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Cardiac electrophysiologic and antiarrhythmic actions of a pavine alkaloid derivative, O-methyl-neocaryachine, in rat heart.

ABSTRACT: 1. O-methyl-neocaryachine (OMNC) suppressed the ischaemia/reperfusion-induced ventricular arrhythmias in Langendorff-perfused rat hearts (EC50=4.3 microM). Its electrophysiological effects on cardiac myocytes and the conduction system in isolated hearts as well as the electromechanical effects on the papillary muscles were examined. 2. In rat papillary muscles, OMNC prolonged the action potential duration (APD) and decreased the maximal rate of depolarization (V(max)). As compared to quinidine, OMNC exerted less effects on both the V(max) and APD but a positive inotropic effect. 3. In the voltage clamp study, OMNC decreased Na+ current (I(Na)) (IC50=0.9 microM) with a negative-shift of the voltage-dependent inactivation and a slowed rate of recovery from inactivation. The voltage dependence of I(Na) activation was, however, unaffected. With repetitive depolarizations, OMNC blocked I(Na) frequency-dependently. OMNC blocked I(Ca) with an IC(50) of 6.6 microM and a maximum inhibition of 40.7%. 4. OMNC inhibited the transient outward K+ current (I(to)) (IC50=9.5 microM) with an acceleration of its rate of inactivation and a slowed rate of recovery from inactivation. However, it produced little change in the steady-state inactivation curve. The steady-state outward K+ current (I(SS)) was inhibited with an IC50 of 8.7 microM. The inward rectifier K+ current (I(K1)) was also reduced by OMNC. 5. In the perfused heart model, OMNC (3 to 30 microM) prolonged the ventricular repolarization time, the spontaneous cycle length and the atrial and ventricular refractory period. The conduction through the AV node and His-Purkinje system, as well as the AV nodal refractory period and Wenckebach cycle length were also prolonged (30 microM). 6. In conclusion, OMNC blocks Na+, I(to) and I(SS) channels and in similar concentrations partly blocks Ca2+ channels. These effects lead to a modification of the electromechanical function and may likely contribute to the termination of ventricular arrhythmias. These results provide an opportunity to develop an effective antiarrhythmic agent with modest positive inotropy as well as low proarrhythmic potential.

SUBMITTER: Chang GJ

PROVIDER: S-EPMC1573366 | biostudies-other | 2002 Jun

REPOSITORIES: biostudies-other

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Project description:Background Noninvasive cardiac radioablation is employed to treat ventricular arrhythmia. However, myocardial changes leading to early-period antiarrhythmic effects induced by high-dose irradiation are unknown. This study investigated dose-responsive histologic, ultrastructural, and functional changes within 1 month after irradiation in rat heart. Methods and Results Whole hearts of wild-type Lewis rats (N=95) were irradiated with single fraction 20, 25, 30, 40, or 50 Gy and explanted at 1 day or 1, 2, 3, or 4 weeks' postirradiation. Microscopic pathologic changes of cardiac structures by light microscope with immunohistopathologic staining, ultrastructure by electron microscopy, and functional evaluation by ECG and echocardiography were studied. Despite high-dose irradiation, no myocardial necrosis and apoptosis were observed. Intercalated discs were widened and disrupted, forming uneven and twisted junctions between adjacent myocytes. Diffuse vacuolization peaked at 3 weeks, suggesting irradiation dose-responsiveness, which was correlated with interstitial and intracellular edema. CD68 immunostaining accompanying vacuolization suggested mononuclear cell infiltration. These changes were prominent in working myocardium but not cardiac conduction tissue. Intracardiac conduction represented by PR and QTc intervals on ECG was delayed compared with baseline measurements. ST segment was initially depressed and gradually elevated. Ventricular chamber dimensions and function remained intact without pericardial effusion. Conclusions Mononuclear cell-related intracellular and extracellular edema with diffuse vacuolization and intercalated disc widening were observed within 1 month after high-dose irradiation. ECG indicated intracardiac conduction delay with prominent ST-segment changes. These observations suggest that early antiarrhythmic effects after cardiac radioablation result from conduction disturbances and membrane potential alterations without necrosis.

Project description:BackgroundPoge heart-saving decoction (PHSD) has been used as a medicine treating heart failure in China for many years. The study aimed to explore the effect of PHSD on cardiac function in heart failure conditions and its underlying mechanism.MethodsAdriamycin was used to induce the model of heart failure (HF) in rats. Sixty rats were randomly divided into six groups: blank control group, sham group, 9.33 g/kg group (low-PHSD, test group), 13.995 g/kg group (moderate-PHSD, test group), 18.66 g/kg group (high-PHSD, test group), and fosinopril group (4.67 mg/kg, comparison test group). Cardiac ultrasound was used to evaluate the cardiac function of the rats, and radioimmunoassay was used to measure aldosterone (ALD) and angiotensin II (AngII) levels in the serum.ResultsCompared with the blank control group, the left ventricular end-diastolic dimension (LVEDd) and left ventricular end-systolic dimension (LVEDs) in the sham group were increased (1.04 ± 0.12 vs. 0.67 ± 0.13 cm; 0.75 ± 0.13 vs. 0.28 ± 0.10 cm; P < 0.05), and the left ventricular ejection fraction was decreased (36.65 ± 5.74 vs. 76.09 ± 4.23%; P < 0.05). The ejection fraction of HF rats was increased in 9.33 g/kg group, 13.995 g/kg group, and 18.66 g/kg group compared with those of the sham group (57.13 ± 1.63, 58.43 ± 1.98, and 59.21 ± 1.37 vs. 36.65 ± 5.74%; P < 0.05). PHSD also improved cardiac function by reducing the LVEDd and LVEDs (0.88 ± 0.11, 0.75 ± 0.13, and 0.72 ± 0.18 vs. 1.04 ± 0.12 cm; 0.62 ± 0.10, 0.63 ± 0.17, and 0.45 ± 0.11 vs. 0.75 ± 0.13 cm; P < 0.05). The levels of ALD and AngII in the serum of rats in the sham group were significantly higher than those in the blank control group (371.58 ± 39.25 vs. 237.12 ± 17.35 μg/L; 232.18 ± 16.33 vs. 159.44 ± 18.42 pg/L; P < 0.05). The ALD and AngII of the rats in all of the three PHSD groups and the fosinopril group were decreased (276.81 ± 25.63, 277.18 ± 21.35, 268.19 ± 19.28, and 271.47 ± 28.96 vs. 371.58 ± 39.25 μg/L; 169.41 ± 27.53, 168.81 ± 19.78, 164.23 ± 21.34, and 174.27 ± 22.84 vs. 232.18 ± 16.33 pg/L; P < 0.05). The histopathological changes of the myocardium in the sham group showed the disorganized fiber, shaded staining, fracture, and zonation. The fracture of the myocardium was relieved in all groups except the sham group and the blank control group.ConclusionTherefore, PHSD could shorten LVEDd and LVEDs of rats and reverse ventricular remodeling. The mechanism might be related to the inhibition of the activation level of renin-angiotensin-aldosterone system (especially ALD and AngII) and decreasing the postload of the heart.

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Cardiac electrophysiologic and antiarrhythmic actions of a pavine alkaloid derivative, O-methyl-neocaryachine, in rat heart.

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