Cardioprotection stimulated by resveratrol and grape products prevents lethal cardiac arrhythmias in an animal model of ischemia and reperfusion

Francisco Sandro Menezes-Rodrigues Paolo Ruggero Errante Erisvaldo Amarante Araújo Mariana Pontes Pacheco Fernandes Michele Mendes da Silva Marcelo Pires-Oliveira Carla Alessandra Scorza Fúlvio Alexandre Scorza Murched Omar Taha Afonso Caricati-Neto About the authors

ABSTRACT

Purpose

To evaluate the preventive cardioprotective effects of resveratrol and grape products, such as grape juice and red wine, in animal model of cardiac ischemia and reperfusion.

Methods

Male Wistar rats orally pretreated for 21-days with resveratrol and grape products were anesthetized and placed on mechanical ventilation to surgically induce cardiac ischemia and reperfusion by obstruction (ischemia) followed by liberation (reperfusion) of blood circulation in left descending coronary artery. These rats were submitted to the electrocardiogram (ECG) analysis to evaluate the effects of pretreatment with resveratrol and grape products on the incidence of ventricular arrhythmias (VA), atrioventricular block (AVB) and lethality (LET) resulting from cardiac ischemia and reperfusion.

Results

It was observed that the incidence of AVB was significantly lower in rats pretreated with resveratrol (25%), grape juice (37.5%) or red wine (12.5%) than in rats treated with saline solution (80%) or ethanol (80%). Similarly, incidence of LET was also significantly lower in rats pretreated with resveratrol (25%), grape juice (25%) or red wine (0%) than in rats treated with saline solution (62.5%) or ethanol (75%).

Conclusions

These results indicate that the cardioprotective response stimulated by resveratrol and grape products prevents the lethal cardiac arrhythmias in animal model of ischemia and reperfusion, supporting the idea that this treatment can be beneficial for prevention of severe cardiac arrhythmias in patients with ischemic heart disease.

Key words
Myocardial ischemia; Reperfusion Injury; Atrioventricular block; Wine; Rats

Introduction

Cardiovascular diseases remain the main cause of deaths in the worldwide being responsible for almost 18 million deaths annually, and about 80% of these deaths are attributed to ischemic heart diseases, such as acute myocardial infarction11 Joseph P, Leong D, McKee M, Anand SS, Schwalm JD, Teo K, Mente A, Yusuf S. Reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors. Circ Res. 2017;121(6):677-94. https://doi.org/10.1161/CIRCRESAHA.117.308903
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. Although the reperfusion is the main treatment of these diseases, this process may aggravate the myocardial injuries produced during ischemia, generating severe and fatal arrhythmias due to collapse of cardiac excitation-contraction coupling (CECC) generated by ionic and bioenergetic deregulation in cardiac cells, such as ventricular arrhythmias and atrioventricular block22 Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455
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-33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
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.The ventricular arrhythmias are tachyarrhythmias that originate in the heart’s ventricles, and include ventricular extrasystoles, ventricular tachycardia and ventricular fibrillation, the latter two being extremely severe forms of arrhythmia that can lead to death44 Roberts-Thomson KC, Lau DH, Sanders P. The diagnosis and management of ventricular arrhythmias. Nat Rev Cardiol. 2001;8(6):311-21. https://doi.org/10.1038/nrcardio.2011.15
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. The causes of these forms of arrhythmias include heart disease or coronary artery disease44 Roberts-Thomson KC, Lau DH, Sanders P. The diagnosis and management of ventricular arrhythmias. Nat Rev Cardiol. 2001;8(6):311-21. https://doi.org/10.1038/nrcardio.2011.15
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. This disease affects 2.5% of the world population and it is estimated that up to 10% of people over 75 are carriers55 Lindberg T, Wimo A, Elmstahl S, Qiu C, Bohman DM, Sanmartin Berglund J. Prevalence and incidence of atrial fibrillation and other arrhythmias in the general older population: findings from the Swedish National Study on Aging and Care. Gerontl Geratr Med. 2019;5:1-8. https://doi.org/10.1177/2333721419859687.eCollection
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.

The first-degree atrioventricular block, or prolongation of the PR interval, corresponds to a disturbance in the cardiac electrical conduction, whose PR interval is prolonged for more than 0.20 seconds. The second-degree atrioventricular block is characterized by constant PR interval, before and after P wave blocked, with QRS complex large; and in the third-degree atrioventricular block there is no electrical communication between atria and ventricles or relationship between P waves and QRS complexes, which can lead to death66 Rudbeck-Resdal J, Christiansen MK, Johansen JB, Nielsen JC, Bundgaard H, Jensen HK. Aetiologies and temporal trends of atrioventricular block in young patients: a 20-years nationwide study. Europace. 2019;21(11):1710-16. https://doi.org/10.1093/europace/euz206
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. Atrioventricular block has a prevalence of 0.65 to 1.1% in the general population, and an incidence of 0.13 for every 1,000 people, and increases the risk of atrial fibrillation66 Rudbeck-Resdal J, Christiansen MK, Johansen JB, Nielsen JC, Bundgaard H, Jensen HK. Aetiologies and temporal trends of atrioventricular block in young patients: a 20-years nationwide study. Europace. 2019;21(11):1710-16. https://doi.org/10.1093/europace/euz206
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. The most common causes of these disturbances that severely compromise the CECC are cardiac diseases related to dysfunctions of the atrioventricular nodules, increased vagal tone, myocarditis, acute myocardial infarction, and also inflammatory and degenerative heart diseases77 Kerola T, Eranti A, Aro AL, Haukilahti MA, Holkeri A, Junttila MJ, Kentta TV, Rissanen H, Vittinghoff E, Knekt P, Heliovaara M, Huikuri HV, Marcus GM. Risk factors associated with atrioventricular block. JAMA Netw Open. 2019;2(5):e194176. https://doi.org/10.1001/jamanetworkopen.2019.4176
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.

Several pharmacological and non-pharmacological strategies for the prevention of cardiac arrhythmias have been proposed to decrease the adverse effects and costs with these patients88 Brenyo A, Aktas MK. Review of complementary and alternative medical treatment of arrhythmias. Am J Cardiol. 2014;113(5):897-903. https://doi.org/10.1016/j.amjcard.2013.11.044
https://doi.org/10.1016/j.amjcard.2013.1...
. Among the various pharmacological prophylactic strategies with anti-arrhythmic potential, the resveratrol stands out, which can be found in high concentration in the grape peel and seed, as well as their manufactured products, especially red wine and grape juice33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
,99 Bertelli AAA, Das DK. Grapes, wines, resveratrol, and heart health. J Cardiovasc Pharmacol. 2009;54(6):468-76. https://doi.org/10.1097/FJC.0b013e3181bfaff3
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,1010 Stephan LS, Almeida ED, Markoski MM, Gravaglia J, Marcadenti A. Red wine, resveratrol and atrial fibrillation. Nutrientes. 2017;9(11):1190. https://doi.org/10.3390/nu9111190
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. In red wine, the concentration of resveratrol varies from 0.09 to 18 mg/L (average of 5 mg/L)99 Bertelli AAA, Das DK. Grapes, wines, resveratrol, and heart health. J Cardiovasc Pharmacol. 2009;54(6):468-76. https://doi.org/10.1097/FJC.0b013e3181bfaff3
https://doi.org/10.1097/FJC.0b013e3181bf...
. The resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a small molecule with a molecular weight of 228.246 g/mol with anti-inflammatory, antioxidant, hypoglycemic and antihypertensive and cardioprotective effects, which acts through multiple mechanisms of action, including the activation of the silent information regulator factor 2-related enzyme 1 (Sirt1), a nicotinamide adenine dinucleotide-dependent deacetylase involved in many physiological functions like oxidative stress99 Bertelli AAA, Das DK. Grapes, wines, resveratrol, and heart health. J Cardiovasc Pharmacol. 2009;54(6):468-76. https://doi.org/10.1097/FJC.0b013e3181bfaff3
https://doi.org/10.1097/FJC.0b013e3181bf...

10 Stephan LS, Almeida ED, Markoski MM, Gravaglia J, Marcadenti A. Red wine, resveratrol and atrial fibrillation. Nutrientes. 2017;9(11):1190. https://doi.org/10.3390/nu9111190
https://doi.org/10.3390/nu9111190...

11 McCalley AE, Kaja S, Payne AJ, Koulen P. Resveratrol and calcium signaling: molecular mechanisms and clinical relevance Molecules. 2014;19(6):7327-40. https://doi.org/10.3390/molecules19067327
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12 Granchi C, Minutolo F. Activators of Sirtuin-1 and their involvement in cardioprotection. Curr Med Chem. 2018;25(34):442-56. https://doi.org/10.2174/092986735666180214115438
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13 Xu RY, Xu XW, Deng YZ, Ma ZX, Li XR, Zhao L, Qiu LJ, Liu HY, Chen HP. Resveratrol attenues myocardial hypoxia/reoxygenation-induced cell apoptosis through DJ-1-mediated SIRT1-p53 pathway. Biochemn Biophys Res Commun. 2019;514(2):401-6. https://doi.org/10.1016/j.bbrc.2019.04.165
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-1414 Barangi S, Hayes AW, Karimi G. The more effective treatment of atrial fibrillation applying the natural compounds; as NADPH oxidase an ion channel inhibitor. Crit Rev Food Sci Nutri. 2018;58(7):1230-41. https://doi.org/10.1080/10408398.2017.1379000
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. Based on our recent studies, we have suggested that the combined molecular actions of resveratrol on Sirt1 and other cellular proteins involved in the regulation of functions of cardiac cells stimulates the cardioprotective response, attenuating or preventing the cytosolic and mitochondrial Ca2+ overload and bioenergetic collapse involved in cardiac arrhythmias caused by ischemia and reperfusion in cardiac cells33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
. However, there is insufficient information regarding the cardioprotective effects of resveratrol and grape products.

Since cardiovascular diseases represent the main cause of deaths in the worldwide, and cardiac arrhythmias are common in the general population, particularly in patients with ischemic heart diseases, our research group has invested efforts to develop new pharmacological strategies to treat these diseases. Thus, the present study aims to investigate the cardioprotective and antiarrhythmic effects produced by preventive treatment with resveratrol and grape products, such as grape juice and red wine, using an animal model of cardiac ischemia and reperfusion developed by our group.

Methods

All experimental protocols were approved by Ethical Committee of the Universidade Federal de São Paulo (UNIFESP) – Process #2367271115.

The study enrolled adult male Wistar weight between 320 to 350 g with 12 to 14-week-old obtained from Center for the Development of Animal Models for Medicine and Biology (CEDEME/UNIFESP). These animals were maintained under standard conditions of nutrition, hydration, temperature, light and humidity, and in accordance to normalization approved were. All groups received treatment with diluted solutions daily and administered by intragastric administration orally (gavage) during 21 days prior to surgery to induction of CIR. Rats were submitted to protocol of cardiac ischemia and reperfusion after treatment with resveratrol (RES), grape juice (GJ) and red wine (RW) to evaluate the anti-arrhythmic effects of these treatments. Since the lethality of CIR+SS animals was previously known to be between 60-70%, a Fisher’s exact test sample size calculator was used to determine a total sample size ofat least 33 animals to detect a biologically relevant reduction of lethality to 20% (one-sided a = 0.05; power 0.8). This total was rounded up to 40 animals, divided in five experimental groups: 1) CIR group - treated with3.715 mL/kg/day of saline solution 0.9%, n = 8; 2) CIR+RES group - treated with RES 1 mg/kg/day, n = 8; 3) CIR+GJ group - treated with 3.715 mL/kg/day of Aurora® whole GJ, n = 8; 4) CIR+ethanol (ET) group - treated with 3.715 mL/kg/day of 12.5% ethanol solution, n = 8; 5) CIR+RW group - treated with 3.715 mL/kg/day of RW (Malbec Wine, Valdorella®, containing 12.5% ethanol, n = 8). The doses administered to the animals corresponded, approximately, to 300 mL of GJ and RW consumed by humans, dose equivalent to1.3 mg/L of polyphenols, including the RES1515 Soares Filho PR, Castro I, Stahlschmidt A. Effect of red wine associated with physical exercise in the cardiovascular system of spontaneously hypertensive rats. Arq Bras Cardiol. 2011;96(4):277-83. https://doi.org/10.1590/S0066-782X2011005000020
https://doi.org/10.1590/S0066-782X201100...
,1616 Poklar Ulrih N, Opara R, Skrt M, Kosmerl T, Wondra M, Abram V. Part I. Polyphenols composition and antioxidant potential during `Balufrankisch`grape maceration and red wine maturation, and the effects of trans-resveratrol addition. Toxicol. 2020;137:111-122. https://doi.org/10.1016/j.fct.2020.111122
https://doi.org/10.1016/j.fct.2020.11112...
.

Surgical procedures for induction of cardiac ischemia and reperfusion (CIR)

Surgical procedures used for induction of CIR in rats were made in accordance with methodology previously described1717 Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, Errante PR, Caricati-Neto A, Bergantin LB. A simple and efficient methodology for the study of cardioprotective drugs in animal model of cardiac ischemia-reperfusion. J Mol Imag Dynamic. 2017;7:1. https://doi.org/10.4172/2155-9937.1000133
https://doi.org/10.4172/2155-9937.100013...

18 Tavares JGP, Errante PR, Govato TCP, Vasques ER, Ferraz RRN, Taha MO, Menezes-Rodrigues FS, Caricati-Neto A. Cardioprotective effect of preconditioning is more efficient than postconditioning in rats submitted to cardiac ischemia and reperfusion. Acta Cir Bras. 2018;33(7):588-96. https://doi.org/10.1590/s0102-865020180070000004
https://doi.org/10.1590/s0102-8650201800...
-1919 Menezes-Rodrigues FS, Tavares JGP, Vasques ER, Errante PR, de Araújo EA, Pires-Oliveira M, Scorza CA, Scorza FA, Taha MO, Caricati-Neto A. Cardioprotective effects of pharmacological blockade of the mitochondrial calcium uniporter on myocardial ischemia-reperfusion injury. Acta Cir Bras. 2020;35(3):e202000306. https://doi.org/10.1590/s0102-865020200030000006
https://doi.org/10.1590/s0102-8650202000...
. Rats were anesthetized with urethane (1.25 g/kg), and fixed in the supine position. After intubation (Jelco 14G, USA), rats were mechanically ventilated using a mechanic ventilator Insight model EFF 312 (Insight Equipamentos Científicos, Ribeirão Preto-SP, Brazil). After stabilization for15 min, thoracotomy was performed to place the vascular tourniquet (4/0 braided silk suture attached to a 10-mm micropoint reverse cutting needle, Ethicon K-890H, USA) around the left anterior descending coronary artery to induce ischemia. After of 10 min of cardiac ischemia, the tourniquet was removed to allow coronary recirculation for 75 min (cardiac reperfusion). The cardiac electrical activity in all groups studied was monitored by electrocardiogram (ECG) system using a method previously described1717 Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, Errante PR, Caricati-Neto A, Bergantin LB. A simple and efficient methodology for the study of cardioprotective drugs in animal model of cardiac ischemia-reperfusion. J Mol Imag Dynamic. 2017;7:1. https://doi.org/10.4172/2155-9937.1000133
https://doi.org/10.4172/2155-9937.100013...

18 Tavares JGP, Errante PR, Govato TCP, Vasques ER, Ferraz RRN, Taha MO, Menezes-Rodrigues FS, Caricati-Neto A. Cardioprotective effect of preconditioning is more efficient than postconditioning in rats submitted to cardiac ischemia and reperfusion. Acta Cir Bras. 2018;33(7):588-96. https://doi.org/10.1590/s0102-865020180070000004
https://doi.org/10.1590/s0102-8650201800...
-1919 Menezes-Rodrigues FS, Tavares JGP, Vasques ER, Errante PR, de Araújo EA, Pires-Oliveira M, Scorza CA, Scorza FA, Taha MO, Caricati-Neto A. Cardioprotective effects of pharmacological blockade of the mitochondrial calcium uniporter on myocardial ischemia-reperfusion injury. Acta Cir Bras. 2020;35(3):e202000306. https://doi.org/10.1590/s0102-865020200030000006
https://doi.org/10.1590/s0102-8650202000...
. ECG analysis was performed during 100 min of duration (stabilization for 15 min, cardiac ischemia for 10 min and cardiac reperfusion for 75 min). The ECG was recorded using a biopotential amplifier by means of needle electrodes placed subcutaneously on the limbs. Successful surgical obstruction of the coronary artery was validated by ECG alterations (increase in R wave and ST segment) caused by cardiac ischemia1717 Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, Errante PR, Caricati-Neto A, Bergantin LB. A simple and efficient methodology for the study of cardioprotective drugs in animal model of cardiac ischemia-reperfusion. J Mol Imag Dynamic. 2017;7:1. https://doi.org/10.4172/2155-9937.1000133
https://doi.org/10.4172/2155-9937.100013...

18 Tavares JGP, Errante PR, Govato TCP, Vasques ER, Ferraz RRN, Taha MO, Menezes-Rodrigues FS, Caricati-Neto A. Cardioprotective effect of preconditioning is more efficient than postconditioning in rats submitted to cardiac ischemia and reperfusion. Acta Cir Bras. 2018;33(7):588-96. https://doi.org/10.1590/s0102-865020180070000004
https://doi.org/10.1590/s0102-8650201800...
-1919 Menezes-Rodrigues FS, Tavares JGP, Vasques ER, Errante PR, de Araújo EA, Pires-Oliveira M, Scorza CA, Scorza FA, Taha MO, Caricati-Neto A. Cardioprotective effects of pharmacological blockade of the mitochondrial calcium uniporter on myocardial ischemia-reperfusion injury. Acta Cir Bras. 2020;35(3):e202000306. https://doi.org/10.1590/s0102-865020200030000006
https://doi.org/10.1590/s0102-8650202000...
. The body temperature was maintained at 37.5 ºC with a heated operating platform and appropriate heating lamps and was evaluated routinely via a rectal thermometer.

Evaluation of cardiac activity by ECG analysis

The cardiac activity in rats submitted to CIR was evaluate by ECG in accordance with methodology previously described1717 Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, Errante PR, Caricati-Neto A, Bergantin LB. A simple and efficient methodology for the study of cardioprotective drugs in animal model of cardiac ischemia-reperfusion. J Mol Imag Dynamic. 2017;7:1. https://doi.org/10.4172/2155-9937.1000133
https://doi.org/10.4172/2155-9937.100013...

18 Tavares JGP, Errante PR, Govato TCP, Vasques ER, Ferraz RRN, Taha MO, Menezes-Rodrigues FS, Caricati-Neto A. Cardioprotective effect of preconditioning is more efficient than postconditioning in rats submitted to cardiac ischemia and reperfusion. Acta Cir Bras. 2018;33(7):588-96. https://doi.org/10.1590/s0102-865020180070000004
https://doi.org/10.1590/s0102-8650201800...
-1919 Menezes-Rodrigues FS, Tavares JGP, Vasques ER, Errante PR, de Araújo EA, Pires-Oliveira M, Scorza CA, Scorza FA, Taha MO, Caricati-Neto A. Cardioprotective effects of pharmacological blockade of the mitochondrial calcium uniporter on myocardial ischemia-reperfusion injury. Acta Cir Bras. 2020;35(3):e202000306. https://doi.org/10.1590/s0102-865020200030000006
https://doi.org/10.1590/s0102-8650202000...
. The ECG data were recorded using an acquisition system AqDados 7.02 (Lynx Tecnologia Ltda., Brazil), an acquisition system AqDados 7.02 (Lynx Tecnologia Ltda., Brazil), and analyzed using the software AqDAnalysis 7 (Lynx Tecnologia Ltda., Brazil). Using this software, the heart rates were evaluated, as well as incidence of ventricular arrhythmias (VA), atrioventricular block (AVB) and lethality (LET), in response to CIR. The ventricular fibrillation, torsades de pointes, and ventricular tachycardia parameters were considered only as VA.

Statistical analysis

The incidence of VA, AVB, and LET were statistically evaluated using the Fisher’s exact test, and Prism 5.0 software (GraphPad, USA). Results were considered statistically significant when p < 0.05.

Results

In all groups studied, cardiac rhythm before CIR was maintained between 325 to 340 bpm, but varied significantly during ischemia and reperfusion, validating this animal CIR model to study of anti-arrhythmic effects produced by the preventive treatment with RES, GJ and RW. Fig. 1 shows the typical ECG record obtained in CIR+SS and CIR+RES. It was observed that the incidence of severe VA at the beginning of reperfusion evolved to AVB after 10 min of reperfusion in CIR+SS, but not in CIR+RES, CIR+GJ and CIR+RW groups. Fig. 2 shows that the incidence of VA in CIR+RES (70%), CIR+GJ (70%), CIR+RW (62.5%) groups was not statistically difference from CIR+SS (80%) and CIR+ET (90%). However, the incidence of AVB was significantly lower in CIR+RES (25%), CIR+GJ (37.5%), CIR+RW (12.5%) groups than in CIR+SS (80%) and CIR+ET (80%) control groups(Fig. 3), indicating the preventive treatment with RES, GJ and RW produced anti-arrhythmic effects in animal CIR model.

Figure 1
Typical record showing ECG obtained in animals from CIR+SS and CIR+RES groups. Note that the incidence of severe ventricular arrhythmias (VA) at the beginning of reperfusion evolved to atrioventricular block (AVB) after 10 min of reperfusion in CIR+SS, but not in CIR+RES group.
Figure 2
Incidence of the ventricular arrhythmias (VA) in the CIR+SS, CIR+RES, CIR+GJ, CIR+ET and CIR+RW groups. The results were expressed as mean, and analyzed by Fisher’s exact test (*p < 0.05).
Figure 3
Incidence of the atrioventricular block (AVB) in the CIR+SS, CIR+RES, CIR+GJ, CIR+ET and CIR+RW groups. The results were expressed as mean, and analyzed by Fisher’s exact test (*p < 0.05).

Fig. 4 shows that incidence of LET also was also significantly lower in CIR+RES (25%), CIR+GJ (25%), CIR+RW (0%) groups than in CIR+SS (62.5%) and CIR+ET (75%) controls groups. It is important note that LET was absence in CIR+RW group. These results confirm that preventive treatment with RES, GJ and RW produced cardioprotective effects in animal CIR model.

Figure 4
Incidence of the lethality (LET) in the in the CIR+SS, CIR+RES, CIR+GJ, CIR+ET and CIR+RW groups. The results were expressed as mean, and analyzed by Fisher’s exact test (*p < 0.05).

Discussion

Severe cardiac arrhythmias following myocardial ischemia and reperfusion are the leading cause of mortality in patients with ischemic heart disease in the worldwide. It is well known that ischemia and reperfusion trigger a cascade of electrophysiological and biochemical events in cardiac cells, which can lead to myocardial damage and the occurrence of cardiac arrhythmias. Then, we have evaluated new cardioprotective strategies to treat the ischemic heart disease, especially reducing or preventing the cardiac arrhythmias. In the present study, we evaluated the antiarrhythmic effects produced by the 21-days oral treatment with resveratrol (1 mg/kg/day), and grape products (red wine and grape juice) in a dose equivalent of resveratrol, in animal model of cardiac ischemia and reperfusion. Our results showed that these treatments significantly reduced the incidence of atrioventricular block and lethality in animal model of cardiac ischemia and reperfusion, supporting the idea that this treatment can be beneficial in the prevention of severe cardiac arrhythmias in patients with ischemic heart disease.

Although pharmacological and non-pharmacological strategies are fundamental in the control and survival of patients with ischemic heart diseases, complementary and alternative therapies for the prevention of cardiac arrhythmias in this diseases have been used in the context of decreasing adverse effects and costs with these patients88 Brenyo A, Aktas MK. Review of complementary and alternative medical treatment of arrhythmias. Am J Cardiol. 2014;113(5):897-903. https://doi.org/10.1016/j.amjcard.2013.11.044
https://doi.org/10.1016/j.amjcard.2013.1...
, mainly after reports of the “French paradox” that suggested the consumption of grape products as beneficial for cardiovascular health due its cardioprotective anti-arrhythmic actions of resveratrol2020 Renaud S, de Lorgeril M. The Frech paradox: dietary factors and cigarette smoking-related health risks. Ann N Y Acad Sci. 1993;686:299-309. https://doi.org/10.1111/j.1749-6632.1993.tb39191.x
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https://doi.org/10.1113/JP271133...
. This recognition of the cardioprotective benefits of resveratrol initiated a range of studies in an attempt to uncover the molecular basis of resveratrol action.

The inconsistent findings between preclinical and clinical studies might be attributable to variable distribution of resveratrol to the desired tissues and cells. Pharmacokinetics studies have shown that the resveratrol is quickly absorbed by the gastrointestinal tract following oral administration with peak plasma concentration occurring within the first 30 minutes after low doses and 90 to 120 minutes after high doses99 Bertelli AAA, Das DK. Grapes, wines, resveratrol, and heart health. J Cardiovasc Pharmacol. 2009;54(6):468-76. https://doi.org/10.1097/FJC.0b013e3181bfaff3
https://doi.org/10.1097/FJC.0b013e3181bf...
. These studies also showed that the resveratrol have significant bioavailability in cardiac tissue and high affinity for liver and kidneys, the latter is involved in its excretion99 Bertelli AAA, Das DK. Grapes, wines, resveratrol, and heart health. J Cardiovasc Pharmacol. 2009;54(6):468-76. https://doi.org/10.1097/FJC.0b013e3181bfaff3
https://doi.org/10.1097/FJC.0b013e3181bf...
. At relatively low doses (1 to 5 mg/kg/day), resveratrol renders the heart resistant to ischemia and reperfusion injury by generating a survival signal in cardiac cells. Single doses of less than 1 g orally administered have not produced adverse effects. These effects such as diarrhea, nausea, abdominal pain, transient headache was only observed after oral administration of doses greater than 500 mg for 30 days99 Bertelli AAA, Das DK. Grapes, wines, resveratrol, and heart health. J Cardiovasc Pharmacol. 2009;54(6):468-76. https://doi.org/10.1097/FJC.0b013e3181bfaff3
https://doi.org/10.1097/FJC.0b013e3181bf...
.

Several studies have shown that ingestion of products obtained from red grapes reduces oxidative stress and inflammatory processes in many organs and tissues, especially cardiovascular system2525 Albers AR, Varghese S, Vitseva O, Vita JA, Freedman JE. The antiinflammatory effects of purple grape juice consumption in subjects with stable coronary artery disease. Arterioscler Thromb Vasc Biol. 2004;24(11):e179-80. https://doi.org/10.1161/01.ATV.0000143479.97844.af
https://doi.org/10.1161/01.ATV.000014347...

26 Sacanella E, Vázquez-Agell V, Mena MP, Antúnez E, Fernández-Solá J, Nicolás JM, Lamuela-Raventós RM, Ros E, Estruch R. Down-regulation of adhesion molecules and other inflammatory biomarkers after moderate wine consumption in healthy women: a randomized trial. Am J Clin Nutr. 2007;86(5):1463-9. https://doi.org/10.1093/ajcn/86.5.1463
https://doi.org/10.1093/ajcn/86.5.1463...
-2727 Shah A, Reyes LM, Morton JS, Fung D, Schneider J, Davidge ST. Effect of resveratrol on metabolic and cardiovascular function in male and female adult offspring exposed to prenatal hypoxia and a high‐fat diet. J Physiol. 2016;594(5):1465-82. https://doi.org/10.1113/JP271133
https://doi.org/10.1113/JP271133...
. It was showed that resveratrol has potent anti-inflammatory, hypolipidemic, platelet antiaggregant, vasodilator and antioxidant activity1111 McCalley AE, Kaja S, Payne AJ, Koulen P. Resveratrol and calcium signaling: molecular mechanisms and clinical relevance Molecules. 2014;19(6):7327-40. https://doi.org/10.3390/molecules19067327
https://doi.org/10.3390/molecules1906732...
,2121 Hung LM, Chen JK, Huang SS, Ren-Shen L, Su MJ. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res. 2000;47(3):549-55. https://doi.org/10.1016/s0008-6363(00)00102-4
https://doi.org/10.1016/s0008-6363(00)00...
,2424 Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MKC, Kunz I, Schrauwen-Hinderling VB, Blaak E, Auwerx J, Schrauwen P. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14(5):612-22. https://doi.org/10.1016/j.cmet.2011.10.002
https://doi.org/10.1016/j.cmet.2011.10.0...
. Cardiovascular activity of resveratrol and grape products has been observed in vitro and in vivo studies2525 Albers AR, Varghese S, Vitseva O, Vita JA, Freedman JE. The antiinflammatory effects of purple grape juice consumption in subjects with stable coronary artery disease. Arterioscler Thromb Vasc Biol. 2004;24(11):e179-80. https://doi.org/10.1161/01.ATV.0000143479.97844.af
https://doi.org/10.1161/01.ATV.000014347...

26 Sacanella E, Vázquez-Agell V, Mena MP, Antúnez E, Fernández-Solá J, Nicolás JM, Lamuela-Raventós RM, Ros E, Estruch R. Down-regulation of adhesion molecules and other inflammatory biomarkers after moderate wine consumption in healthy women: a randomized trial. Am J Clin Nutr. 2007;86(5):1463-9. https://doi.org/10.1093/ajcn/86.5.1463
https://doi.org/10.1093/ajcn/86.5.1463...
-2727 Shah A, Reyes LM, Morton JS, Fung D, Schneider J, Davidge ST. Effect of resveratrol on metabolic and cardiovascular function in male and female adult offspring exposed to prenatal hypoxia and a high‐fat diet. J Physiol. 2016;594(5):1465-82. https://doi.org/10.1113/JP271133
https://doi.org/10.1113/JP271133...
. In vivo studies performed in animal model of ischemia and reperfusion showed that the treatment with resveratrol produces potent antiarrhythmic effects, reducing the incidence and duration of ventricular tachycardia and ventricular fibrillation2121 Hung LM, Chen JK, Huang SS, Ren-Shen L, Su MJ. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res. 2000;47(3):549-55. https://doi.org/10.1016/s0008-6363(00)00102-4
https://doi.org/10.1016/s0008-6363(00)00...
. These effects have been attributed to antioxidant activity of resveratrol as a consequence of inhibition of inducible nitric oxide synthase (iNOs) and modulation of production of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS), with significant reduction in the incidence of atrioventricular block and lethality2121 Hung LM, Chen JK, Huang SS, Ren-Shen L, Su MJ. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res. 2000;47(3):549-55. https://doi.org/10.1016/s0008-6363(00)00102-4
https://doi.org/10.1016/s0008-6363(00)00...
,2828 Hung LM, Su MJ, Chen JK. Resveratrol protects myocardial ischemia-reperfusion injury through both NO-dependent and NO-independent mechanisms. Free Radic Biol Med. 2004;36(6):774-81. https://doi.org/10.1016/j.freeradbiomed.2003.12.016
https://doi.org/10.1016/j.freeradbiomed....
. These cardioprotective effects of resveratrol is also resultant from its stimulant action on the production of antioxidant enzymes, such as catalase, superoxide dismutase and glutathione peroxidase, consequently reducing the production of reactive oxygen2929 Kazemirad H, Kazerani HR. Cardioprotective effects of resveratrol following myocardial ischemia and reperfusion. Mol Biol Rep. 2020;47(8):5843-50. https://doi.org/10.1007/s11033-020-05653-7
https://doi.org/10.1007/s11033-020-05653...
. It is important note that adstringinin (3.3’, 4’, 5-tetrahydroxystilbene), a resveratrol analogue with potent antioxidant activity and stimulant action on nitric oxide (NO) biosynthesis, also reduces the incidence of atrioventricular block and lethality in animal model of cardiac ischemia and reperfusion3030 Hung LM, Chen JK, Lee RS, Liang HC, Su MJ. Beneficial effects of adstringinin, a resveratrol analogue, on the ischemia and reperfusion damage in rat heart. Free Radic Biol Med. 2001;30(8):877-83. https://doi.org/10.1016/s0891-589(01)00474-9
https://doi.org/10.1016/s0891-589(01)004...
.

The present study showed that the preventive treatment with resveratrol and grape products (grape juice and red wine) significantly reduced the incidence of atrioventricular block and lethality in animal model of cardiac ischemia and reperfusion, demonstrating the cardioprotective efficacy of this treatment. Our previous studies indicate that these treatments can attenuate or prevent the collapse of CECC caused by ischemia and reperfusion due to combination of multiple actions of resveratrol33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
. It is well established that this collapse is primarily triggered by ionic and bioenergetic deregulation caused by ischemia and reperfusion in cardiac cells22 Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455
https://doi.org/10.1146/annurev.physiol....
-33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
. During ischemia, the ionic deregulation in Ca2+ homeostasis in cardiac cells due mainly to inadequate functioning of Ca2+-ATPases and L-type voltage-activated Ca2+ channels (L-type Cav) results in cytosolic and mitochondrial Ca2+ overload, collapsing the mitochondrial function and ATP production22 Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455
https://doi.org/10.1146/annurev.physiol....
,33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
. During reperfusion, this Ca2+ overload is aggravated due to increased Ca2+ influx into cytosol through Na+/Ca2+ exchanger activity and the increment in formation of free radicals22 Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455
https://doi.org/10.1146/annurev.physiol....
,33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
. This last event produces oxidation of structural proteins and proteins involved in the respiratory chain, oxidation of pyridine nucleotides, changes in the permeability of internal mitochondrial membrane, decoupling of oxidative phosphorylation, and in consequence collapsing the mitochondrial ATP production and Ca2+ homeostasis in cardiac cells22 Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455
https://doi.org/10.1146/annurev.physiol....
,33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
.

In vitro studies using patch clamp methodology3131 Zhang Y, Liu Y, Wang T, Li B, Wang Z, Yang B. Resveratrol, a natural ingredient of grape skin: antiarrhythmic efficacy and ionic mechanisms. Biochem Biophys Res Commum. 2006;340(4):1192-9. https://doi.org/10.1016/j.bbrc.2005.12.124
https://doi.org/10.1016/j.bbrc.2005.12.1...

32 Chen WP, Su MJ, Hung LM. In vitro electrophysiological mechanisms for antiarrhythmic efficacy of resveratrol, a red wine antioxidant. Eur J Pharmacol. 2007;554(2-3):196-204. https://doi.org/10.1016/j.ejphar.2006.10.016
https://doi.org/10.1016/j.ejphar.2006.10...

33 Baczko I, Light PE. Resveratrol and derivates for the treatment of atrial fibrillation. Ann N Y Acad Sci. 2015;1348(1):68-74. https://doi.org/10.1111/nyas.12843
https://doi.org/10.1111/nyas.12843...
-3434 Zhang LP, Yin JX, Liu Z, Zhang Y, Wang QS, Zhao J. Effect of resveratrol on L-type calcium current in rat ventricular myocytes. Acta Pharmacol Sin. 2006;27(2):179-83. https://doi.org/10.1111/j.1745-7254.2006.00250.x
https://doi.org/10.1111/j.1745-7254.2006...
showed that the antiarrhythmic effects of resveratrol result from its inhibitory actions on the of L-type Cav combined with its excitatory actions on the slow-acting rectifier K+ channels (IKs). It is well known that IKs are important for the cardiac cell repolarization, without interfering with thefunction of rapid-acting rectifier K+ channels (IKr). In addition, resveratrol also selectively increased the K+ current mediated by ATP-sensitive K+ channels (KATP) in cardiac cells, reducing excitability of cardiac cells. The actions of resveratrol on these channels prevent the CECC collapse, reducing the incidence of severe arrhythmias resulting from ischemia and reperfusion3535 Chen YR, Yi FF, Wang CY, Chen L, Yang XC, Su PX, Cai J. Resveratrol attenuates ventricular arrhythmias and improves the long-term survival in rats with myocardial infarction. Cardiovasc Drugs Ther. 2008;22(6):479-85. https://doi.org/10.1007/s10557-008-6141-8
https://doi.org/10.1007/s10557-008-6141-...
.

Our previous studies have shown that pharmacological blockade of cardiac L-type Cav constitutes an effective strategy to attenuate or prevent the cytosolic Ca2+ overload and collapse of the CECC, and consequently the cardiac arrhythmias resulting from myocardial ischemia and reperfusion33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
,1717 Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, Errante PR, Caricati-Neto A, Bergantin LB. A simple and efficient methodology for the study of cardioprotective drugs in animal model of cardiac ischemia-reperfusion. J Mol Imag Dynamic. 2017;7:1. https://doi.org/10.4172/2155-9937.1000133
https://doi.org/10.4172/2155-9937.100013...
. We showed that blocking cardiac L-type Cav with nifedipine(1 and 30 mg/kg, IV, before cardiac I/R) significantly reduced the incidence of AVB (from 79% to 14%) and LET (from 70% to 14%), in animals subjected to CIR. Similarly, we showed in the present study that treatment with resveratrol(1 mg/kg/day, VO, for 21 days) significantly reduced the incidence of AVB (from 80% to 25%), and LET (from 62.5% to 25%), in animals subjected to CIR, due to its anti-arrhythmic action produced by the blocking of cardiac L-type Cav. This hypothesis was reinforced by the observation that treatment with grape products rich in resveratrol, such as red wine and grape juice, also significantly reduced the incidence of AVB (from 80% to 12.5% and 37.5%, respectively) and LET (from 62.5% to 25% and 0%, respectively), in animals subjected to CIR.

Another mechanism through which resveratrol suppresses ventricular arrhythmias involves an increase of the cardiac refractory period by inhibiting Na+ channels, and transient and sustained K+ currents3636 Qian C, Ma J, Zhang P, Luo A, Wang C, Ren Z, Kong L, Zhang S, Wang X, Wu Y. Resveratrol attenuates the Na(+)-dependent intracellular Ca(2+) overload by inhibiting H(2)O(2)-induced increase in late sodium current in ventricular myocytes. PLoS One. 2012;7(12):e51358. https://doi.org/10.1371/journal.pone.0051358
https://doi.org/10.1371/journal.pone.005...
. The antiarrhythmic effects of resveratrol also result from its action on the late Na+ current (INaL) mediated by increase the activity of Na+-Ca2+ exchanger (NCX) currents, modifying the intracellular Ca2+diastolic concentration in ventricular myocytes3636 Qian C, Ma J, Zhang P, Luo A, Wang C, Ren Z, Kong L, Zhang S, Wang X, Wu Y. Resveratrol attenuates the Na(+)-dependent intracellular Ca(2+) overload by inhibiting H(2)O(2)-induced increase in late sodium current in ventricular myocytes. PLoS One. 2012;7(12):e51358. https://doi.org/10.1371/journal.pone.0051358
https://doi.org/10.1371/journal.pone.005...
. These results are compatible with in vivo studies that demonstrated that treatment with resveratrol reduced ventricular arrhythmia and tachycardia induced by coronary artery ligation, with an increase in survival and suppression of cardiac remodeling in animals subjected to myocardial infarction, with electrocardiographic signals monitored using a telemetry transmitter implanted3535 Chen YR, Yi FF, Wang CY, Chen L, Yang XC, Su PX, Cai J. Resveratrol attenuates ventricular arrhythmias and improves the long-term survival in rats with myocardial infarction. Cardiovasc Drugs Ther. 2008;22(6):479-85. https://doi.org/10.1007/s10557-008-6141-8
https://doi.org/10.1007/s10557-008-6141-...
.

In accordance with concepts and results published by our group33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
, there is a great interest in the role of cytosolic Ca2+ overload, mitochondrial dysfunction, oxidative stress on cardiac injury, such as atrial fibrillation by the modulation of signals that regulate the ionic channels that control the cardiac excitability by resveratrol3333 Baczko I, Light PE. Resveratrol and derivates for the treatment of atrial fibrillation. Ann N Y Acad Sci. 2015;1348(1):68-74. https://doi.org/10.1111/nyas.12843
https://doi.org/10.1111/nyas.12843...
,3737 Li W, Wang YP, Gao L, Zhang PP, Zhou Q, Xu QF, Zhou ZW, Guo K, Chen RH, Yang HT, Li YG. Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Cadocsum-journal-citation2+docsum-journal-citation overload. Acta Pharmacol Sin. 2013;34(9):1164-73. https://doi.org/10.1038/aps.2013.82
https://doi.org/10.1038/aps.2013.82...
, or the regulation of the number of ectopic ventricular heartbeats by the combination of resveratrol with others drugs, for example 1,25-dihydroxyvitamin D (1,25 D)3838 Safari F, Zarei F, Shekarforiush S, Fekri A, Klishadi MS, Hekmatimoghaddam S. Combined 1,25-dihydroxy-vitamin D and resveratrol: a novel therapeutic approach to ameliorate ischemia reperfusion-induced myocardial injury. Vitam Nutr Res. 2015;85(3-4):174-84. https://doi.org/10.1024/0300-9831/a000236
https://doi.org/10.1024/0300-9831/a00023...
. The arrhythmogenic activity similar to post-depolarization and delayed post-depolarization induced by cytosolic and mitochondrial Ca2+ overload and oxidative stress mediated by L-type Cav in ventricular cardiomyocytes by a mechanism dependent on calmodulin II (CaMKII) can be suppressedby the use of resveratrol3737 Li W, Wang YP, Gao L, Zhang PP, Zhou Q, Xu QF, Zhou ZW, Guo K, Chen RH, Yang HT, Li YG. Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Cadocsum-journal-citation2+docsum-journal-citation overload. Acta Pharmacol Sin. 2013;34(9):1164-73. https://doi.org/10.1038/aps.2013.82
https://doi.org/10.1038/aps.2013.82...
, just as atrial fibrillation induced bycoronary artery ligation in rabbits can be reduced by regulating ion channels via phosphoinositide 3-kinase (PI3K)/AKT/eNOS signaling pathway3939 Chong E, Chang SL, Hsiao YW, Singhal R, Liu SH, Leha T, Lin WY, Hsu CP, Chen YC, Chen YJ, Wu TJ, Higa S, Chen AS. Resveratrol, a red wine antioxidant, reduces atrial fibrillation susceptibility in the failing heart by PI3K/AKT/eNOS signaling pathway activation. Heart Rhythm. 2015;12(5):1046-56. https://doi.org/10.1016/j.hrthm.2015.01.044
https://doi.org/10.1016/j.hrthm.2015.01....
. Ex vivo performed in tissue samples obtained from patients with atrial fibrillation showed that resveratrol was able to attenuate mitochondrial changes and activation of target genes by NF-kB by controlling the Ca2+ input current through the L-type Cav4040 Bukoska A, Schild L, Keilhoff G, Hirte D, Neurmann M, Gardemann A, Neumann KH, Rohl FW, Huth C, Goette A, Lendeckel U. Mitochondrial dysfunction and redox signaling in atrial tachyarrhythmia. Exp Biol Med (Maywood). 2008;233(5):558-74. https://doi.org/10.3181/0706-RM-155
https://doi.org/10.3181/0706-RM-155...
. In addition to its anti-arrhythmic effect, resveratrol promotes a positive inotropic effect, similar to phosphodiesterase inhibitors 3-isobutylmethylxanthine (IBMX), and protects against the proarrhythmic effects of sympathomimetic drugs4141 Hernadez-Cascales. Resveratrol enhances the inotropic effect but inhibits the proarrhythmic effect of sympathomimetic agents in rat myocardium. PeerJ. 2017;5:e3113. https://doi.org/10.7717/peerj.3113.eCollection2017
https://doi.org/10.7717/peerj.3113.eColl...
.

Due to antiarrhythmic effects of resveratrol observed in vitro and in vivo models of ischemia and reperfusion, its preventive use has been evaluated under different pathological conditions that can lead to the appearance of arrhythmias. Arrhythmias secondary to cardiac disorders such as myocardial infarction are common in patients with diabetes mellitus4242 Haas AV, McDonnell ME. Pathogenesis of cardiovascular disease in diabetes. Endocrinol Metab Clin North Am. 2018;47(1):51-63. https://doi.org/10.1016/j.ecl.2017.10.010
https://doi.org/10.1016/j.ecl.2017.10.01...
, and the combination of resveratrol and glibenclamide in diabetic animals decreases the frequency of arrhythmias during cardiac reperfusion associated with restoration of Kir6 protein expression and ion channels autonomy, such as KATP channels4343 Kaya ST, Bozdogan O, Ozarslan TO, Taskin E, Eksioglu D, Erim F, Yasar S. The protection of resveratrol and its combination with glibenclamide, but not berberine on the diabetic hearts against reperfusion-induced arrhytmias: the role of myocardial K(ATP) channel. Arch Physiol Biochem 2019;125(2):114-21. https://doi.org/10.1080/13813455.2018.1440409
https://doi.org/10.1080/13813455.2018.14...
. In humans with chagasic chronic cardiomyopathy, the oxidative stress can cause arrhythmias; however, resveratrol is able to reduce prolonged PR and QTc intervals, reversing sinus arrhythmias, atrial and atrioventricular conduction disorders via the AMPK pathway and reducing the production of reactive oxygen species4444 Vilar-Pereira G, Carneiro VC, Mata-Santos H, Vicentino AR, Ramos IP, Giarola NL, Feijó DF, Meyer-Fernades JR, Paula-Neto HA, Medei E, Bozza MT, Lannes-Vieira J, Paiva CN. Resveratrol reverses functional chagas heart disease in mice. PLoS Pathog. 2016;12(10):e1005947. https://doi.org/10.1371/jounal.ppat.1005947
https://doi.org/10.1371/jounal.ppat.1005...
. In rheumatoid arthritis, an autoimmune disease, atrial remodeling occurs which can lead to the appearance of atrial fibrillation, but in collagen-induced arthritis rats, resveratrol was able to reduce the duration of atrial fibrillation episodes, in part by decreasing the production of IL-6, TNF-a and lower atrial remodeling4545 Zhang Y, Zhang S, Liu Z, Zhao X, Yuan Y, Sheng L, Li Y. Resveratrol prevents atrial fibrillation by inhibiting atrial structural and metabolic remodeling in collagen-induced arthritis rats. Naunyn Shmiedeberrgs Arch Pharmacol. 2018;391(11):1179-90. https://doi.org/10.1007/s00210-01-1554-9
https://doi.org/10.1007/s00210-01-1554-9...
. Humans with very long chain acetyl-CoA dehydrogenase deficiency (VLCAD), an electron transfer flavoprotein-dependent enzyme located in the internal mitochondrial matrix, have a defect in the mitochondrial oxidation of long-chain fatty acids, leading to the development of hypertrophic heart disease and arrhythmias that can lead to death. The treatment of these patients involves the administration of glucose, a high caloric diet with medium chain triglycerides and supplementation with L-carnitine4646 Cecatto C, Amaral AU, da Silva JC, Wajner A, Schimit MOV, da Silva LHR, Wajner SM, Zanatta A, Castilho RF, Wajner M. Metabolite accumulation in VLCAD deficiency markedly disrupts mitochondrial bioenergetics and Ca2+ homeostasis in the heart. FEBS J. 2018;285(8):1437-55. https://doi.org/10.1111/febs.14419
https://doi.org/10.1111/febs.14419...
. Using differentiated cardiomyocytes from pluripotent stem cells of a patient with VLCAD, it was found that resveratrol led to increased fatty acid oxidation by increasing mitochondrial biogenesis and control of cytosolic Ca2+ concentration, which could lead to better control of arrhythmias in these patients by consuming food containing resveratrol4747 Knottnerus SJG, Mengarelli I, Wust RCI, Baartscheer A, Bleeker JC, Coronel R, Ferdinandusse S, Guan K, IJIst L, Li W, Luo X, Portero VM, Ulbricht Y, Visser G, Wansers RJA, Wijburg FA, Verkerk AO, Houtkooper RH, Bezzina CR. Electrophysiological abnormalities in VLCAD deficient hiPSC-cardiomyocytes can be improved by lowering accumulation of fatty acid oxidation intermediates. Int J Mol Sci. 2020;21(7):2589. https://doi.org/10.3390/ijms21072589
https://doi.org/10.3390/ijms21072589...
.

In addition to cardiac activity, resveratrol also produces vasodilation by synthesis of NO4848 Rush JW, Quadrilatero J, Levy AS, Ford RJ. Chronic resveratrol enhances endothelium-dependent relaxation but does not alter eNOS levels in aorta of spontaneously hypertensive rats. Exp Biol Med. 2007;232(6):814-22., but this phenomenon can also attribute to its ability to modulate Ca2+ concentration in the endothelial and vascular smooth muscle cells4949 Chen Y, Xu C, Wei Y, Zhang Y, Cao A. Endothelium-dependent and independent relaxation induced by resveratrol in rat superior mesenteric arteries. Exp Ther Med. 2016;12(4):2241-6. https://doi.org/10.3892/etm.2016.3605
https://doi.org/10.3892/etm.2016.3605...

50 Protic D, Beleslin-Čokić B, Novaković R, Kanjuh V, Heinle H, Sćepanović R, Gojković-Bukarica L. Effect of wine polyphenol resveratrol on the contractions elicited electrically or by norepinephrine in the rat portal vein. Phytother Res. 2013;27(11):1685-93. https://doi.org/10.1002/ptr.4907
https://doi.org/10.1002/ptr.4907...

51 Buluc M, Demirel-Yilmaz E. Resveratrol decreases calcium sensitivity of vascular smooth muscle and enhances cytosolic calcium increase in endothelium. Vasc Pharmacol. 2006;44(4):231-7. https://doi.org/10.1016/j.vph.2005.12.003
https://doi.org/10.1016/j.vph.2005.12.00...

52 Li H, Xia N, Forstermann U. Cardiovascular effects and molecular targets of resveratrol. Nitric Oxide. 2012;26(2):102-10. https://doi.org/10.1016/j.niox.2011.12.006
https://doi.org/10.1016/j.niox.2011.12.0...
-5353 Liu W, Chen P, Deng J, Lv J, Liu J. Resveratrol and polydatin as modulators of Ca2+ mobilization in the cardiovascular system. Ann N Y Acad Sci. 2017;1403(1):82-91. https://doi.org/10.1111/nyas.13386
https://doi.org/10.1111/nyas.13386...
. In these smooth cells, resveratrol inhibits intracellular Ca2+ release from the sarcoplasmic reticulum mediated by ryanodine (RyR) and inositol 1,4,5-triphosphate (IP3R) receptors, decreases the sensitivity of troponin-C to Ca2+, and promote an increase in sensitivity of cardiomyocytes5151 Buluc M, Demirel-Yilmaz E. Resveratrol decreases calcium sensitivity of vascular smooth muscle and enhances cytosolic calcium increase in endothelium. Vasc Pharmacol. 2006;44(4):231-7. https://doi.org/10.1016/j.vph.2005.12.003
https://doi.org/10.1016/j.vph.2005.12.00...
. We have proposed that the combination of pharmacological effects of resveratrol on the cardiomyocytes (antiarrhythmic actions) and coronary vascular cells (vasodilator actions) could decisively contribute to attenuate the myocardial injury and severe arrhythmias caused by long-term cardiac ischemia and reperfusion33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
.

These findings indicate that resveratrol is able to shorten the duration of cardiac arrhythmias, incidence of ventricular tachycardia and mortality caused by ischemia and reperfusion due to its multiple cardioprotective actions, especially by attenuation or prevention of production of reactive oxygen species (antioxidant activity), cytosolic Ca2+ overload and bioenergetic mitochondrial collapse in cardiac cells33 Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent advances in pharmacological and non-pharmacological strategies of cardioprotection. Int J Mol Sci. 2019;20(16):4002. https://doi.org/10.3390/ijms20164002
https://doi.org/10.3390/ijms20164002...
,1111 McCalley AE, Kaja S, Payne AJ, Koulen P. Resveratrol and calcium signaling: molecular mechanisms and clinical relevance Molecules. 2014;19(6):7327-40. https://doi.org/10.3390/molecules19067327
https://doi.org/10.3390/molecules1906732...
,1414 Barangi S, Hayes AW, Karimi G. The more effective treatment of atrial fibrillation applying the natural compounds; as NADPH oxidase an ion channel inhibitor. Crit Rev Food Sci Nutri. 2018;58(7):1230-41. https://doi.org/10.1080/10408398.2017.1379000
https://doi.org/10.1080/10408398.2017.13...
.

Conclusion

The results obtained in this study support the idea that the prophylactic use of resveratrol-containing grape-derived products prevents lethal cardiac arrhythmias in an animal model of ischemia and reperfusion, supporting the idea that this treatment can be similarly beneficial for prevention of severe cardiac arrhythmias in patients with ischemic heart disease. Further efforts are still required to broaden our understanding of how potential mechanisms, such as control of oxidative stress, intracellular Ca2+ homeostasis and mitochondrial dysfunction contribute towards the underlying mechanistic network and to narrow the knowledge gap between preclinical studies and human trials of resveratrol.

Acknowledgments

Not applicable.

  • Funding

    Fundação de Amparo à Pesquisa do Estado de São Paulo
    Grant# 2017/25565-1
  • Data availability statement

    Data will be available upon request.
  • Research performed at Laboratory of Autonomic and Cardiovascular Pharmacology, Universidade Federal de São Paulo, São Paulo (SP), Brazil.

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Publication Dates

  • Publication in this collection
    07 May 2021
  • Date of issue
    2021

History

  • Received
    06 Nov 2020
  • Reviewed
    08 Jan 2021
  • Accepted
    07 Feb 2021
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