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(Circulation. 1995;91:2712-2716.)
© 1995 American Heart Association, Inc.

Articles

Suppression of Ventricular Arrhythmias During Ischemia-Reperfusion by Agents Inhibiting Ins(1,4,5)P₃ Release

Xiao-Jun Du, MB, PhD; Karen E. Anderson, BSc; Alexander Jacobsen, BSc, MBBS; Elizabeth A. Woodcock, PhD; Anthony M. Dart, MRCP, PhD

From the Alfred and Baker Medical Unit and Cellular Biochemistry Laboratory, Alfred Hospital and Baker Medical Research Institute, Melbourne, Australia.

Correspondence to Dr Anthony Dart, Alfred and Baker Medical Unit, Baker Medical Research Institute, Commercial Rd, Prahran (Melbourne), Victoria 3181, Australia.

	Abstract

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Background Reperfusion following myocardial ischemia causes a rapid and transient release of inositol (1,4,5)triphosphate [Ins(1,4,5)P₃]. The aim of this study was to test whether this increased Ins(1,4,5)P₃ release was important for the development of ventricular arrhythmias and whether agents that inhibit this signal transduction pathway, such as aminoglycoside antibiotics, suppress arrhythmias.

Methods and Results In perfused rat hearts, ventricular tachycardia (VT), ventricular fibrillation (VF), and accumulation of Ins(1,4,5)P₃ were measured during early reperfusion. A number of different compounds, including neomycin, gentamicin, streptomycin, spermine, reserpine, and prazosin, were effective in inhibiting the reperfusion-induced Ins(1,4,5)P₃ release and the onset of VT and VF in parallel. A strong correlation existed between Ins(1,4,5)P₃ content, measured at 2 minutes of reperfusion, and the incidence of reperfusion VT and VF. In addition, intravenous gentamicin suppressed the onset of arrhythmias under ischemic and reperfusion conditions in vivo.

Conclusions Our results are consistent with the view that Ins(1,4,5)P₃ release plays a pivotal role in mediating arrhythmias during early reperfusion. Agents inhibiting Ins(1,4,5)P₃ release are antiarrhythmic and may have potential use clinically.

Key Words: arrhythmia • ischemia • reperfusion

	Introduction

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In cardiac tissue, inositol (1,4,5)triphosphate [Ins(1,4,5)P₃] has been shown to cause a slow release of Ca²⁺, which is associated with activation of Na⁺-Ca²⁺ exchange and Ca²⁺ oscillation.^{1 2} Activation of ₁-adrenoceptors was demonstrated during postischemic reperfusion,³ and recently an enhanced release of Ins(1,4,5)P₃ was also shown to occur.⁴ Oscillations of intracellular Ca²⁺ are known to be arrhythmogenic.⁵ These findings raise the possibility that release of Ins(1,4,5)P₃ might initiate and facilitate arrhythmias and thus that inhibition of this release might prove to be antiarrhythmic. Aminoglycoside antibiotics and spermine were shown to inhibit Ins(1,4,5)P₃ release by binding to its precursor phosphatidylinositol (4,5)biphosphate in many tissues,^{6 7 8} and we recently reported an enhanced potency of neomycin in inhibiting Ins(1,4,5)P₃ release under conditions of postischemia reperfusion.⁴ However, no studies have tested whether other aminoglycosides have similar inhibitory effects on Ins(1,4,5)P₃ release during reperfusion or on whether such interventions are antiarrhythmic.

Thus, the present study was undertaken to examine the effects of aminoglycosides neomycin, gentamicin, streptomycin, and spermine on reperfusion-induced ventricular arrhythmias and Ins(1,4,5)P₃ release in perfused rat hearts. To evaluate the potential significance of these findings, the antiarrhythmic activity of gentamicin was further investigated in intact animals.

	Methods

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Animals and Agents
Male Sprague-Dawley rats (200 to 350 g) were anesthetized with pentobarbital (60 mg/kg IP) when required. The following agents were used: neomycin (Alfred Hospital pharmacy), gentamicin (Delta West), streptomycin (Servipharm), propranolol (Sigma Chemical Co.), lithium chloride (LiCl, Sigma), reserpine (Sigma), prazosin (Pfizer), spermine (Calbiochem), staurosporine (Boehringer Mannheim), and assay kits for Ins(1,4,5)P₃ measurement (Amersham).

Mass Analysis of Ins(1,4,5)P₃ in Isolated Perfused Hearts
The methods used to measure the myocardial content of Ins(1,4,5)P₃ were as described previously in detail.⁴ In brief, isolated hearts were perfused through the aorta at 5 mL · g^-1 · min^-1 with HEPES-buffered Krebs' medium (37°C) according to the Langendorff procedure. The medium contained (mmol/L) Na⁺ 138, K⁺ 5.9, Ca²⁺ 2.0, Mg²⁺ 1.2, HCO₃^- 25, PO₄^3- 1.2, HEPES 20, and glucose 11 and was equilibrated with 95% O₂/5% CO₂ (pH 7.4). Global ischemia was produced when perfusion was stopped for 20 minutes, and reperfusion was produced when flow was reinitiated. Propranolol (1 µmol/L), LiCl (50 mmol/L with the concentration of Na⁺ reduced accordingly), and investigational agents were added to the medium 10 minutes before ischemia and maintained throughout the remainder of the ischemia-reperfusion protocol.⁴ We ended the experiment by freezing the heart in liquid nitrogen either immediately before reperfusion or 2 minutes after reperfusion. A reperfusion period of 2 minutes was chosen because our previous studies showed that the enhanced release of Ins(1,4,5)P₃ was maximal at this time.⁴ Ins(1,4,5)P₃ was extracted in 3.5 mL of 5% trichloroacetic acid containing 2.5 mmol/L EDTA and 5 mmol/L ATP, as previously described in detail.⁴ Ins(1,4,5)P₃ mass was measured with Amersham assay kits and expressed as picomoles per milligram of protein.⁴

Preparations and Protocols for Arrhythmia Experiments
Arrhythmia Experiments In Vitro
Experiments were performed in rat hearts perfused in situ at approximately 5 mL · g^-1 · min^-1 with Krebs-Henseleit solution at 37°C.⁹ The perfusate contained (mmol/L) Na⁺ 145, K⁺ 4.0, Ca²⁺ 1.85, Mg^2- 1.05, HCO₃^- 25, PO₄^3- 0.5, glucose 11, and EDTA 0.027 and was constantly gassed with O₂-CO₂ (95%-5%, pH 7.4). Regional ischemia was produced by occlusion of the left coronary artery about 3 mm from its origin with subsequent release to allow reperfusion. The perfusion flow rate was adjusted coincidently with coronary occlusion or reperfusion to maintain a constant perfusion pressure. Epicardial ECG, perfusion pressure, and in some preparations, left ventricular pressure were recorded on a Grass polygraph.⁹

In all experiments, drug or vehicle infusion was started 10 minutes before coronary occlusion and then was maintained throughout the remainder of the ischemia-reperfusion protocol. A 20-minute ischemic period was used, followed by a 5-minute reperfusion period. The ECG was monitored during the ischemic period and for 5 minutes after reperfusion to ensure that the development of arrhythmias was inhibited rather than postponed by the agents tested. Ventricular arrhythmias, ie, ventricular premature beats (VPB), tachycardia (VT), and fibrillation (VF), were measured during the 5-minute reperfusion period and defined and analyzed according to the guidelines of the Lambeth Conventions.¹⁰ All experiments were performed in the presence of propranolol (1 µmol/L) and LiCl (10 mmol/L). The incidence of ischemic VT and VF was reduced significantly by treatment with propranolol to 40% and 30%, respectively, compared with 80% and 75% in control group (both P<.05) but was unaffected by LiCl (70% and 60%, respectively). The incidence of reperfusion arrhythmias was unaffected by either single agent (100% and 86% versus 67% for VT; 72% and 71% versus 67% for VF) or a combination of agents. In view of the effect of propranolol on ischemic arrhythmias, analysis was limited to reperfusion for the in vitro experiments.

Arrhythmia Experiments In Vivo
An anesthetized, ventilated, and open-chest rat model was used to test the effect of gentamicin on ventricular arrhythmias during regional ischemia and reperfusion in vivo.¹¹ The right carotid artery was cannulated with a Millar microtipped transducer catheter to measure arterial blood pressure. A loose ligature was positioned around the left coronary artery for subsequent occlusion. The ischemic period was 10 minutes, followed by reperfusion for 5 minutes. We found 10 minutes to be the optimal ischemic period for the development of reperfusion arrhythmias in this model. Gentamicin infusion, at either 2.5 or 7.5 mg · kg^-1 · min^-1, began 10 minutes before the onset of ischemia and continued for the remainder of the experiment. In hearts without irreversible VF, the coronary artery was reoccluded at the end of the experiment, and the ischemic area was measured by a dye method and expressed as percentages of the total ventricular weight. Arrhythmias were defined and analyzed according to the Lambeth Conventions.¹⁰

Statistics
The ² test with Fisher's exact calculation was used to estimate the significance of differences in the incidence of VT and VF between control and drug-treated groups. Comparison for the difference in frequencies of VPB was performed by the Mann-Whitney test. The significance of differences for all other comparisons was determined with paired or unpaired Student's t test, with results presented as mean±SEM. The least-squares method was used for linear correlation and regression between mass content of Ins(1,4,5)P₃ and incidence of arrhythmias.

	Results

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Ins(1,4,5)P₃ Content in Perfused Hearts During Reperfusion
The mass content of Ins(1,4,5)P₃ in rat ventricles after 20 minutes of global ischemia was 103±18 pmol/mg protein (mean±SEM, n=4). This increased during 2 minutes of reperfusion with oxygenated medium to 207±11 pmol/mg (P<.01). The aminoglycosides neomycin, gentamicin, and streptomycin at concentrations of 0.015 to 5 mmol/L produced dose-dependent inhibition of the reperfusion-induced release of Ins(1,4,5)P₃. Spermine (5 mmol/L), reserpine (5 mg/kg by IP injection 18 hours before experimentation), and prazosin (10 µmol/L) also inhibited Ins(1,4,5)P₃ release at 2 minutes of reperfusion (Table 1).

View this table: [in this window] [in a new window]   Table 1. Effects of Inhibitors on the Incidence of Ventricular Arrhythmias During 5 Minutes of Reperfusion After 20 Minutes of Regional Ischemia in Hearts Perfused In Situ and on Mass Content of Ins(1,4,5)P3 Measured at 2 Minutes of Reperfusion After 20 Minutes of Global Ischemia in Isolated Perfused Rat Hearts

Reperfusion Arrhythmias in Perfused Hearts
There was no significant difference in the incidence of reperfusion arrhythmias between control groups from the different experiments; therefore, combined data from 64 control rats were used. All three aminoglycosides tested suppressed reperfusion VPB, VT, and VF in a dose-dependent manner (Table 1). Spermine 5 mmol/L was also antiarrhythmic. To further establish the role of norepinephrine and ₁-adrenoceptors in mediating reperfusion arrhythmias, other agents were tested. Interventions that depleted cardiac norepinephrine (reserpine) or blocked ₁-adrenoceptors (prazosin) also reduced the incidence of reperfusion arrhythmias (Table 1). On the other hand, staurosporine at a concentration known to be effective in inhibiting protein kinase C (PKC) in perfused rat hearts¹² did not inhibit reperfusion VT and VF, although the frequency of VPB was reduced. This indicates that the activation of PKC by 1,2-diacylglycerol released coincidently with Ins(1,4,5)P₃¹³ is not important in inducing severe reperfusion arrhythmias. All agents that inhibited Ins(1,4,5)P₃ release were also effective in suppressing reperfusion arrhythmias. A strong correlation was observed between tissue Ins(1,4,5)P₃ levels and the incidence of VPB, VT, and VF during reperfusion (Figure).

View larger version (11K): [in this window] [in a new window]   Figure 1. Graphs showing correlation between inositol (1,4,5)triphosphate [Ins(1,4,5)P3] content in the ventricles and the incidence of ventricular premature beats (VPB), ventricular tachycardia (VT), and ventricular fibrillation (VF) during reperfusion in perfused rat hearts subjected to 20 minutes of ischemia. Ins(1,4,5)P3 results (means of four measurements in each group) were obtained in isolated perfused hearts subjected to global ischemia, with Ins(1,4,5)P3 measured at 2 minutes of reperfusion. Arrhythmia experiments were performed in in situ perfused rat hearts subjected to regional ischemia with monitoring of arrhythmias during a 5-minute period of reperfusion. Table 1 also shows all the data.

Ischemic and Reperfusion Arrhythmias In Vivo
Coronary artery occlusion induced high incidences of ischemic VPB, VT, and VF in control rats that were reduced by intravenous gentamicin in a dose-dependent manner (Table 2). Sustained VF occurred in 30% of control rats but in only 10% and 0% of rats receiving gentamicin at 2.5 and 7.5 mg · kg^-1 · min^-1, respectively.

View this table: [in this window] [in a new window]   Table 2. Frequency of Ventricular Arrhythmias During a 10-Minute Period of Coronary Artery Occlusion and the Following 5-Minute Reperfusion Period in Anesthetized, Ventilated, and Open-Chest Rats In Vivo

In 13 control rats that did not have sustained VF, reperfusion was performed after 10 minutes of ischemia. All control rats developed VT, and 69% developed VF during early reperfusion. These reperfusion-mediated arrhythmias were inhibited by gentamicin at 7.5 mg · kg^-1 · min^-1 but not at 2.5 mg · kg^-1 · min^-1 (Table 2).

There was no significant difference between groups in the size of ischemic area as a percentage of total ventricular weight (38.1±1.5% and 38.0±3.3% versus 34.9±2.8%).

Effects of Aminoglycosides on Cardiovascular Function In Vitro and In Vivo
In in situ perfused hearts, heart rate (HR) was unchanged by aminoglycosides at concentrations <1 mmol/L but reduced at the high concentration (data not shown). The pressure developed by contraction of the left ventricle (LVDevP) did not differ between groups and was constant during the stabilizing period (between 30 and 50 mm Hg). At the end of the 10-minute infusion with gentamicin 1.5 mmol/L, LVDevP was reduced to 45±7% of pretreatment values. However, LVDevP was well maintained in hearts treated with gentamicin at two lower doses (110±6% and 96±3% of control, respectively). Neomycin and streptomycin produced very similar effects on LVDevP compared with gentamicin.

In intact rats, infusion of gentamicin 7.5 mg · kg^-1 · min^-1 for 10 minutes reduced HR (from 429±11 to 374±14 beats per minute [bpm], P<.05) and mean arterial pressure (MAP, from 120±4 to 92±7 mm Hg, P<.05). Infusion with gentamicin 2.5 mg · kg^-1 · min^-1 caused only mild reductions in HR and MAP (443±6 to 428±5 bpm and 113±2 to 100±3 mm Hg, both P<.05). At the end of 10 minutes of ischemia, HR remained significantly lower in treated rats compared with untreated rats only in the high-dose group (355±12 and 422±15 versus 439±11 bpm). MAP was lower in both treated groups compared with controls (79±5 and 81±5 versus 107±6 mm Hg, both P<.05).

	Discussion

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Previous in vitro experiments have shown that reperfusion after a period of global ischemia caused a rapid and transient release of Ins(1,4,5)P₃ in rat ventricles.⁴ This release depended on local release of norepinephrine and was mediated by ₁-adrenoceptors.⁴ In the current study, the importance of this pathway in initiating reperfusion arrhythmias was investigated by use of agents that inhibited this pathway at various stages. Agents that prevented release of norepinephrine or blocked ₁-adrenoceptors were shown to prevent reperfusion arrhythmias. In addition, the aminoglycosides neomycin, gentamicin, streptomycin, and spermine, which inhibited Ins(1,4,5)P₃ release, were effective antiarrhythmic agents. Such inhibitory effects of aminoglycosides on both Ins(1,4,5)P₃ release and arrhythmias were dose dependent. Most importantly, a high degree of correlation has been demonstrated between Ins(1,4,5)P₃ release and the incidence of VPB, VT, and VF during reperfusion. The correlation is surprisingly strong, considering the variability of arrhythmia indexes in this model and that the two parameters were obtained from independent experiments. Thus, these findings provide strong evidence that the release of Ins(1,4,5)P₃ is instrumental in initiating reperfusion arrhythmias under these conditions.

Gentamicin, the most effective agent in vitro, was also very effective in vivo in suppressing ischemic and reperfusion arrhythmias. It remains to be established whether the effect of gentamicin in vivo is also due to inhibition of Ins(1,4,5)P₃ release. While local norepinephrine release and -adrenoceptors are likely to be important in mediating arrhythmias in vivo,^{3 14 15 16} bloodborne factors, such as neutrophils or platelet-derived factors,^{17 18} are also likely to have important influences. Thus, ischemic and reperfusion arrhythmias in vivo may have more complex origins than those in our in vitro model. Furthermore, the degree of ischemia in vivo may not be uniform and thus may lead to differences in the pattern of inositol phosphate release. Studies currently under way in our laboratory demonstrate that while inositol phosphate content is decreased under conditions of global and severe ischemia, the response to norepinephrine remains intact under more moderate ischemic conditions. Thus, it is possible that under the less-defined conditions of ischemia in vivo, Ins(1,4,5)P₃ has a role in the development of arrhythmias during early ischemia and reperfusion. Studies by Anyukhovsky and coworkers¹⁹ showed a pivotal role of ₁-adrenoceptors in mediating the onset of "ischemic arrhythmias" in Purkinje fibers incubated under conditions of simulated moderate ischemia.

The intracellular events following Ins(1,4,5)P₃ release have not been examined in this study. In normoxic cardiac tissues, ₁-adrenergic stimulation has no proarrhythmic effect.^{3 19} ₁-Agonists, however, are arrhythmogenic in cardiac preparations exposed to ischemic (or hypoxic) and reperfusion conditions.^{3 19 20} The electrophysiological changes induced by ₁-stimulation include potentiated abnormal automaticity, enhanced afterdepolarizations and triggered activity, and prolonged action potential duration, which favors reentry.²¹ The intracellular events leading to these changes are most probably increased and oscillating levels of intracellular calcium.⁵ In most cell types, addition of Ins(1,4,5)P₃ causes a rapid and transient release of Ca²⁺.²² The heart is relatively insensitive to Ins(1,4,5)P₃, which causes a slow release of calcium.¹ However, Ins(1,4,5)P₃ was reported to enhance calcium oscillations in myocardial preparations.² Furthermore, while norepinephrine stimulation does not increase Ins(1,4,5)P₃ in normoxic hearts,²³ reperfusion is associated with marked stimulation.⁴ It is of interest that the sensitivity of Ins(1,4,5)P₃ receptors is enhanced under conditions of oxidizing stress or increased intracellular Ca²⁺,^{24 25 26} situations pertaining during ischemia-reperfusion.²⁷ This raises the possibility that in addition to enhanced Ins(1,4,5)P₃ release under reperfusion conditions, the response to Ins(1,4,5)P₃ is also potentiated. These speculations remain to be investigated.

The present study, together with other recent findings,⁴ provides evidence for a pivotal role of Ins(1,4,5)P₃ in the genesis of reperfusion arrhythmias and perhaps of ischemic arrhythmias in vivo. These findings potentially have important clinical implications because not only catecholamines but also other factors such as thrombin, angiotensin II, endothelin, and mechanical stretch^{28 29 30} stimulate Ins(1,4,5)P₃ formation in the heart, and many of these factors are found to be present under pathological conditions such as myocardial ischemia and reperfusion and heart failure. Agents that interfere with Ins(1,4,5)P₃ release may prove to be effective clinically, constituting a new approach in antiarrhythmic drug therapy.

	Acknowledgments

 
This study was supported by grants from the National Health and Medical Research Council, Australia, the Australian National Heart Foundation, and the Alfred Hospital Research Fund (Z9407). K.E.A. is the recipient of a Dora Lush biochemical postgraduate scholarship. A.J. is the recipient of a medical postgraduate scholarship from the National Heart Foundation.

Received February 9, 1995; revision received March 15, 1995; accepted March 27, 1995.

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