ABSTRACT
The mechanism of reentrant ventricular tachyarrhythmias complicating acute myocardial ischemia is largely based on the interaction between an arrhythmogenic substrate and triggers. Melatonin was proposed as an antiarrhythmic medication and was shown to ameliorate the arrhythmogenic substrate. Also, melatonin provides a sympatholytic effect in different settings and might attenuate ectopic activity, which provides reentry triggers. In the present study, we aimed at evaluating the melatonin effects on cardiac sympathetic activity and the incidence of premature ventricular beats during the episode of ischemia-reperfusion. Experiments were done in a total of 26 control and 28 melatonin-treated (10 mg/kg, daily, for 7 days) male rats. Sympathetic fibers density was assessed by glyoxylic acid-induced fluorescence. Continuous electrocardiograms recording was performed during ischemia-reperfusion episodes (5 min/5 min, respectively) induced by reversible coronary occlusion. Myocardial expression of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis was assessed by Western blotting. No differences in the state of sympathetic innervation were observed in histochemical analysis. However, Western blotting analysis demonstrated that melatonin treatment suppressed tyrosine hydroxylase expression in the non-ischemic (p < 0.05 versus control) but not ischemic regions of myocardium. The melatonin-treated animals had longer RR-intervals in the baseline state than the control animals (264 ± 48 ms versus 237 ± 33 ms, p = 0.044, respectively), but this difference decayed during the period of ischemia due to the increase of heart rate in the treated group. The number of premature ventricular beats did not differ between the control and treated groups during the ischemic and reperfusion periods. One-week melatonin pretreatment caused a slight peripheral sympatholytic effect that attenuated during ischemia and completely disappeared by the onset of reperfusion. The slight expression of sympathetic downregulation was associated with the lack of any effect of melatonin on extrasystolic burden. Collectively, the data suggest that melatonin cannot target the triggers of reentrant arrhythmias.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Melatonin/pharmacology , Myocardial Ischemia/drug therapy , Tachycardia, Ventricular/prevention & control , Animals , Anti-Arrhythmia Agents/administration & dosage , Disease Models, Animal , Electrocardiography , Heart Rate/drug effects , Male , Melatonin/administration & dosage , Myocardial Ischemia/physiopathology , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/physiopathology , Rats , Rats, Wistar , Tachycardia, Ventricular/etiologyABSTRACT
We hypothesized that the repolarization phase of action potentials (APs) in mammals with large body mass and high cardiac output could not be reliably controlled by only one of the delayed rectifier potassium IK current components. To test this hypothesis experimentally, we performed a comparative study of the response of AP phases to the rapid IKr channels blocker E-4031 and slow IKs blocker chromanol 293B in APs spontaneously generated in strips of sinoauricular (SA) tissue from mouse, guinea pig, and pig hearts. Application of a slow channels blocker chromanol 293B caused a decrease of Aps generation frequency in SA area strips from mouse, guinea-pig and pig by 5.3, 16, and 18% compared to the control. Treatment with the IKr blocker E-4031 caused a significant reduction of APs generation frequency in the mouse, guinea pig, and pig SA strips by 24, 26, and 36%, respectively, compared to the control values. These results suggest that the rapid IKr current is the key component responsible for AP generation in sinoauricular node cells of the pig heart.
Subject(s)
Action Potentials/drug effects , Potassium Channels/metabolism , Potassium/metabolism , Sinoatrial Node/physiology , Animals , Chromans/pharmacology , Guinea Pigs , Male , Mice , Potassium Channel Blockers/pharmacology , Sinoatrial Node/metabolism , Sulfonamides/pharmacology , SwineABSTRACT
Duration of the plateau phase (phase 2) of action potentials in pacemaker cells in mouse sinoatrial node characterized by low upstroke rate during the rapid depolarization (dV/dt max <7 V/sec, phase 0) and in atrial-like cells with dV/dt max <100 V/sec were prolonged by 50% with 4-aminopyridine in concentrations of 0.7 and 0.1 mM, respectively. This blocker did not lengthen the terminal repolarization (phase 3). The above changes were accompanied by a 20-80% decrease in dV/dt max in comparison to the control. It is hypothesized that the short-term (transient) outward current Ito takes a part in the plateau formation and modulates the duration of the rapid depolarization phase of action potentials in mouse sinoatrial node cells.
Subject(s)
4-Aminopyridine/pharmacology , Action Potentials/drug effects , Potassium Channel Blockers/pharmacology , Sinoatrial Node/physiology , Animals , In Vitro Techniques , Male , Mice , Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/physiology , Sinoatrial Node/cytology , Sinoatrial Node/drug effectsABSTRACT
Experiments on spontaneously contracting strips from sinoatrial region of the hearts of 2-month-old albino mice showed that cesium (Cs(+)), a blocker of hyperpolarization-activated I(f) current, in a concentration of 1 mM produced the greatest negative chronotropic effect on the duration of diastolic depolarization phase (75%), its rate (59%), and action potential duration (29%). The threshold concentration of Cs(+) was approximately 0.15 mM. In a concentration of about 8.5 mM, spontaneous generation of action potentials stopped. The effect was reversible. Thus, blockade of I(f) current by Cs(+) reduced the rate of action potential generation in cells of mouse sinoatrial node by app. 42% in comparison with controls.
