The effects of 20-min ligations of the anterior branch of the left coronary artery were studied in Langendorff-perfused rabbit hearts with 92 μM d-sotalol added to the perfusate to induce long QT intervals and triggered arrhythmias. Epicardial electrograms, a left ventricular endocardial monophasic action potential, and simulated X and Y lead electrocardiograms were used to characterize ventricular conduction and recovery. In contrast to previous work showing that global ischemia eliminated triggered activity, coronary occlusion did not alter its mean incidence. Although the anatomic distribution of earliest sites of epicardial activation by triggered beats was altered, triggered beats still appeared on the epicardial surface in the nonperfused regions. Coronary occlusion had a small and variable effect on epicardial conduction velocity but caused a significantly greater percent shortening of epicardial activation-recovery intervals in the nonperfused region of hearts given d-sotalol than in control hearts. In hearts given d-sotalol, preconditioning significantly attenuated the shortening of epicardial activation-recovery intervals in response to coronary occlusion. However, preconditioning had no effect on the mean incidence of triggered activity during coronary occlusion. Thus, the persistence of triggered activity and the shortened myocardial recovery time associated with coronary occlusion could contribute to increasing the likelihood of occurrence of malignant ventricular arrhythmias. Preconditioning by attenuating the shortening of recovery would be anti-arrhythmic.
Protein kinase A (PKA) activation has been implicated in early-phase ischemic preconditioning. We recently found that during ischemia PKA activation causes inactivation of cytochrome- c oxidase (CcO) and contributes to myocardial damage due to ischemia-reperfusion. It may be that β-adrenergic stimulation during ischemia via endogenous catecholamine release activates PKA. Thus β-adrenergic stimulation may mediate both myocardial protection and damage during ischemia. The present studies were designed to determine the role of the β 1 -adrenergic receptor (β 1 -AR) in myocardial ischemic damage and ischemic preconditioning. Langendorff-perfused rabbit hearts underwent 30-min ischemia by anterior coronary artery ligation followed by 2-h reperfusion. Occlusion-reperfusion damage was evaluated by delineating the nonperfused volume of myocardium at risk and volume of myocardial necrosis after 2-h reperfusion. In some hearts ischemic preconditioning was accomplished by two 5-min episodes of global low-flow ischemia separated by 10 min before coronary occlusion-reperfusion. Orthogonal electrocardiograms were recorded, and coronary flow was monitored by a drip count. Three hearts from each experimental group were used to determine mitochondrial CcO and aconitase activities. Two-hour reperfusion after occlusion caused an additional decrease in CcO activity vs. that after 30-min occlusion alone. Blocking the β 1 -AR during occlusion-reperfusion reversed CcO activity depression and preserved myocardium at risk for necrosis. Similarly, mitochondrial aconitase activity exhibited a parallel response after occlusion-reperfusion as well as for the other interventions. Furthermore, classic ischemic preconditioning had no effect on CcO depression. However, blocking the β 1 -AR during preconditioning eliminated the cardioprotection. If the β 1 -AR was blocked after preconditioning, the myocardium was preserved. Interestingly, in both of the latter cases the depression in CcO activity was reversed. Thus the β 1 -AR plays a dual role in myocardial ischemic damage. Our findings may lead to therapeutic strategies for preserving myocardium at risk for infarction, especially in coronary reperfusion intervention.
Experiments were performed on open-chest anesthetized dogs to determine the quantitative effects of autonomic nerve stimulation on pacemaker activity and conduction. The lead II electrocardiogram together with bipolar electrograms were recorded from the atria, the His bundles, and the ventricles. The vagi or the stellate ganglia were stimulated in dogs which exhibited either sinus rhythm, ectopic atrial rhythm, junctional rhythm, or ectopic ventricular rhythm. The time courses of the change in heart rate in response to vagal or stellate stimulation were characteristic for each type of rhythm. The characteristic responses of different cardiac pacemaker sites to autonomic influence were demonstrated to be important factors in the production of wandering pacemakers and in the emergence of ectopic beats. Sinus pacemaker activity was more sensitive to modification by autonomic stimulation than was atrioventricular (AV) conduction. However, subliminal autonomic effects on AV transmission were brought out during conduction of premature atrial beats, thereby demonstrating a coupling interval dependency of autonomic influences on AV conduction. The present experiments also showed how fluctuations in autonomic activity could result in Mobitz type II second-degree heart block, pseudosupernormal conduction, and the concertina effect observed in the preexcitation syndrome.
In the present study, we evaluated the antiarrhythmic interaction (s) of metoprolol and lidocaine in 16 dogs using the ventricular fibrillation threshold (VFT) method. The right ventricle was stimulated with a 100 Hz train of 12.4 ms pulses delivered after every eighth atrial paced beat at a basic cycle length of 300 ms. Lidocaine dosage was 2 mg/kg followed by a 70 micrograms/kg/min infusion and metoprolol dosage was a 75 micrograms/kg bolus. In Group 1, lidocaine was followed by metoprolol; in Group 2, first lidocaine then metoprolol and again lidocaine were given; and in Group 3, dogs received first metoprolol, then lidocaine, and subsequently metoprolol. Drug dose intervals were 45 min. In Group 1, lidocaine elevated the VFT to 149% +/- 20% and metoprolol to 204% +/- 30% of control, (p less than 0.01). In group 2, the VFT remained elevated after the second lidocaine administration (p less than 0.05 vs. Group 1). In Group 3, the VFT was increased by metoprolol to 227% +/- 30% of control (p less than 0.01). Interestingly, defibrillation induced by the combination of metoprolol and lidocaine occurred after 3.2 +/- 0.5 s in four out of 16 animals (p less than 0.05). This "chemical" defibrillation never occurred when only metoprolol or lidocaine alone was administered. Fibrillation was often more organized in the presence of the combination of metoprolol plus lidocaine, which might relate to the observed defibrillation associated with metoprolol plus lidocaine. In conclusion, the combination of metoprolol and lidocaine has no proarrhythmic effects and may enhance the electrical stability of the ventricles as measured by the VFT method.
Digitalis glycosides have been implicated in increased vulnerability to ventricular fibrillation in man. In order to investigate the genesis and occurrence of ventricular fibrillation in the presence of digitalis, the effects of both acetylstrophanthidin and ouabain on the ventricular fibrillation threshold (VFT) were studied in the open-chest anesthetized dog. The current required to induce ventricular fibrillation was determined by passing a train of 12 constant current pulses through epicardial electrodes during the vulnerable period of the cardiac cycle. It was found that an intravenous bolus infusion of acetylstrophanthidin (0.050-0.097 mg/kg) or ouabain (0.035-0.075 mg/kg) in intact innervated dog hearts raised the VFT from 40% to 260% above control values. Continuous infusions of acetylstrophanthidin to toxic levels also resulted in an elevated VFT. Vagotomy alone did not qualitatively change the effects of acetylstrophanthidin on VFT. However, following vagotomy and stellate sympathectomy, infusions of both toxic and subtoxic doses of acetylstrophanthidin resulted in a decrease in the VFT from 40 to 80% below control values. In denervated animals in which the peripheral ramifications of the left stellate ganglion nerves were stimulated, the VFT decreased below control values in the absence of acetylstrophanthidin, but during stellate stimulation in the presence of acetylstrophanthidin the VFT was increased above control values. These studies demonstrated that the increase in VFT by digitalis in the healthy, innervated heart was mediated via an associated increase in sympathetic activity; in the absence of neural influences digitalis decreased the VFT.
Abstract A canine model of chronic myocardial infarction has been studied in which animals are susceptible to the initiation of sustained ventricular tachyarrhythmias using routine methods of programmed stimulation. The pacinginduced arrhythmias in this model are similar to those observed in man in their mode of initiation and termination, as well as in their response to both pacing and pharmacologic interventions. Indirect evidence has suggested a localized protected reentrant mechanism for these arrhythmias. The susceptibility to arrhythmia initiation in this model has been related to both electrophysiologic and histopathologic findings. Consistently, animals have demonstrated a marked heterogeneity of local properties of excitability and refractoriness at sites within areas of infarction. Correspondingly, animals have shown a marked inhomogeneity of histopathologic findings within areas of infarction, with close interspersing of normal and abnormal myocardium. Remarkably, even animals with small mottled infarctions, often less than 1 cm × 2 cm and electrocardiographically silent, were highly susceptible to the initiation of ventricular tachyarrhythmias, and especially fibrillation. Thus, initial provocative studies in this model have suggested its potential importance both in studying arrhythmia mechanisms and in evaluating the efficiency of potential antiarryhthmic interventions. In addition, this should be an ideal model in which to correlate pathophysiologic and morphologic alterations in the setting of chronic myocardial infarction.
