AJP - Heart Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 283: H2606-H2611, 2002; doi:10.1152/ajpheart.00156.2002
0363-6135/02 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cai, J. J.
Right arrow Articles by Lee, H.-C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cai, J. J.
Right arrow Articles by Lee, H.-C.
Vol. 283, Issue 6, H2606-H2611, December 2002

alpha 2-Adrenergic stimulation is protective against ischemia-reperfusion-induced ventricular arrhythmias in vivo

John J. Cai1, Donald A. Morgan1, William G. Haynes1, James B. Martins1, and Hon-Chi Lee2

1 Department of Internal Medicine, University of Iowa College of Medicine, and Veterans Administration Medical Center, Iowa City, Iowa 52242; and 2 Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We previously reported that alpha 2-adrenergic receptor (alpha 2-AR) stimulation in Purkinje fibers in vitro prolongs action potential duration and suppresses beta -adrenergic-induced delayed afterdepolarizations and sustained triggered activities. We examined the effects of alpha 2-AR stimulation on reperfusion-induced ventricular arrhythmias [ventricular tachycardia/ventricular fibrillation (VT/VF)] in vivo. Arterial blood pressure, heart rate, surface electrocardiogram, and renal sympathetic nerve activities were recorded simultaneously in Sprague-Dawley rats. The incidence of VT/VF was 87.5% for controls, 50% for the beta -blocker group, 72% for the alpha 1-blocker group, and 12.5% for the alpha 1 + beta -blockers group (unopposed alpha 2-adrenergic activation). Direct alpha 2-AR stimulation with UK-14304 also prevented VT/VF. These effects were reversed by the alpha 2-adrenergic antagonist yohimbine. Increases in renal sympathetic nerve activity were associated with left anterior descending coronary artery ligation and reperfusion (33 ± 1.5 and 62 ± 1.7% over baseline, respectively) in controls. Similar patterns were observed among all experimental groups irrespective of the incidence of VT/VF on reperfusion. We conclude that alpha 2-AR stimulation has a potent antiarrhythmic effect on ischemia-reperfusion-induced VT/VF in vivo and that this effect is not centrally mediated.

sympathetic nerve activities; ventricular tachycardia; ventricular fibrillation; Purkinje fibers


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

SUDDEN CARDIAC DEATH due to ventricular arrhythmias accounts for ~300,000-400,000 deaths each year in this country (24, 33). In the adult population, ischemic heart disease represents the most common substrate underlying such devastating events (11, 33). During the early hours of acute coronary occlusion, intense adrenergic activation of the ischemic myocardium may contribute to the evolution of abnormal cellular electrical behavior and, ultimately, result in lethal ventricular arrhythmias, ventricular tachycardia (VT) or ventricular fibrillation (VF) (9, 16).

Until recently, postjunctional alpha 2-adrenergic receptors (ARs) were thought not to be present in the heart. We found that postjunctional alpha 2-ARs are present in canine cardiac Purkinje fibers but not in working myocardium (18, 26). alpha 2-AR stimulation prolongs the action potential duration and suppresses the beta -adrenergic stimulation-induced delayed afterdepolarizations and sustained triggered activities in isolated canine Purkinje fibers in vitro (26). These alpha 2-AR effects were abolished after incubation of the Purkinje fibers with pertussis toxin (PTX), suggesting that the alpha 2-AR effects were mediated through a PTX-sensitive G protein, Gi (26, 28). With the use of a Langendorff rat heart model, alpha 2-AR stimulation was indeed protective against ischemia-reperfusion-induced VT/VF (8). In addition, the cardiac Purkinje system has long been suspected of being an important site of origin for ventricular arrhythmias occurring during early ischemia (15). This contention is supported by a recent study showing that the alpha 2-adrenergic agonist UK-14304 suppresses ischemia-induced focal VT originating from the Purkinje fibers in intact dog hearts (3).

This study tests the hypothesis that alpha 2-adrenergic stimulation prevents ischemia-reperfusion-induced VT/VF in vivo and that such effects are not centrally mediated.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animal preparations. A modified method of Manning et al. (21) and Brooks et al. (5, 6) was used to assess the antiarrhythmic effect of alpha 2-AR stimulation on ischemia-reperfusion-induced VT/VF. All procedures were approved by the University of Iowa Animal Care and Use Committee. Male or female Sprague-Dawley rats (350-500 g body wt) were anesthetized with methohexital sodium (Brevital, 50 mg/kg ip). A section of PE-50 tubing was inserted into the femoral artery for hemodynamic monitoring, and another section of PE-50 tubing was inserted into the femoral vein for infusion of drugs and maintenance of anesthesia with chloralose (50 mg/kg initially, then 25 mg · kg-1 · h-1). Animals were intubated with mechanical ventilation, and arterial blood gas values were checked to ensure that the animals were appropriately ventilated, and the arterial pH was maintained between 7.35 and 7.45 with PO2 >80 mmHg. Surface electrocardiogram was obtained through minigrip leads on shaven skin. A rectal thermistor was inserted for monitoring core temperature, which was maintained at 37.5°C with a heating pad.

Renal sympathetic nerve activity recordings. Renal sympathetic nerve activity (RSNA) recording is an established method for measuring sympathetic discharge during physiological and pathological conditions (12, 23) and was performed as previously described (12). Specifically, the left renal sympathetic nerve was exposed retroperitoneally through a left flank incision. Under a dissection microscope, a nerve branch of the left kidney was carefully dissected free of surrounding tissue, and a bipolar platinum-iridium electrode (Cooner Wire, Chatsworth, CA) was applied to the nerve. In all studies, the nerve was transected distally to exclude renal afferent signals. Nerve recording electrodes were connected to a high-impedance probe (model HIP-511, Grass Instrument, Quincy, MA), amplified by 105, and filtered at low- and high-frequency cutoffs of 100 and 1,000 Hz with a nerve traffic analysis system (model 662-C, Department of Bioengineering, University of Iowa). The filtered and amplified nerve signal was 1) displayed on an oscilloscope, 2) acquired through a MacLab analog-to-digital converter (AD Instruments, Grand Junction, CO) for permanent recording of the neurogram on a Macintosh 9500 computer, and 3) processed by a nerve traffic analyzer (model 706, Department of Bioengineering, University of Iowa), which counts the number of spikes exceeding a threshold cursor set just above background. RSNA was recorded throughout the experiment.

Left anterior descending coronary artery ligation and reperfusion. Animals were allowed to stabilize for 45-60 min after the recording system was established. A midsternotomy was performed, and the heart was exposed. A 6-0 silk suture was passed through the myocardium under the proximal portion of the left anterior descending coronary artery (LAD) ~1.5 mm distal to the ostium of the vessel. Temporary LAD occlusion was achieved by tightening the suture over the PE-50 tubing for 10 min. Discoloration of the ischemic area compared with the rest of the myocardium indicated successful LAD occlusion (21). Reperfusion was achieved by releasing the suture after a 10-min ligation. Diluted Evans blue dye was injected to determine whether there was permanent myocardial damage at the end of the experiment. No permanent necrosis of the myocardium was found from the 10-min LAD ligation.

Evaluation of rhythm disturbances. The incidence of ventricular extrasystole (VES), VT, and VF was continuously recorded for >= 10 min after reperfusion. VES, VT, and VF were defined according to the Lambeth convention criteria (30) with more stringent modifications. Specifically, VES was defined as ventricular contraction without atrial depolarization. VT was defined as more than six consecutive VESs. VF was characterized by a loss of synchronicity of electrocardiogram plus decreased amplitude and a precipitous fall in blood pressure (BP) for >1 s.

Study protocols. All drugs were infused through the femoral vein ~5 min before LAD ligation. Protocol 1 consisted of five experimental groups: 1) the control group was studied with normal saline injection, 2) the beta -blocker group was treated with the nonselective beta -blocker propranolol (1 mg/kg), 3) the alpha 1-blocker group was treated with prazosin (0.2 mg/kg), 4) the beta  + alpha 1-blockers group (unopposed endogenous alpha 2-adrenergic stimulation) was established by using propranolol (1 mg/kg) and prazosin (0.2 mg/kg), and 5) the beta  + alpha 1 + alpha 2-blockers group (establishing the reversibility of the endogenous alpha 2-adrenergic stimulation) was treated with propranolol (1 mg/kg), prazosin (0.2 mg/kg), and the alpha 2-adrenergic-specific blocker yohimbine (0.03 mg/kg).

Protocol 2 was carried out by directly stimulating alpha 2-AR with UK-14304 (0.03 mg/kg), and the alpha 2-AR specificity was established by reversing the effect with addition of yohimbine. After the drug treatments, animals were subjected to 10 min of LAD ligation followed by reperfusion.

Statistical analysis. Eight determinations were obtained for each experimental protocol. Group data are expressed as means ± SE. Comparisons between the different hemodynamic measurements and the incidence of ischemia-reperfusion-induced VT/VF among the groups were performed by one-way analysis of variance and a mixed-model analysis for repeated measures. Pairwise comparisons among the groups were performed using post hoc tests, and the P values were adjusted using Bonferroni's method to account for the multiple tests performed. Bonferroni-adjusted P < 0.05 was considered statistically significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Hemodynamic parameters. Table 1 summarizes the hemodynamic data of all study groups at baseline and during LAD ligation. There were no statistical differences in heart rate (HR) and mean arterial blood pressure (MBP) among the groups at baseline. HR decreased significantly during ischemia only in the beta -blocker (propranolol) group compared with its baseline (341 ± 11.4 vs. 308 ± 7.6, n = 8, P = 0.027). During LAD ligation, significant decreases in MBP from baseline were found in controls (P = 0.007) and in the beta  + alpha 1-blockers group (propranolol + prazosin, P = 0.011) but not in the other groups. However, there were no statistical differences in MBP among all treatment groups (P > 0.7).

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Hemodynamic effects of drug interventions

Effects of unopposed endogenous alpha 2-adrenergic stimulation on the incidence of reperfusion-induced ventricular arrhythmias and RSNA. Figure 1 shows representative recordings from the experiments. During a control experiment (Fig. 1A), there was a decrease in BP associated with LAD ligation. On reperfusion, the heart developed polymorphic VT and rapidly deteriorated into sustained VF with loss of BP. There was an increase in RSNA during LAD ligation and an additional increase during reperfusion. In the presence of beta  + alpha 1-blockers (Fig. 1B), there was a similar decrease in BP during LAD ligation, as in controls. However, VT/VF did not occur on reperfusion, suggesting that endogenous alpha 2-adrenergic stimulation is protective against ischemia-reperfusion-induced VT/VF. The RSNA changes in the beta  + alpha 1-blockers group were also similar to the control, with an increase in activity during LAD ligation and a further increase during reperfusion.


View larger version (28K):
[in this window]
[in a new window]
  		Fig. 1.   Representative traces from typical experiments. A: control experiment. B: experiment with alpha 2-adrenergic stimulation. ECG, surface electrocardiogram; BP, blood pressure; RSNA, renal sympathetic nerve activity. There was a decrease in BP associated with left anterior descending coronary artery (LAD) ligation in control and alpha 2-adrenergic stimulation groups. On reperfusion, the control animal developed polymorphic ventricular tachycardia (VT), which quickly deteriorated to ventricular fibrillation (VF) with loss of BP (A). There was no reperfusion-induced VT/VF with alpha 2-adrenergic stimulation (treatment with beta  + alpha 1-blockers; B). There were similar increases in RSNA during LAD ligation and during reperfusion in both groups.

Figure 2 shows the incidence of ischemia-reperfusion-induced VT/VF. The incidence of VT/VF was 87.5% for controls, indicating that, under control conditions, short periods of LAD occlusion with reperfusion resulted in a high incidence of lethal ventricular arrhythmias in these animals. The incidence of VT/VF was 50% for the beta -blocker group, suggesting that beta -adrenergic blockade may have antiarrhythmic effects, but the difference did not reach statistical significance. alpha 1-Adrenergic blockers had no apparent protective effect, with 72% incidence of VT/VF. However, there was only 12.5% VT/VF in the beta  + alpha 1-blockers group (P < 0.05 vs. control). This effect was completely reversed by addition of the alpha 2-adrenergic-specific antagonist yohimbine, suggesting a specific alpha 2-adrenergic-mediated effect.


View larger version (40K):
[in this window]
[in a new window]
  		Fig. 2.   Incidence of reperfusion-induced ventricular arrhythmias (VT/VF) in protocol 1: 87.5% for controls, 50% for beta -blocker group, 72% for alpha 1-blocker group, and 12.5% for beta  + alpha 1-blockers [unopposed alpha 2-adrenergic receptor (AR) stimulation] group. The beta  + alpha 1-blockade effect was completely reversed by addition of the alpha 2-adrenergic receptor (alpha -AR) antagonist yohimbine and beta  + alpha 1 + alpha 2-blockers (n = 8 for all groups). * P < 0.05 vs. control. ** P < 0.05 vs. beta  + alpha 1-blockers.

Figure 3 summarizes the RSNA at baseline, during LAD ligation, and during reperfusion for protocol 1. All groups showed an increase in RSNA during LAD ligation, with further increase in activity on reperfusion. Although not statistically significant, the beta -blocker group and the beta  + alpha 1-blockers group (unopposed alpha 2-adrenergic effect) appeared to have blunted RSNA during LAD ligation and during reperfusion compared with the other treatment groups. These two groups also had the lowest incidence of ischemia-reperfusion-induced VT/VF. The incidence of VT/VF, however, was significantly reduced in the beta  + alpha 1-blockers group but not in the beta -blocker group, suggesting that unopposed alpha 2-adrenergic stimulation is protective. On the basis of these experiments, we were still unable to determine whether this alpha 2-adrenergic effect is centrally or locally mediated. Hence, we performed the experiments in protocol 2 using direct alpha 2-adrenergic stimulation and blockade.


View larger version (41K):
[in this window]
[in a new window]
  		Fig. 3.   RSNA in protocol 1 at baseline, during LAD ligation, and on reperfusion. RSNA increased during LAD ligation, with additional increase on reperfusion in all groups (n = 8). No RSNA values in treatment groups were significantly different from controls. * P < 0.05 vs. baseline.

Effects of direct alpha 2-adrenergic stimulation on ischemia-reperfusion-induced VT/VF. Pretreatment with the alpha 2-adrenergic agonist UK-14304 resulted in a slight increase in HR but not in MBP, and these changes were not altered by the addition of yohimbine. Also, after treatment with UK-14304, alone or with yohimbine, there was no significant decrease in BP during LAD ligation. Rather dramatically, after treatment with UK-14304, reperfusion could no longer induce VT/VF in these animals. Furthermore, the protective effects of UK-14304 were reversed by the addition of yohimbine (0% incidence of VT/VF for UK-14304 vs. 87.5% for UK-14304 + yohimbine, n = 8, P < 0.05; Fig. 4). The RSNA patterns, however, were similar between UK-14304 (114 ± 4.2% over baseline during LAD ligation and 129 ± 11% during reperfusion) and UK-14304 + yohimbine (112 ± 3% during LAD ligation and 134 ± 8% during reperfusion, n = 8; Fig. 5). Similar to the treatments with unopposed endogenous alpha 2-AR effects (beta  + alpha 1-blockers, Fig. 3), UK-14304 appeared to have blunted the RSNA during LAD ligation and during reperfusion, but these changes were not statistically significant. In addition, when the results of reperfusion-induced VT/VF (Fig. 4) were compared with the corresponding RSNA (Fig. 5), there was no correlation between the centrally mediated sympathetic activity and the incidence of VT/VF. These results suggest that the antiarrhythmic effect of alpha 2-adrenergic stimulation is not centrally mediated.


View larger version (26K):
[in this window]
[in a new window]
  		Fig. 4.   Incidence of ischemia-reperfusion-induced ventricular arrhythmias (VT/VF) in protocol 2. Incidence of ischemia-reperfusion induced VT/VF and effect of direct alpha 2-adrenergic stimulation by UK-14304 (UK) are shown with and without yohimbine (YO). * P < 0.05 vs. control (n = 8).



View larger version (26K):
[in this window]
[in a new window]
  		Fig. 5.   RSNA in protocol 2 at baseline, during LAD ligation, and during reperfusion. RSNA was very similar between UK-14304 and UK-14304 + yohimbine. RSNA was not significantly different among all groups (n = 8 for all groups). * P < 0.05 vs. baseline.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We have made the following novel observations. First, we found that alpha 2-adrenergic stimulation was protective against ischemia-reperfusion-induced VT/VF in open-chest anesthetized rats induced with 10 min of LAD ligation followed by reperfusion. This protective alpha 2-adrenergic effect was blocked by the alpha 2-AR-specific antagonist yohimbine. Second, we found that the antiarrhythmic effect of alpha 2-adrenergic stimulation was independent of sympathetic discharge measured by RSNA, suggesting that the alpha 2-adrenergic effects were not centrally mediated. We also found that sympathetic activities increased with coronary ligation, and we observed an additional increase during reperfusion. This pattern of sympathetic activity changes was observed in all treatment groups with various adrenergic blockades. Only the groups with alpha 2-adrenergic stimulation, both endogenously with beta  + alpha 1-blockade and exogenously through direct infusion of UK-14304, showed significant reduction in ischemia-reperfusion-induced VT/VF.

The results of this study are consistent with our previously published in vitro studies suggesting that alpha 2-adrenergic stimulation has potent antiarrhythmic effects (8, 18, 26, 28). Increased intracellular cAMP has been implied to cause arrhythmias under ischemia and reperfusion (20). In isolated canine Purkinje fibers in vitro, we have demonstrated that the alpha 2-adrenergic effects on Purkinje action potential were mediated through a PTX-sensitive G protein, Gi (26, 28), which is known to inhibit adenylate cyclase activity, thereby counteracting the beta -adrenergic stimulation on cAMP production. Electrophysiologically, alpha 2-adrenergic stimulation prolongs the action potential duration and suppresses the beta -adrenergic stimulation-induced delayed afterdepolarizations and sustained triggered activities in canine Purkinje fibers (26). The present study not only corroborated the in vitro findings but also brought new insight to our understanding of the ischemia-reperfusion-induced ventricular arrhythmia mechanism in vivo. This study is unique, in that we incorporated RSNA recordings in the study of ischemia-reperfusion-induced arrhythmias.

The relationship between sympathetic activities and VF has long been debated (27). Ischemia-reperfusion is known to cause sympathetic activation, resulting in elevated systemic catecholamine levels (22, 31), and is associated with a decrease in the VF threshold (19). Catecholamine levels are frequently measured during ischemia in arrhythmia-related studies (19, 22, 31). Some of the animal studies dismissed the effect of central nervous system activation as the main culprit for reperfusion-induced arrhythmia (20), and the important role of sympathetic activation in VF was strongly implicated in other studies (19, 27, 31). Our study showed that the beta -blocker and the beta  + alpha 1-blockers (unopposed alpha 2-AR stimulation) groups had the lowest incidence of reperfusion-induced VT/VF, and both also had blunted RSNA compared with the controls and the other experimental groups (Figs. 2 and 3). This observation suggests that sympathetic activation may well be a determinant in ischemia-reperfusion-induced VT/VF. Although there are ample clinical data suggesting a protective role of beta -adrenergic blockade on sudden cardiac death in patients with ischemic heart disease (13, 14), this study was not adequately powered to detect a significant effect of these agents on ischemia-reperfusion arrhythmias. beta -Adrenergic blockade may serve to blunt the sympathetic activity in the development of VT/VF. Hence, beta -adrenergic blockade plus unopposed alpha 2-adrenergic stimulation could have an even more significant antiarrhythmic effect, because the generation of cAMP would be reduced through reduced stimulation at the receptor level and the inhibition of adenylate cyclase at the intracellular level. However, the results of protocol 2 indicated that direct alpha 2-adrenergic stimulation alone, without simultaneous beta -blockade, not only is adequate and effective but is also significantly more potent than beta -blocker alone in preventing the development of ischemia-reperfusion-induced VT/VF (Fig. 4). More importantly, our data also indicated that the protective alpha 2-adrenergic effects were independent of sympathetic nerve activities as measured by RSNA profiles (Figs. 3 and 5). These important findings prompted us to speculate that the alpha 2-adrenergic protective effect might be mediated through the alpha 2-ARs in the Purkinje fibers in the heart. Our findings have significant clinical implications, inasmuch as alpha 2-adrenergic agonists are not used for the treatment of ischemia-related cardiac arrhythmias. This should be further explored in the clinical arena.

Research and clinical data have supported and confirmed unequivocally the beneficial effects of beta -blocker in patients with ischemic heart disease and in the prevention of sudden cardiac death (13, 14). In contrast, the effects of alpha 1-adrenergic blockade on the development of ventricular arrhythmias are unclear. The predominant effect of alpha 1-adrenergic blockade is vasodilatation, which may result in reflex tachycardia and may further activate the sympathetic system (17). However, recent studies suggested that stimulation of the alpha 1-AR activates the second messenger inositol trisphosphate, which appears to be arrhythmogenic during ischemia-reperfusion, suggesting that alpha 1-adrenergic blockade could be beneficial for control of arrhythmia (32). Our data did not substantiate such an effect in vivo, because there was no statistically significant effect of prazosin on ischemia-reperfusion-induced VT/VF (72% vs. 87.5% in controls). There are only limited data on alpha 2-adrenergic effects on ischemia-reperfusion-induced arrhythmia in vivo (3). In intact dogs, stimulation of alpha 2-ARs prolongs the Purkinje relative refractory period (7) and selectively prevents ischemia- and pacing-induced VT of focal Purkinje fiber (3).

The primary limitation of this study is that we were unable to delineate that the antiarrhythmic alpha 2-adrenergic effects are dependent on the alpha 2-AR in cardiac Purkinje fibers. We were not able to directly assess the origin of the ventricular arrhythmias in our model. However, the Purkinje system has long been suspected to be the site of origin of ventricular arrhythmias during acute ischemia (2, 3, 15), and our previously published canine in vitro data showed that alpha 2-ARs are present only in Purkinje fibers (18, 26, 28). We would speculate that the noncentrally mediated alpha 2-adrenergic antiarrhythmic effect could well be a result of the action on the cardiac Purkinje fibers.

We have not been able to establish the presence of alpha 2-ARs in human Purkinje fibers because of limited tissue availability, inasmuch as the only source for human Purkinje fibers is explanted hearts from cardiac transplantation. Further studies are needed to demonstrate the presence of alpha 2-ARs and to identify the alpha 2-AR subtypes in human Purkinje fibers, and these results may help us determine whether the proposed mechanism is relevant to human ischemia-reperfusion-induced arrhythmia. Interestingly, clinical trials have shown that carvedilol, a third-generation beta -blocker that also has an alpha 1-AR blockade effect, provides significant additional benefits for prevention of cardiac sudden death in patients with heart failure and ischemic heart disease (1, 4, 10, 25). A recent animal study by Takusagawa et al. (29) also showed clear beneficial effects of carvedilol on ischemia-reperfusion-induced ventricular arrhythmia over the beta -blocker alone. Our study may provide an alternative explanation that the beneficial effects of carvedilol could be from its unopposed alpha 2-adrenergic stimulation effects.

In conclusion, the results of our study suggest that alpha 2-adrenergic stimulation has a potent antiarrhythmic effect on ischemia-reperfusion-induced VT/VF in vivo and that this effect is not mediated through the alpha 2-adrenergic effects at presynaptic sites.


    ACKNOWLEDGEMENTS

Statistical analysis was performed by Dr. Bridget Zimmerman (Biostatistics Consulting Center, Department of Biostatistics, College of Public Health, University of Iowa).


    FOOTNOTES

J. J. Cai is a recipient of the 2000 North American Society Pacing and Electrophysiology Fellowship Award. This work was supported in part by National Heart, Lung, and Blood Institute Grant R01 HL-63754, a Merit Award from the Department of Veterans Affairs, and American Heart Association Grant-in-Aid 0051311Z.

Address for reprint requests and other correspondence: J. J. Cai, Div. of Cardiac Electrophysiology, Loyola University Medical Center, 2160 South First Ave., Maywood, IL 60153 (E-mail: jcai{at}lumc.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

10.1152/ajpheart.00156.2002

Received 4 March 2002; accepted in final form 1 August 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Anonymous Effects of carvedilol, a vasodilator beta -blocker, in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group. Circulation 92: 212-218, 1995[Abstract/Free Full Text].

2.   Arnar, DO, Bullinga JR, and Martins JB. Role of the Purkinje system in spontaneous ventricular tachycardia during acute ischemia in a canine model. Circulation 96: 2421-2429, 1997[Abstract/Free Full Text].

3.   Arnar, DO, Xing D, Lee H, and Martins JB. Prevention of ischemic ventricular tachycardia of Purkinje origin: role for alpha 2-adrenoceptors in Purkinje? Am J Physiol Heart Circ Physiol 280: H1182-H1190, 2001[Abstract/Free Full Text].

4.   Basu, S, Senior R, Raval U, van der Does R, Bruckner T, and Lahiri A. Beneficial effects of intravenous and oral carvedilol treatment in acute myocardial infarction: a placebo-controlled, randomized trial. Circulation 96: 183-191, 1997[Abstract/Free Full Text].

5.   Brooks, RR, Carpenter JF, Miller KE, and Maynard AE. Efficacy of the class III antiarrhythmic agent azimilide in rodent models of ventricular arrhythmia. Proc Soc Exp Biol Med 212: 84-93, 1996[Abstract].

6.   Brooks, RR, Miller KE, Carpenter JF, and Jones SM. Broad sensitivity of rodent arrhythmia models to class I, II, III, and IV antiarrhythmic agents. Proc Soc Exp Biol Med 191: 201-209, 1989[Abstract].

7.   Cable, DG, Rath TE, Dreyer ER, and Martins JB. Refractory period response of cardiac Purkinje tissue to alpha 1- and alpha 2-adrenergic influences. Am J Physiol Heart Circ Physiol 267: H376-H382, 1994[Abstract/Free Full Text].

8.   Cai, JJ, Caldon JJ, Henderson AR, and Nyhof RA. Effect of alpha 2-adrenergic receptor on reperfusion-induced cardiac arrhythmia and coronary flow (Abstract). FASEB J 13: A761, 1999.

9.   Corr, PB, and Gillis RA. Autonomic neural influences on the dysrhythmias resulting from myocardial infarction. Circ Res 43: 1-9, 1978[Free Full Text].

10.   Freedman, SB, Jamal SM, Harris PJ, and Kelly DT. Comparison of carvedilol and atenolol for angina pectoris. Am J Cardiol 60: 499-502, 1987[ISI][Medline].

11.   Gillum, RF. Sudden coronary death in the United States: 1980-1985. Circulation 79: 756-765, 1989[Abstract/Free Full Text].

12.   Haynes, WG, Morgan DA, Walsh SA, Mark AL, and Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 100: 270-278, 1997[ISI][Medline].

13.   Herlitz, J, Hjalmarson A, Swedberg K, Waagstein F, Holmberg S, and Waldenstrom J. Relationship between infarct size and incidence of severe ventricular arrhythmias in a double-blind trial with metoprolol in acute myocardial infarction. Int J Cardiol 6: 47-60, 1984[ISI][Medline].

14.   Hjalmarson, A, Elmfeldt D, Herlitz J, Holmberg S, Malek I, Nyberg G, Ryden L, Swedberg K, Vedin A, Waagstein F, Waldenstrom A, Waldenstrom J, Wedel H, Wilhelmsen L, and Wilhelmsson C. Effect on mortality of metoprolol in acute myocardial infarction: a double-blind randomized trial. Lancet 2: 823-827, 1981[ISI][Medline].

15.   Janse, MJ, Kleber AG, Capucci A, Coronel R, and Wilms-Schopman F. Electrophysiological basis for arrhythmias caused by acute ischemia: role of the subendocardium. J Mol Cell Cardiol 18: 339-355, 1986[ISI][Medline].

16.   Kuller, L, Lilienfeld A, and Fisher R. Epidemiological study of sudden and unexpected deaths due to arteriosclerotic heart disease. Circulation 34: 1056-1068, 1966[Abstract/Free Full Text].

17.   Lee, H, and Martins JB. alpha -Adrenergic receptors and cardiac arrhythmias. In: Cardiac Arrhythmia: Mechanism, Diagnosis and Management, edited by Podrid PJ, and Kowey PR.. Baltimore, MD: Williams & Wilkins, 1995, p. 181-195.

18.   Lee, H, Samson RA, and Cai JJ. alpha 2-Adrenergic receptor binding in canine Purkinje fibers. FEBS Lett 380: 39-43, 1996[ISI][Medline].

19.   Lombardi, F, Verrier RL, and Lown B. Relationship between sympathetic neural activity, coronary dynamics, and vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion. Am Heart J 105: 958-965, 1983[ISI][Medline].

20.   Lubbe, WF, Podzuweit T, and Opie LH. Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: implications for prophylactic effects of beta -blockers in myocardial infarction and proarrhythmic effects of phosphodiesterase inhibitors. J Am Coll Cardiol 19: 1622-1633, 1992[Abstract].

21.   Manning, AS, Coltart DJ, and Hearse DJ. Ischemia- and reperfusion-induced arrhythmias in the rat: effects of xanthine oxidase inhibition with allopurinol. Circ Res 55: 545-548, 1984[Abstract/Free Full Text].

22.   Meredith, IT, Broughton A, Jennings GL, and Esler MD. Evidence of a selective increase in cardiac sympathetic activity in patients with sustained ventricular arrhythmias. N Engl J Med 325: 618-624, 1991[Abstract].

23.   Morgan, DA, Balon TW, Ginsberg BH, and Mark AL. Nonuniform regional sympathetic nerve responses to hyperinsulinemia in rats. Am J Physiol Regul Integr Comp Physiol 264: R423-R427, 1993[Abstract/Free Full Text].

24.   Myerburg, RJ, Kessler KM, and Castellanos A. Sudden cardiac death: epidemiology, transient risk, and intervention assessment. Ann Intern Med 119: 1187-1197, 1993[Abstract/Free Full Text].

25.   Packer, M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, and Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure: US Carvedilol Heart Failure Study Group. N Engl J Med 334: 1349-1355, 1996[Abstract/Free Full Text].

26.   Samson, RA, Cai JJ, Shibata EF, Martins JB, and Lee H. Electrophysiological effects of alpha 2-adrenergic stimulation in canine cardiac Purkinje fibers. Am J Physiol Heart Circ Physiol 268: H2024-H2035, 1995[Abstract/Free Full Text].

27.   Schwartz, PJ, and Zipes DP. Autonomic modulation of cardiac arrhythmias and sudden cardiac death. In: Cardiac Electrophysiology: From Call to Bedside (3rd ed.), edited by Zipes DP, and Jalife J.. Philadelphia, PA: Saunders, 2000, p. 300-314.

28.   Stephenson, RS, Cai JJ, Drews TA, and Lee H. Effect of alpha 2-adrenoceptor stimulation on isolated canine Purkinje fiber contraction. Eur J Pharmacol 345: 261-267, 1998[ISI][Medline].

29.   Takusagawa, M, Komori S, Matsumura K, Osada M, Kohno I, Umetani K, Ishihara T, Sawanobori T, Ijiri H, and Tamura K. The inhibitory effects of carvedilol against arrhythmias induced by coronary reperfusion in anesthetized rats. J Cardiovasc Pharmacol Ther 5: 105-112, 2000[Medline].

30.   Walker, MJ, Curtis MJ, Hearse DJ, Campbell RW, Janse MJ, Yellon DM, Cobbe SM, Coker SJ, Harness JB, and Harron DW. The Lambeth conventions: guidelines for the study of arrhythmias in ischaemia, infarction, and reperfusion. Cardiovasc Res 22: 447-455, 1988[ISI][Medline].

31.   Williams, FM, Rochette L, Kane KA, and Parratt JR. Effects of alterations in sympathetic nervous activity on the severity of reperfusion-induced arrhythmias in anaesthetized rats. J Cardiovasc Pharmacol 10: 555-561, 1987[ISI][Medline].

32.   Woodcock, EA, Arthur JF, and Matkovich SJ. Inositol 1,4,5-trisphosphate and reperfusion arrhythmias. Clin Exp Pharmacol Physiol 27: 734-737, 2000[ISI][Medline].

33.   Zipes, DP, and Wellens HJ. Sudden cardiac death. Circulation 98: 2334-2351, 1998[Free Full Text].

Am J Physiol Heart Circ Physiol 283(6):H2606-H2611



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cai, J. J.
Right arrow Articles by Lee, H.-C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cai, J. J.
Right arrow Articles by Lee, H.-C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online