Phenylephrine-induced ventricular arrhythmias in dogs with inherited sudden death.

INTRODUCTION: Dogs with an inherited predisposition to sudden death display ventricular arrhythmias having certain characteristics, such as pause dependence, that are suggestive of early afterdepolarization-induced triggered activity. We hypothesized that alpha-adrenergic stimulation may facilitate the development of these arrhythmias by inducing a reflex bradycardia and by exerting a direct myocardial effect. METHODS AND RESULTS: Twenty affected dogs and 7 unaffected dogs were studied. The incidence and severity of ventricular arrhythmias were determined after administration of phenylephrine (0.01 mg/kg IV), with or without pretreatment with propranolol (0.1 to 0.3 mg/kg IV), atropine (0.04 mg/kg IV), or prazosin (0.5 mg/kg IV). Third-degree heart block was induced by AV nodal ablation in 4 affected dogs. Phenylephrine increased ventricular arrhythmias in affected dogs, with or without pretreatment with propranolol, but did not induce ventricular arrhythmias in unaffected dogs. In dogs with intact AV nodal conduction, atropine increased sinus rate, which suppressed baseline and phenylephrine-induced arrhythmias. In dogs with heart block, arrhythmias were increased during baseline and after phenylephrine, with or without pretreatment with atropine. Prazosin and overdrive ventricular pacing suppressed phenylephrine-induced arrhythmias. CONCLUSION: Phenylephrine increases ventricular arrhythmias in dogs with inherited sudden death via both an induction of reflex bradycardia and a direct myocardial effect. Superimposition of heightened alpha-adrenergic and vagal tone may facilitate the development of sudden death in these animals.

Stable fetal cardiomyocyte grafts in the hearts of dystrophic mice and dogs.

This report documents the formation of stable fetal cardiomyocyte grafts in the myocardium of dystrophic dogs. Preliminary experiments established that the dystrophin gene product could be used to follow the fate of engrafted cardiomyocytes in dystrophic mdx mice. Importantly, ultrastructural analyses revealed the presence of intercalated discs consisting of fascia adherens, desmosomes, and gap junctions at the donor-host cardiomyocyte border. To determine if isolated cardiomyocytes could form stable intracardiac grafts in a larger species, preparations of dissociated fetal canine cardiomyocytes were delivered into the hearts of adult CXMD (canine X-linked muscular dystrophy) dogs. CXMD dogs, like Duchenne muscular dystrophy patients and mdx mice, fail to express dystrophin in both cardiac and skeletal muscle. Engrafted fetal cardiomyocytes, identified by virtue of dystrophin immunoreactivity, were observed to be tightly juxtaposed with host cardiomyocytes as long as 10 wk after engraftment, the latest date analyzed. Confocal laser scanning microscopy revealed the presence of connexin43, a major constituent of the gap junction, at the donor-host cardiomyocyte border. The presence of intracardiac grafts was not associated with arrhythmogenesis in the CXMD model. These results indicate that fetal cardiomyocyte grafting can successfully augment cardiomyocyte number in larger animals.

Reperfusion arrhythmias: role of early afterdepolarizations studied by monophasic action potential recordings in the intact canine heart during autonomically denervated and stimulated states.

INTRODUCTION: The precise mechanism of reperfusion arrhythmias is not established. The role of early afterdepolarizations (EADs) and triggered activity in the genesis of reperfusion ventricular arrhythmia was investigated. METHODS AND RESULTS: Monophasic action potentials (MAPs) were recorded in the canine heart using Ag-AgCl contact electrodes from the left and right ventricular endocardium and the left ventricular epicardial border zone during 10 minutes of occlusion of the proximal left anterior descending coronary artery followed by 2 minutes of reperfusion. Ventricular arrhythmias during ischemia and reperfusion were studied in three autonomically varied groups. Group 1 (n = 8) had intact autonomic neural innervation; group 2 (n = 8) had bilateral transection of ansae subclavii and vagi; and group 3 (n = 8) underwent bilateral transection of ansae subclavii and vagi with bilateral ansae subclavii stimulation during reperfusion. Ventricular fibrillation (VF) on reperfusion occurred in 2, 3, and 5 animals in the innervated, denervated, and sympathetically stimulated groups, respectively. Rapid ventricular tachycardia during ansae subclavii stimulation, antecedent to VF, occurred in 4 of 5 episodes in the sympathetically stimulated group. The frequency of premature ventricular complexes, couplets, and triplets on reperfusion was not significantly different among the three groups. Phase 2 or phase 3 EADs were noted during the acute ischemic phase in 6 of 8, 7 of 8, and 7 of 8 animals in the three groups, respectively (and persisted during reperfusion in the majority). Thus, these EADs were not a de novo phenomenon during reperfusion. Of the 72 MAP recording sites, only one demonstrated de novo phase 2 EADs during reperfusion. EADs disappeared during reperfusion in 6 animals (prior to the onset of VF in 4), and 5 dogs developed reperfusion VF without EADs being recorded. There was no direct correlation between the presence of EADs during reperfusion and the development of VF. The prevalence and onset of reperfusion VF was not significantly different in the presence of sympathetic stimulation. CONCLUSION: This study demonstrates that EADs can be recorded in the majority of dogs during both ischemia and reperfusion and do not appear to be a major mechanism responsible for reperfusion ventricular tachycardia and VF.

Microwave ablation of canine atrial tachycardia induced by aconitine.

We tested the efficacy of microwave-frequency energy for ablating atrial tachycardia in eight open-chest dogs. Five other dogs served as controls. Atrial tachycardia was induced by direct application of aconitine crystals to the epicardial atrial surface or by injection of aconitine solution (0.15 mg/ml) into the right or left atrial myocardium. Atrial tachycardias (n = 15) developed at a cycle length of 253 +/- 64 msec or within 245 +/- 116 sec after topical application or injection of aconitine. Catheter ablation was attempted on 10 atrial tachycardias in 8 experiment dogs by using continuous, unmodulated microwave energy from a 915 MHz frequency signal generator via a 7F helical or whip antenna catheter. Successful ablation was defined as conversion of atrial tachycardia to sinus rhythm during delivery of microwave energy and maintenance of sinus rhythm for > 5 minutes after termination of energy delivery. All 10 atrial tachycardias were successfully ablated by 2.3 +/- 1.6 applications of microwave energy for each atrial tachycardia induced. Forward microwave power level was 50.5 +/- 8.1 W, and the duration of energy application was 25.0 +/- 27.6 seconds. Sinus rhythm resumed 9.5 +/- 9.2 seconds after the onset of microwave energy application. After a mean follow-up of 10.4 minutes, seven atrial tachycardias recurred, most likely the result of diffusion of aconitine beyond the perimeter of rhe ablation lesions. Atrial tachycardia did not recur in 3 of 3 dogs that had larger ablation lesion. Gross examination revealed 10 demarcated round or oval transmural lesions in the right or left atrium, ranging from 12.6 to 105.6 mm2 in area.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs.

BACKGROUND: The purpose of this study was to prevent induction of sustained atrial fibrillation (AF) by radiofrequency catheter ablation (RFCA) of the atria in an open-chest canine model. METHODS AND RESULTS: In dogs randomized to acute studies, RFCA of the atria was performed after reproducible induction of sustained AF (lasting > 30 minutes) with burst stimulation or premature atrial pacing and perpetuation by low level cervical vagal stimulation or IV infusion of methacholine. Additionally, in four dogs, the long-term effectiveness of RFCA was assessed 7 to 21 days after ablation. Continuous discrete transmural lesions were produced with radiofrequency energy pulses (20 to 40 W for 60 seconds) delivered to five atrial epicardial sites and endovascularly to the coronary sinus wall. RFCA electrically isolated regions of the atria that became dissociated from the nonisolated parts. Atrial RFCA markedly attenuated vagally induced shortening of effective refractory period (ERP) at both isolated and nonisolated test sites located in the left and right atria (P < .001, n = 5). RFCA rendered noninducible sustained AF maintained by cervical vagal stimulation. The dose-response curve relating the dose of methacholine required to maintain AF was shifted down and to the right. AF was only inducible with high doses of methacholine. Atrial RFCA reduced the maximal sinus rate and prolonged the corrected sinus-node recovery time (P < .001, n = 6). However, RFCA did not affect atrial contractile function, AV-nodal ERP, or AV-nodal or His-Purkinje conduction times. In dogs in the chronic group, normal sinus rhythm and normal AV conduction were preserved and AF was only inducible with a high dose of methacholine. No atrial perforations resulted. CONCLUSIONS: RFCA in open-chest dogs produces partial vagal denervation and reduces the inducibility of AF.

Glibenclamide enhances but pinacidil reduces attenuation in sympathetic responsiveness after acute coronary artery occlusion.

To investigate the role of ATP-sensitive K+ channels in modulating the efferent autonomic response following acute myocardial ischemia/infarction, we examined the effects of a blocker (glibenclamide) and an opener (pinacidil) of ATP-sensitive K+ channels on the time course and extent of the attenuation in efferent cardiac sympathetic responsiveness in anesthetized dogs. We measured the effective refractory periods (ERPs) at nonischemic sites basal and apical to the area of myocardial ischemia/infarction in the baseline state and during bilateral stimulation of the ansae subclaviae before and after each drug administration and 5, 30, 60, 120, and 180 minutes after latex injection of a diagonal branch of the left anterior descending coronary artery. Animals received either vehicle (n = 12), glibenclamide (0.3 mg.kg-1, n = 10), pinacidil (0.15 mg.kg-1 + 0.2 mg.kg-1 infusion, n = 10), or a combination of these two drugs (n = 9) intravenously. In another group of dogs receiving just pinacidil (n = 10), an intra-aortic balloon was inflated distal to the renal arteries to prevent pinacidil-induced hypotension. Another group of dogs received either high-dose glibenclamide (0.3 mg.kg-1 + 0.15 mg.kg-1, n = 4), low-dose glibenclamide (0.06 mg.kg-1, n = 4), medium-dose pinacidil (0.03 mg.kg-1 + 0.04 mg.kg-1 infusion, n = 4), or low-dose pinacidil (0.0075 mg.kg-1 + 0.01 mg.kg-1 infusion, n = 4). In all dogs, basal sites exhibited no attenuation of sympathetically induced shortening of the ERP throughout the period of acute myocardial ischemia/infarction. Cumulative attenuation in sympathetic responsiveness (shortening of ERP < or = 2 milliseconds induced by bilateral stimulation of the ansae subclaviae) at nonischemic test sites apical to the area of ischemia/infarction during a 3-hour period was greater in the glibenclamide group (26 of 44 sites, P = .008) and less in the pinacidil (2 of 44 sites, P = .002) and pinacidil-balloon (1 of 48 sites, P < .001) groups compared with the vehicle group (14 of 46 sites). Glibenclamide abolished the protective effect of pinacidil so that 10 of 45 sites had < 2-millisecond shortening during a 3-hour period in the glibenclamide + pinacidil group (P = .018 versus pinacidil group, P = .286 versus vehicle group). Such effects of glibenclamide and pinacidil on sympathetic attenuation were dose dependent. Maintaining the blood glucose level during glibenclamide administration did not affect the sympathetic attenuation after acute coronary artery occlusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Defibrillating shocks delivered to the heart impair efferent sympathetic responsiveness.

BACKGROUND: Functional studies indicate that sympathetic efferents are located in the superficial subepicardium and vagal efferents are located in the subendocardium. It is possible that electrical shocks applied directly to the heart might affect the function of these autonomic nerves. METHODS AND RESULTS: Low- (< or = 1 J), medium- (6 to 16 J), or high- (30 to 35 J) energy truncated monophasic exponential shocks, synchronized to the R wave during sinus rhythm, were delivered over implantable patches sutured inside the pericardium in anesthetized open-chest dogs. Shortening of ventricular effective refractory period (ERP), produced by bilateral ansae subclaviae stimulation (SS), was measured before and after shock delivery. High-energy shocks shifted the SS frequency-ERP response curves downward and to the right (P < .001) for sites beneath and apical to the patches; ERP shortening at basal sites remained unchanged. Such sympathetic attenuation occurred with shocks > 10 J but not with shocks < or = 10 J, was noted 15 minutes after the shock, and showed incomplete return to control values at 3 hours. Neither low- nor high-energy shocks affected norepinephrine dose-ERP response curves, indicating normal myocardial responsiveness. Low- and high-energy shocks did not attenuate bilateral cervical vagal stimulation-induced ERP prolongation. High-energy shocks delivered over patches sutured to the outside of the pericardium showed no effects on sympathetic response, suggesting a protective effect of the pericardium against shock-induced sympathetic attenuation. CONCLUSIONS: DC shocks > 10 J delivered directly to the epicardium attenuated efferent sympathetic neural function. Such changes may affect electrophysiological, as well as hemodynamic, responses to sympathetic neural stimulation after cardioversion-defibrillation.

Electrophysiological mechanisms in a canine model of erythromycin-associated long QT syndrome.

BACKGROUND: Erythromycin is known to prolong ventricular repolarization and has been associated with the occurrence of torsades de pointes. In this study, we have investigated potential mechanisms in vivo and in vitro for induction of an acquired long QT syndrome by erythromycin. METHODS AND RESULTS: Ventricular electrograms and endocardial monophasic action potentials were recorded in anesthetized open-chest dogs before and after administration of 40 to 120 mg/kg of erythromycin lactobionate. Conventional microelectrode techniques were used to record transmembrane action potentials in isolated dog Purkinje fibers and papillary muscles. Erythromycin at concentrations > 20 mg/L prolonged action potential duration. At higher concentrations (100 to 200 mg/L), erythromycin induced phase 2 and phase 3 early afterdepolarizations (EADs) both in vivo and in vitro. The effects of erythromycin on repolarization were more marked in Purkinje fibers than in papillary muscle. Pretreatment of Purkinje fibers with erythromycin antagonized the effects of dofetilide, a selective delayed-rectifier potassium channel (IK) blocker. Pretreatment with prazosin or tetrodotoxin had no effect on erythromycin-induced changes in action potential duration. CONCLUSIONS: These pharmacological studies suggest that erythromycin prolongs repolarization to a large extent by block of IK. In turn, prolongation of action potential duration resulting from erythromycin's actions on IK may promote the development of EADs. The induction of ventricular arrhythmias observed clinically after exposure to erythromycin may be related to the development of EADs. The rarity of occurrence of ventricular arrhythmias suggests that other predisposing factors contribute to the acquired long QT syndrome associated with erythromycin.

Simulated ischemia does not protect against efferent sympathetic denervation following acute myocardial infarction in canine hearts.

INTRODUCTION: Preconditioning the myocardium with brief episodes of ischemia preserves efferent autonomic responsiveness of noninfarcted myocardium apical to a site of acute transmural ischemia by mechanism(s) still unknown. We hypothesized that repeated brief exposure of the myocardium to a simulated ischemic milieu including hypoxia, high K+, low pH, and adenosine would be as effective as brief coronary occlusions in creating this protection. METHODS AND RESULTS: Open chest anesthetized dogs received an extracorporeal bypass between the left carotid artery and a diagonal branch of the left anterior descending coronary artery. We analyzed the effects of simulated ischemia on the time course and extent of efferent sympathetic denervation during a subsequent 3-hour sustained ischemia in three groups of dogs: two groups of dogs underwent four cycles of 5-minute intracoronary perfusion with either hypoxic altered Tyrode's solution (12 mM K+, 6.8 pH, and 10 microM adenosine; n = 11) or normal Tyrode's solution (n = 11). Each Tyrode's perfusion was separated by 5 minutes of blood perfusion prior to permanent coronary occlusion by latex embolization of the cannulated coronary artery. A third group received a continuous 3-hour blood perfusion before the final ischemic episode (n = 5). Shortening of effective refractory periods (ERPs) induced by bilateral ansae subclaviae stimulation (2 to 4 Hz) basal and apical to the intervention site was determined before and after perfusions and 20, 60, 120, and 180 minutes after sustained occlusion. In all groups, sympathetically-induced ERP shortening was unchanged at basal sites throughout the experiment. ERP shortening at apical sites was unchanged after perfusions with either the altered or normal Tyrode's solution or after a continuous 3-hour blood perfusion. However, ERP shortening became significantly attenuated at apical sites after coronary occlusion in all groups. Neither the size in reduction of sympathetically-induced ERP shortening at apical test sites nor the cumulative percentage of denervated apical test sites (< or = 2-msec shortening) during a 3-hour period of permanent ischemia differed significantly among groups (P = 0.052 and P = 0.752, respectively). The degree of subepicardial involvement in the myocardial infarction was comparable among groups. CONCLUSION: Thus, brief exposure of the left ventricular myocardium to ischemic metabolites prior to a subsequent permanent coronary occlusion does not trigger mechanism(s) that are responsible for protection against efferent sympathetic denervation apical to an area of transmural myocardial infarction/ischemia.

Canine left ventricular hypertrophy predisposes to ventricular tachycardia induction by phase 2 early afterdepolarizations after administration of BAY K 8644.

OBJECTIVES: The purpose of this study was to test the hypothesis that the longer duration of ventricular action potentials in hypertrophied hearts predisposes to the development of early after-depolarizations and triggered ventricular tachyarrhythmias. BACKGROUND: For unknown reasons, the incidence of sudden death is greater in patients with myocardial hypertrophy. METHODS: We measured left ventricular monophasic action potentials in normal dogs and dogs with left ventricular hypertrophy before and after administration of the calcium agonist BAY K 8644 and the potassium channel blocker cesium. RESULTS: We demonstrated longer action potential durations in dogs with than in those without left ventricular hypertrophy. Also, BAY K 8644 produced phase 2 early afterdepolarizations and ventricular tachyarrhythmias more frequently in the dogs with than in those without left ventricular hypertrophy. Phenylephrine, an alpha agonist, further increased the action potential duration in hypertrophied hearts and the propensity to develop early afterdepolarizations and ventricular tachyarrhythmia after administration of BAY K 8644. Control and hypertrophied hearts developed early afterdepolarizations and ventricular tachyarrhythmia equally when exposed to cesium. CONCLUSIONS: Although in vitro studies have shown that fibers of hypertrophied ventricular myocardium can develop triggered activity as a result of both early and late afterdepolarizations, the present study is the first to show in vivo that the hypertrophied ventricular myocardium compared with the normal ventricle is predisposed to develop phase 2 early afterdepolarizations that appear to trigger ventricular tachyarrhythmia. It is possible that such a mechanism contributes to the development of ventricular tachyarrhythmia and sudden cardiac death in patients with left ventricular hypertrophy. If this is shown to be true, specific pharmacologic interventions can be suggested.

Prostaglandin modulation of early afterdepolarizations and ventricular tachyarrhythmias induced by cesium chloride combined with efferent cardiac sympathetic stimulation in dogs.

Prostaglandins inhibit efferent cardiac sympathetic nerve effects by acting at presynaptic sites and may act to suppress some arrhythmias. In the present study, the effects of intravenous administration of prostacyclin (PGI2) and prostaglandin E2 (PGE2) on early afterdepolarizations and ventricular tachycardia induced by cesium chloride (0.5 mmol/liter per kg body weight intravenously) combined with stimulation of bilateral ansae subclaviae in anesthetized dogs were examined. The right atrium was paced at a constant cycle length of 600 ms. A left ventricular endocardial monophasic action potential catheter was used to detect early afterdepolarizations. Prostacyclin (0.2 microgram/kg per min) reduced the amplitude of the early afterdepolarizations (39.2 +/- 8.4% of the monophasic action potential amplitude during control study to 28.7 +/- 5.5%, n = 10; p less than 0.001) as well as the prevalence of ventricular tachycardia (11 of 14 dogs during control study to 5 of 14 dogs; p = 0.031). Prostaglandin E2 (0.2 to 0.6 microgram/kg per min) did not significantly reduce the early afterdepolarization amplitude (34.7 +/- 8.9% to 25.1 +/- 10.7%, n = 8; p = 0.085) or the prevalence of ventricular tachycardia (8 of 10 versus 6 of 10 dogs; p = 0.50). Alpha- and beta-adrenoceptor blockade with combined intravenous administration of propranolol (0.5 mg/kg) and phentolamine (0.3 mg/kg) decreased the amplitude of the early afterdepolarizations induced by cesium chloride and bilateral ansae subclaviae stimulation from 38.6 +/- 11.2% to 18.8 +/- 3.3% (n = 6; p = 0.005). Additional administration of PGI2 further reduced the early afterdepolarization amplitude from 18.8 +/- 3.3% to 9.8 +/- 4.8% (n = 6; p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandins in the pericardial fluid modulate neural regulation of cardiac electrophysiological properties.

In response to various stimuli, the pericardium produces prostaglandins that might play a role in neural regulation of cardiac electrophysiological properties by modulating epicardial nerve effects. We determined the effects of various epicardial superfusates on efferent cardiac responses, induced by bilateral efferent ansae subclaviae (SS) and cervical vagal (VS) stimulation, and afferent cardiac reflexes elicited by intracoronary injections of bradykinin (25 micrograms) and nicotine (50 micrograms). Pericardial instillation of arachidonic acid in normal Tyrode's solution (3 micrograms/ml) increased the concentration of pericardial prostacyclin (PGI2), measured by radioimmunoassay as the stable metabolite 6-keto-PGF1 alpha, and of prostaglandin E2 (PGE2). Arachidonic acid superfusion reduced SS-induced shortening of sinus cycle length (SCL), atrio-His interval (AH), and effective refractory period (ERP) of the right and left ventricular myocardium and prevented intra-aortic angiotensin II (30 ng/kg/min) from augmenting SS effects on these variables. Pericardial arachidonic acid plus indomethacin (1 microgram/ml) eliminated the prostaglandin increase and restored the responses of SCL, AH, and ERP to SS and to angiotensin II infusion. Pericardial PGE2 (30 or 50 ng/ml) or PGI2 (50 ng/ml) reversibly suppressed SS-induced shortening of SCL and ERP. Pericardial arachidonic acid or PGI2, however, did not blunt the shortening of ERP induced by intravenous infusion of norepinephrine. Pericardial arachidonic acid did not affect VS-induced lengthening of ERP or the duration of sinus arrest, or arterial blood pressure and heart rate responses to bradykinin or nicotine. We conclude that an increase in the concentration of prostaglandins in the pericardial fluid inhibits efferent sympathetic nerve effects on cardiac electrophysiological variables and antagonizes the facilitatory action of angiotensin II on efferent sympathetic stimulation by acting at presynaptic sites. Increased concentration of pericardial prostaglandins in response to various stimuli may constitute a physiological negative-feedback control mechanism that regulates efferent cardiac sympathetic stimulation.

Modulation of cardiac autonomic neurotransmission by epicardial superfusion. Effects of hexamethonium and tetrodotoxin.

The heart contains superficial cardiac nerves whose effects may be modulated by pericardial fluid bathing the epicardium. We tested this hypothesis in open-chest dogs anesthetized with secobarbital. Oxygenated normal Tyrode's solution (NT) or NT containing hexamethonium, a ganglionic blocker (500 microM), or tetrodotoxin, a blocker of axonal neurotransmission (5 microM, TTX), was instilled into the pericardial cavity to superfuse the epicardium of the whole heart. During each superfusion, effective refractory period (ERP) was determined in deep intramyocardium (greater than or equal to 4 mm in depth from the epicardium) of anterior and posterior left ventricle and in the subendocardium of the right ventricle in the baseline state and during bilateral cervical vagal stimulation (VS) or ansae subclaviae stimulation (SS). Lengthening of ERP induced by VS during superfusion with NT (6.9 +/- 0.3 msec, mean +/- SEM, n = 36) was eliminated during subsequent superfusion with hexamethonium (0.9 +/- 0.5 msec, p less than 0.001). Hexamethonium also prevented sinus arrest induced by VS but did not affect shortening of ERP induced by SS (17.3 +/- 1.3 to 16.6 +/- 1.0 msec, n = 26). TTX suppressed VS-induced changes in ERP (6.3 +/- 0.3 to 1.5 +/- 0.5 msec, n = 32, p less than 0.001) and SS-induced changes in ERP (18.8 +/- 1.6 to 6.0 +/- 0.9 msec, n = 23, p less than 0.001) but did not affect changes in ERP induced by intravenous administration of norepinephrine or methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Scintigraphic and electrophysiological evidence of canine myocardial sympathetic denervation and reinnervation produced by myocardial infarction or phenol application.

Epicardial phenol application or transmural myocardial infarction in dogs produces sympathetic denervation of myocardium apical to the site of the intervention. Because efferent denervation is probably postganglionic, reinnervation most likely occurs but has not been shown. We investigated whether 123I-labeled metaiodobenzylguanidine (MIBG), a norepinephrine analogue taken up by sympathetic nerve terminals, could provide a scintigraphic image that would detect apical sympathetic denervation and possible reinnervation. Dogs underwent MIBG scintigraphic imaging at various times after phenol application or transmural myocardial infarction. The results of MIBG scintigraphy were correlated with electrophysiological responses obtained during ansae subclaviae and norepinephrine stimulation to establish the presence of neural denervation and reinnervation. Apical defects in the MIBG scan, which were associated with either normal perfusion by thallium or a smaller-sized defect, were found consistently in dogs that had apical sympathetic innervation. MIBG scintigraphic images returned to normal after 14 weeks (mean) at a time when reinnervation was shown to have occurred. Thus, the results of MIBG scintigraphy correlated accurately with the presence of denervation and reinnervation established by neuroelectrophysiological testing. Supersensitive refractory period shortening in response to norepinephrine infusion was present after denervation and persisted for more than 3 weeks after scintigraphic and electrophysiological evidence of reinnervation. Conclusions are that 1) MIBG can be used noninvasively to determine the presence of regional myocardial efferent sympathetic denervation and subsequent reinnervation, 2) reinnervation occurs after phenol application or transmural myocardial infarction, and 3) denervation supersensitivity persists even after reinnervation occurs.