained animals could restore cardiac reserve function and antioxidant levels against oxidative damage (P<0.05). Cr+, E(2) , and Cr+E(2) combined with exercise training showed highly protected cardiac reserve function against oxidative stress compared to Cr+, E(2) , and Cr+E(2) without exercise (P<0.05). The myocardial antioxidant levels were improved greatly in E(2) and Cr+E(2) combined with exercise training (P<0.05). In conclusion, estrogen replacement and creatine supplementation plus estrogen replacement when combined with exercise training show significant protective effects for cardiac reserve function and antioxidant reservation against oxidative stress in estrogen-deficient hamsters.