The herbal drug Catuama reverts and prevents ventricular fibrillation in the isolated rabbit heart

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ogy 40 (2007) 534.e1–534.e8www.jecgonline.com

Journal of Electrocardiol

The herbal drug Catuama reverts and prevents ventricular fibrillationin the isolated rabbit heart☆

Vera Pontieri, BSc, Augusto Scalabrini Neto, PhD, MD,⁎ André Ferrari de França Camargo, MD,Marcia Kiyomi Koike, PhD, BSc, Irineu Tadeu Velasco, PhD, MDEmergency Medicine Research Laboratory, Medical School of University of São Paulo, São Paulo, Brazil

Received 10 October 2006; accepted 11 June 2007

Abstract Introduction: Catuama, an herbal drug very popular in Brazil, was tested on the reversion and

☆ This research wEstado de São PauloUniversity of São Paufor providing all the h

⁎ CorrespondingSchool of UniversityTel.: +55 11 3085 712

E-mail address: au

0022-0736/$ – see frodoi:10.1016/j.jelectroc

prevention of ventricular fibrillation (VF) in the isolated rabbit heart.Materials and Methods: Catuama (a mixture of Trichilia catigua, Paullinia cupana, Ptychopeta-lum olacoides, and Zinziber officinalis) was perfused in the isolated perfused rabbit heart. Its effectson intraventricular conduction, heart rate, and monophasic action potential (MAP) duration wereevaluated, and sustained VF was induced. The effects on reversion and reinduction of arrhythmiawere observed, and new measures were taken in the hearts that reverted.Results: Catuama and T catigua reverted VF in all hearts, prevented reinduction, and prolongedintraventricular conduction. Catuama prolonged MAP phase 2. On the other hand, P cupanareverted VF in 3 of 5 hearts, but depressed automatism, prolonged MAP phase 3, and did not preventreinduction.Discussion: Catuama reverted and prevented VF in this model. T catigua extract is probably themain agent responsible for the beneficial actions observed. Further studies are now in progress toclarify these actions.© 2007 Elsevier Inc. All rights reserved.

Keywords: Fibrillation; Pharmacology; Resuscitation; Antiarrhythmia agents

Introduction

The herbal drug Catuama has been widely used in Brazilsince 1980 for physical and mental fatigue, neuromuscularasthenia, and weakness disorders. It can be orallyadministered long term with no reported important toxicside effects.

The Catuama preparation consists of hydroalcoholicextracts from 4 well-known medicinal plants, namely, Tri-chilia catigua (Meliaceae), Paullinia cupana (Sapindaceae),Ptychopetalum olacoides (Olacaceae), and Zinziber offici-nalis (Zingiberaceae). The dried extract of Catuama contains40.31% P cupana, 28.23% T catigua, 28.23% P olacoides,and 3.26% Z officinalis.

as supported by Fundação de Amparo a Pesquisa do(FAPESP) and Fundação Faculdade de Medicina,

lo. The authors thank Laboratório Catarinense, Brazil,erbal extracts.author. Emergency Medicine Department, Medicalof São Paulo, CEP: 05403-010 São Paulo, Brazil.7; fax: +55 11 3085 [email protected]

nt matter © 2007 Elsevier Inc. All rights reserved.ard.2007.06.002

Although most of the plants that constitute part of theherbal extract have been studied to some degree, eitherchemically or pharmacologically, the therapeutic actions ofthe herbal extract Catuama itself have not yet been studied. Ithas a potent relaxant effect on vessels from different animalspecies, largely dependent on the release of nitric oxide ornitric oxide–derived substances,1 a relaxant effect on theisolated rabbit corpus cavernosum,2 and an antidepressant-like action.3 Recently, it has been reported that T catiguaextract alone showed potent inhibition of phospholipase A2

activity in human platelets.4

Our group was interested in evaluating the cardiovascularactions of the herbal Catuama on rabbit cardiac contractility.We have found that during these experiments, some of thehearts showed spontaneous ventricular fibrillation (VF)before Catuama infusion. In these hearts, we were surprisedby the fact that starting Catuama completely reverted thearrhythmia in all of them.

The objectives of this study were to investigate the effectsof Catuama and each herbal component on (1) VF reversionand prevention and (2) ventricular repolarization in theisolated perfused rabbit heart.

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Materials and methods

The present study was approved by the Medical School ofUniversity of São Paulo Board of Ethics and conductedaccording to National Institutes of Health Guidelines for theCare and Use of Laboratory Animals.5

Drug dilution

The dried extracts of Catuama, T catigua, P cupana,P olacoides, and Z officinalis were dissolved in 10%polyoxyethylene sorbitan monolaurate (Tween 80) andfiltered in Millipore ester cellulose membrane filter (1.2 μm).

Animal instrumentation

Adult male white New Zealand rabbits weighing 2 to 3 kgwere used in the experiments. Each animal received heparinintravenously (200 UI/kg) and was euthanized by a strike tothe back of the head.6 The heart was quickly excised andconnected to the classical Langendorff system with retro-grade perfusion with modified Krebs-Henseleit solution(NaCl, 120 mmol/L; KCl, 4.7 mmol/L; CaCl2, 1.8 mmol/L;NaHCO3, 25 mmol/L; MgSO4, 1.2 mmol/L; NaH2PO4,1.2 mmol/L; and glucose, 5.5 mmol/L; pH 7.2) oxygenatedwith 95% oxygen/5% carbon dioxide at 16 mL/min andtemperature between 37°C and 38°C. A catheter was insertedinto the apex of the heart to drain the thebesian effluent. Adetailed procedure for the setup of this preparation has beendescribed previously.7

Studies on VF reversion and prevention

In 37 rabbit hearts, 2 pairs (proximal [P] and distal [D]) ofwire electrodes (Monicrom 2-0) were sutured to theepicardial surface of the left ventricle to estimate changesin intraventricular conduction times (CTs; P-D time interval).

The electrograms were acquired through the ECG 100BSystem (Biopac Systems, Inc., Goleta California, USA).Recordings were obtained continuously with AcKnowledgeIII software for the MP1000WSW analog-digital systemconnected to amicrocomputer with an acquisition sample rateof 2000 samples per second and a bandpass of 50 to 500 Hz.

After 20 minutes of stabilization, baseline measures wereperformed. The heart rate (HR) was calculated as thetemporal distance between 2 subsequent ventricular electro-grams, expressed as beats per minute and CT as thetemporal distance between the electrograms recorded at Pand D in milliseconds. Every value is the mean of 5consecutive measures.

Ventricular fibrillation was induced by burst electricalstimulation of the right ventricular apex: current, 10 mA;pulse duration, 2 milliseconds; frequency, 50 Hz; voltage,10 V; duration of stimulation, 5 minutes. If a stable VF wasnot achieved even after 2 repetitions of this protocol, theheart was rejected. This model has been previouslydescribed in detail and allows a stable VF for more than30 minutes.7

After the stabilization period, a test extract solution(200 μg/mL) was added to the perfusion solution andrecordings were obtained again, up to reversion of thearrhythmia or for another 20-minute period. A pilot study

was performed to determine the best effective concentrationof extract for successful VF reversion.

If VF reverted, new measures were obtained: time ofreversal, pause after reversion, HR, and CTs. Then, the sameprotocol of VF was applied to induce a VF again.

Five groups (n = 5-6 each) were constituted accordingto the extract solution added to the perfusion: Catuama,T catigua, P cupana, Z officinalis, P olacoides. Controlexperiments were performed in parallel to test the effectsof the vehicle (Tween 80), and any significant influenceswere observed. In addition, 2 other groups were studied forcomparison of antiarrhythmic drugs classically used indefibrillation: lidocaine (n = 4; 3 μg/mL of lidocainechloride) and amiodarone (n = 4; 1.5 μg/mL ofamiodarone hydrochloride).

Results are expressed as mean ± SD. Statistical analysiswas performed by Kruskal-Wallis analysis of variance byranks complemented with the Tukey test when differenceswere found. Significance level was set at 5%.

Studies on ventricular repolarization

In 30 rabbit hearts, a pacemaker was implanted on theright atrium to maintain constant HR (160 beats per minute).

Left ventricular epicardial monophasic action potential(MAP) waveforms were acquired with a custom-made,nonpolarizable, unipolar silver–silver chloride electrode.The electrode was connected to the ECG 100B System(Biopac Systems, Inc). Recordings were obtained with anAcKnowledge III for the MP1000WSW analog-digitalsystem connected to a microcomputer with an acquisitionsample rate of 2000 samples per second.

The criteria of MAP quality were amplitude not lessthan 10 mV; fast and clean upstroke not longer than5 milliseconds; no contamination by QRS or intrinsicdeflection; mild plateau with convexity facing upward; andhorizontal diastolic baseline without deflections.8

After a stabilization period of 20 minutes, 10 to 15MAP waveforms were recorded 5 minutes before additionof extract solution and 2, 5, 10, 15, 20, 25, and 30 minutesafter. Then, hearts were perfused with fresh Krebs solutionfor drug withdrawal, and new recordings were obtainedafter 5, 10, 15, and 20 minutes. In the control group, thesame measurements with corresponding times were made.

Six groups (n = 5 each) were constituted according to thesolution (25 μg/mL of each herbal extract solution) added tothe perfusion solution: control, Catuama, T catigua,P olacoides, P cupana, and Z officinalis. This dose wasdetermined to be the smallest to cause detectable alterationsin MAP measures.

Three parameters were studied: MAP duration at 20% ofrepolarization (T20), at 50% of repolarization (T50), and at90% of repolarization (T90). Five MAP curves wereselected at each time point to obtain mean values withintermeasurement variation less than 10%. All measure-ments were made manually to avoid the bias often found incomputer-based formulas.

Results are expressed as mean ± SD. Statisticalanalysis was performed by 1-way repeated-measuresanalysis of variance complemented with the Holm-Sidak

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test when differences were found. Significance level wasset at 5%.

Fig. 2. Ventricular electrograms from the isolated perfused rabbit heart. Notethe stable induced VF, reversion after perfusion with T catigua extract, andthe prevention of reinduction, with the same stimulation protocol, after druginfusion. The arrow indicates end of burst stimulation.

Results

Studies on VF reversion and prevention

Herbal extract Catuama consistently reverted VF inducedby burst stimulation in the rabbit heart. According toobservations in previous experiments with spontaneous VF,all the hearts reverted to sinus rhythm in a short time interval(2.7 ± 1.6 minutes). Of note, when a new stimulation wasapplied, VF did not occur, showing a complete protectiverather than a preventive effect on rabbit arrhythmia induction(Fig. 1).

Similarly, T catigua extract also consistently defibrillatesall the rabbit hearts in a short interval of 2.3 ± 1.0 minutes.When a new stimulation was tried, VF did not develop(Fig. 2).

The extracts of the plants P cupana and Z officinalis didnot interfere with VF. On the other hand, P olacoides extractshowed a partial effect, defibrillating 3 of 5 hearts; however,the interval for defibrillation was significantly higher (6.5 ±2.6 minutes) and failed to prevent VF again (Fig. 3).

The positive control drugs, lidocaine and amiodarone,showed different actions. Amiodarone did not have anyshort-term action on VF in this model. On the other hand,lidocaine interrupted VF in all hearts, after 3.5 ± 1.3 minutes,but similarly to P olacoides completely failed to preventreinduction (Fig. 4).

As mentioned in the “Materials and methods” section,Tween 80 had no effect on the arrhythmia.

Figures of experiments from the other groups are notshown because the drugs had no effect on the arrhythmia.

Effects of drugs on VF reversion, time of delay forreversion, postreversion pause, and incidence of VFreinduction are shown in Table 1.

Effects of the various drugs tested on HR and CTs areshown in Table 2.

Studies on ventricular repolarization

In the control group, T20, T50, and T90 did notchange along the time of observation (P = .101, .699, and.316, respectively).

The Catuama group showed differences among T20, T50,and T90 in all intervals (P b .001). Compared with the initial

Fig. 1. Ventricular electrograms from the isolated perfused rabbit heart. Notethe stable induced VF, reversion after perfusion with Catuama extract, andthe prevention of reinduction, with the same stimulation protocol, after druginfusion. The arrow indicates end of burst stimulation.

values, after 5 minutes of Catuama, all 3 variables showed anincrease: 22% in T20 (P b .001), 18% in T50 (P b .001), and16% in T90 (P b .001). The maximum increase was observed10 minutes after addition of Catuama: 29% in T20 (P ≤.001), 26% in T50 (P b .001), and 26% in T90 (P b .001).After this, the values gradually decreased and becamecomparable to initial values 25 minutes after addition ofCatuama (Fig. 5 and 6).

Trichilia catigua showed comparable values of T20, T50,and T90 (P = .500, .285, and .417, respectively).

In the P cupana group, there were differences in thevalues of T20, T50, and T90 (P b .001 in all cases).Compared with the initial values, all variables shortened10 minutes after drug addition, decreasing 13% in T20 (P b.001), 11% in T50 (P b .001), and 10% in T90 (P b .001). Themaximum shortening was observed 20 minutes after Pcupana: 16% in T20 (P b .001), 15% in T50 (P b .001), and13% in T90 (P b .001). Five minutes after beginning ofcleansing, the values gradually increased until they becamecomparable with initial values. Figs. 7 and 8 illustrate theresults for the P cupana group.

Zinziber officinalis showed no statistical differences inthe values of T20, T50, and T90 (P = .352, .377, and.699, respectively).

The P olacoides group showed differences in the valuesof T20, T50, and T90 (P b .001) in all intervals. Five minutesafter the addition of P olacoides to the perfusion solution,T50 increased 9% (P = .008) and T90 by 11% (P b .001). Themaximum increase was observed 20 (T90) and 25 (T20 andT50) minutes after adding the drug, increasing 17% in T20(P b .001), 19% in T50 (P b .001), and 21% in T90 (P b .001).Then, the values gradually decreased until they reachedinitial values after 15 minutes of cleansing. Figs. 9 and 10illustrate the results for the P olacoides group.

Fig. 3. Ventricular electrograms from the isolated perfused rabbit heart. Notethe stable induced VF and reversion after perfusion with P olacoides, with along postreversion pause. Reinduction is not prevented after drug infusion.The arrow indicates end of burst stimulation.

Table 2Effect of the various drugs tested on HR and intraventricular CTs

HR (beats/min) CT (ms)

Before druginfusion

After druginfusion

Before druginfusion

After druginfusion

Catuama 127 ± 18 128 ± 47 9 ± 2 15 ± 1⁎⁎

T catigua 125 ± 13 146 ± 30 7 ± 3 13 ± 3⁎⁎

P olacoides 105 ± 2 72 ± 6⁎ 11 ± 1 15 ± 9Lidocaine 142 ± 17 147 ± 14 14 ± 3 18 ± 3

⁎ P b .03.⁎⁎ P = .02.

Fig. 4. Ventricular electrograms from the isolated perfused rabbit heart. Notethe stable induced VF and reversion after perfusion with lidocaine.Reinduction is not prevented after drug infusion. The arrow indicates endof burst stimulation.

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In 9 other different hearts, the defibrillating dose (200 μg/mL) of Catuama (3 hearts), P cupana (3 hearts), andP olacoides (3 hearts) was added to the superfusate, andMAP recordings were obtained continuously for 10 minutes.The results were very similar to those obtained with the smalldose: Catuama increased T20 by 27%, T50 by 24%, and T90by 25%; P cupana reduced T20 by 16%, T50 by 12%, andT90 by 10%; and P olacoides increased T20 by 5%, T50 by11%, and T90 by 13%.

Discussion

Ventricular fibrillation is one of the most important causesof sudden death in the Western world,9 accounting for anestimated 300000 deaths per year in the United States alone.It is traditionally defined as multiple electrical wavestraveling randomly, constantly changing their direction andnumber, so that there is no effective contraction of themyocardium.10 However, studies propose that the dynamicsof VF would not be a random process11,12 and that “rotors”play an important role in the initiation and maintenanceof VF.13,14

Since it was first used in 1956,15 defibrillation has beenconsidered the only effective treatment of thisarrhythmia.16 Although very effective indeed, defibrillationitself carries several operational problems17,18: it demandsa defibrillator, which is not always available, and a stafftrained in the use of this device. Although strong effortshave been made to have automatic external defibrillators(AED) and trained people everywhere,19-22 the situation isstill far from ideal, especially in less developed countries.

Prevention of sudden death and, consequently, of VF, isalso an important matter. To this day, the automaticimplantable cardioverter/defibrillator has proven to be the

Table 1Effect of the various drugs tested on VF reversion, delay for reversion (time),pause after VF reversion (pause), and incidence of VF reinduction

Reversion Time (min) Pause (ms) Reinduction

Catuama 6/6 2.7 ± 1.6 790.8 ± 284.6 0/6T catigua 6/6 2.3 ± 1.0 602.5 ± 188.2 0/6P olacoides 3/5 6.5 ± 2.6 2341.7 ± 1036.3⁎ 3/3Z officinalis 0/5P cupana 0/5Lidocaine 4/4 3.5 ± 1.3 628.3 ± 105.6 3/4Amiodarone 0/4

⁎ P b .04.

most effective intervention to prevent sudden death byinterrupting VF. Recently, clinical trials such as MulticenterAutomatic Defibrillator Implantation Trial (MADIT) 223

have expanded the indications for device therapy to morethan 4 million patients in the United States alone, at astaggering cost estimated to exceed US $50 billion if fullyimplanted. Thus, the existence of a medication capable ofinterfering with the mechanisms of induction and main-tenance of VF would be more than desirable.

It has been postulated that wave break leading to spiralwave reentry is essential for the development of multiplereentrant circuits and VF.24,25 Traditionally, wave break inVF was attributed to preexisting anatomic and electrophy-siologic heterogeneities, but more recently, it was recognizedthat dynamic factors combined with preexisting tissueheterogeneities amplify wave instability synergistically,promoting both initiation and maintenance of VF. Thesedynamic factors can be related to action potential durationand conduction velocity restitutions.

Most antiarrhythmic drugs of different classes primarilyprevent initiation of ventricular tachycardia by suppressingtriggering events or altering the reentrant circuits, with noregard to its action on electrical restitution, which mayexplain their failure in preventing sudden death. Thus, a newdrug combining antitachycardia and antifibrillatory actions,taking into account action potential duration and conductionvelocity restitutions, should be developed. In our model, theherbal extract Catuama seems to combine these actions: itreverted VF in all hearts and prevented its reinduction.Although Catuama is composed of a combination of 4different medicinal plants, our data show that the extract ofthe plant T catigua seems to be mainly responsible for theprotective action on VF: only T catigua extract was found

Fig. 5. The effects of Catuama on the evolution of T20, T50, and T90 alongthe experiment. Drug infusion starts after 5 minutes and is followed byinfusion of fresh Krebs solution for drug removal.

ig. 7. The effects of P cupana on the evolution of T20, T50, and T90 alonge experiment. Drug infusion starts after 5 minutes and is followed byfusion of fresh Krebs solution for drug removal.

Fig. 6. MAP waveforms before (top) and after (bottom) 15 minutes of Catuama addition.

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effective to reproduce the actions of Catuama. The extract ofthe plant P olacoides shows only a partial effect, defibrillat-ing some of the hearts, but only after a prolonged period andafter inducing severe depression of automatism. Z officinalisand P cupana seem to have no effect.

The mechanisms through which the extract of the herbaldrug Catuama exerts its actions are still unknown. LikeT catigua, it prolongs significantly intraventricular conduc-tion during sinus rhythm, but the effects of these substanceson ventricular repolarization are an important matter, becausemuch of the antiarrhythmic effect is due to this action.

Catuama exerts an important action on repolarization,mainly prolonging phase 2 of MAP. This infers blocking of

Fthin

Fig. 8. MAP waveforms before (top) and after (bottom) 15 minutes of P cupana addition.

Fig. 9. The effects of P olacoides on the evolution of T20, T50, and T90along the experiment. Drug infusion starts after 5 minutes and is followed byinfusion of fresh Krebs solution for drug removal.

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slow and rectifying channels, especially calcium channels.Whether this represents a group IV antiarrhythmic action isstill to be determined. P olcaloides, on the other hand, alsoprolongs repolarization, but its main effect is on phase 3, thefast repolarization phase. This infers, differently fromCatuama, blocking of fast potassium channels instead ofslow calcium channels. From the other components ofCatuama, only P cupana shows electrophysiologic action,which reduces the duration of MAP probably because of thepresence of caffeine that also acts to block calcium channels.

Thus, the main electrophysiologic effect of Catuama onrepolarization seems to be blocking of slow calciumchannels, leading to prolonged repolarization, which com-

Fig. 10. MAP waveforms before (top) and after (bottom) 15 minutes of P olacoides addition.

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bined with its action on stimulus conduction providesconsistent antiarrhythmic effect. This effect is not the sumof every component's effect, but rather a new one.

In summary, the herbal extract Catuamawas found effectiveto revert VF in the isolated rabbit heart model, and mostimportantly, is capable of preventing its reinduction. Ourresults also demonstrated that the extract of the plant Tcatiguaseems to play a major role in this effect. The mechanism ofaction of herbal extract Catuama still needs to be betterinvestigated: it seems to prolong intraventricular conductionand the plateau duration of repolarization on MAP.

Although preliminary, the results of these experiments areencouraging; further studies must be performed to confirm

and increase knowledge about the antiarrhythmic effects ofthis medication. Studies are now in progress to isolate andchemically characterize the active substance(s) responsiblefor this effect present in the extract of the plant T catigua. Inaddition, we are also performing additional experiments tounderstand the mechanisms through which the activeprinciple present in the Catuama extract or in the plantT catigua exert their beneficial action on VF.

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