Search

Myocardial ischemia–reperfusion arrhythmia after cardiac surgery is common and seriously affects quality of life. Remote ischemic preconditioning can reduce the myocardial damage caused by severe ischemia. However, the underlying mechanism is not well understood. This study aimed to investigate the effects of exosomes derived from C2C12 mouse myoblasts after hypoxic preconditioning (HP) on ventricular conduction in hypothermic ischemia–reperfusion hearts. Myocardial ischemia–reperfusion model rats were established using the Langendorff cardiac perfusion system. Exosomes derived from normoxic (ExoA) and hypoxia-preconditioned (ExoB) C2C12 cells were injected into the jugular vein of the model rats. The time to heartbeat restoration, arrhythmia type and duration, and heart rate were recorded after myocardial ischemia–reperfusion. Conduction velocity on the surface of left ventricle was measured using a microelectrode array after 30 min of balanced perfusion, 15 min of reperfusion, and 30 min of reperfusion. Immunohistochemistry and western blotting were performed to determine the distribution and relative expression of connexin 43 (Cx43). ExoB contained more exosomes than ExoA, showing that HP stimulated the release of exosomes. The IR + ExoB group showed faster recovery of ventricular myocardial activity, a lower arrhythmia score, faster conduction velocity, and better electrical conductivity than the IR group. ExoB increased the expression of Cx43 and reduced its lateralization in the ventricular muscle. Our study showed that exosomes induced by hypoxic preconditioning can improve ventricular myocardial conduction and reperfusion arrhythmia in isolated hearts after hypothermic ischemia–reperfusion. [ABSTRACT FROM AUTHOR]

Background. Myocardial ischemia-reperfusion (I/R) injury is still thought to be an unsolved puzzle that may lead to reperfusion arrhythmias and sudden cardiac death. Inflammation plays a key role in myocardial I/R. Studies have indicated that purinoceptor 2Y12 (P2Y12) antagonists have anti-inflammatory properties that are cardioprotective. Objectives. In this study, we explored whether inhibition of P2Y12 in macrophages could reduce cardiac inflammation and attenuate reperfusion arrhythmias after myocardial I/R. Materials and methods. Rats were randomly divided into 4 groups: group A (control + vehicle); group B (control + P2Y12 shRNA lentiviral vector); group C (myocardial I/R + vehicle); and group D (myocardial I/R + P2Y12 shRNA lentiviral vector). Infarct size, reperfusion arrhythmias, and P2Y12 and platelet endothelial cell adhesion molecule-1 (CD31) protein expression were measured. Results. The incidence of reperfusion ventricular tachycardia and fibrillation (VT/VF) was 90% in the I/R group, while it was reduced to 50% by P2Y12 shRNA treatment. Ionized calcium binding adapter molecule 1 and P2Y12 immunoreactivity in the myocardial I/R + P2Y12 shRNA group was lower compared to the myocardial I/R group. P2Y12 shRNA treatment increased α-smooth muscle actin (α-SMA) and CD31 protein expression, as evidence by western blot and immunohistochemistry analyses (0.31 ±0.01 compared to 0.26 ±0.008, group D compared to group C, p < 0.05). Conclusions. Inhibition of P2Y12 in macrophages improved reperfusion arrhythmias in our rat I/R model, suggesting that blocking P2Y12 could decrease the inflammatory response after cardiac perfusion. [ABSTRACT FROM AUTHOR]

Aims: The restoration of coronary circulation plays a crucial role in treating ST-segment elevation myocardial infarction (STEMI), however successful reperfusion with primary percutaneous coronary intervention (PPCI) may induce life-threatening arrhythmias. The relation between myocardial electrical instability, as a background factor in reperfusion arrhythmia, and magnesium administered periprocedurally is still questionable. Several randomized clinical trials have been conducted predominantly in the thrombolysis era. Due to the contradictory results of these studies, there is little evidence of the potential preventive effect of magnesium on reperfusion arrhythmias. The aim of our study is to review and meta-analytically analyze data from all studies published so far in the PPCI era, comparing STEMI patients who have undergone primary PCI and received either magnesium or a placebo before the reperfusion procedure.Methods and Results: Our meta-analysis follows the points in the PRISMA protocol and, meets all of their criteria. We conducted a search in five scientific databases using the following keyword combination: (myocardial infarction OR myocardial injury OR acute coronary syndrome OR acs OR stemi) AND magnesium. The 7,295 collected publications were filtered with the Endnote program by title, abstract and full-text based on predefined criteria. A statistical analysis was performed on three randomized-controlled trials using three common parameters, involving 336 patients Trial sequential analysis (TSA) was applied to assess the risk of random error associated with sparse data and multiple testing which can affect cumulative meta-analysis. The incidence of ventricular tachycardias (VTs) was not significantly increased in the non-magnesium control group. (OR: 1.36; CI: 0.619; −2.986, P = 0.263). For the ejection fraction (EF), a non-significant decrease was observed in the magnesium group by weighted mean difference calculation. (WMD: 7.262, 95% CI: −0.238; 0.053; P = 0.057). There was significant decrease in the infarct zone wall motion index (IZWMSI) in the magnesium treatment group. (WMD: 0.384, 95% CI: −0.042; 0.811, P = 0.015). Based on the TSA assessments, the results of all parameters are not significant, objectively demonstrating the lack of reasonable data pertaining to our question.Conclusions: The preventive effect of magnesium on reperfusion arrhythmia associated with primary PCI can still be considered contradictory based on previous studies. In our study, we found, that magnesium is ineffective with a very weak evidence, due to the small number of patients and the biases of the included studies, and a well-designed clinical trial is needed in this area, based on the TSA.

Reperfusion of ischemic myocardium is crucial for salvaging myocardial cells from ischemic cell death. However, reperfusion itself induces various deleterious effects on the ischemic myocardium. These effects, known collectively as reperfusion injury, comprise stunned myocardium, reperfusion-induced arrhythmia, microvascular reperfusion injury, and lethal reperfusion injury. No approach has proven successful in preventing any of these injuries in the clinical setting. My colleagues and I recently proposed a new postconditioning protocol, postconditioning with lactate-enriched blood (PCLeB), for the prevention of reperfusion injury. This new approach consists of intermittent reperfusion and timely coronary injections of lactated Ringer's solution, aiming to achieve controlled reperfusion with cellular oxygenation and minimal lactate washout from the cells. This approach appeared to be effective in preventing all types of reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI), and we have already reported excellent in-hospital outcomes of patients with STEMI treated using PCLeB. In this review article, I discuss a possible mechanism of reperfusion injury, which we believe to be valid and which we targeted using this new approach, and I report how the approach worked in preventing each type of reperfusion injury.

Objective: To observe the effects of electroacupuncture at Neiguan (PC6) at different time points on reperfusion arrhythmia (RA) after myocardial ischemia and reperfusion in rats, and to investigate the correlation of this protective effect with nerve growth factor (NGF), tyrosine kinase A (TrkA), tyrosine hydroxylase (TH), and norepinephrine (NE). METHODS：A total of 72 Sprague-Dawley male rats were randomly divided into six groups ( n = 12 rats/group): normal group (Norm), sham operation group (Sham), ischemia reperfusion group (I/R), pre-ischemic electroacupuncture group (EAI), pre-reperfusion electroacupuncture group (EAII), post-reperfusion electroacupuncture group (EAIII). The myocardial ischemia-reperfusion injury (MIRI) model was induced by occlusion of left anterior descending coronary artery for 20 min followed by reperfusion for 40 min in rats. With no intervention in the Norm group and only threading without ligation in the Sham group. Electroacupuncture pre-treatment at 20 min/d for 7 d before ligation in the EAⅠ group, 20 min of electroacupuncture before reperfusion in the EAII group and 20 min of electroacupuncture after reperfusion in the EAIII group. The electrocardiogram (ECG) of each group was recorded throughout the whole process, and the success of the MIRI model was determined based on the changs of J-point and T-wave in the ECG. The arrhythmia score was used to record premature ventricular contractions, ventricular tachycardia and ventricular fibrillation during the reperfusion period to assess the reperfusion induced arrhythmias. The expression levels of NGF, TrkA, TH protein were measured by Western blot. Moreover, the expression levels of plasma and myocardial NE levels were detected by enzyme linked immunosorbent assay., Results: The differences between Norm group and Sham group were not statistically significant in all indexes. Arrhythmia score, myocardial NGF, TrkA, TH, and NE expression were significantly higher in the I/R group compared with the Sham group. Arrhythmia score, myocardial NGF, TrkA, TH, and NE expression were significantly lower in each EA group compared with the I/R group., Conclusion: Electroacupuncture at Neiguan (PC6) at different time points can reduce the incidence and severity of reperfusion arrhythmias in rats. This protective effect is related to electroacupuncture regulating NGF, TrkA, TH, NE expression and reducing sympathetic hyperactivation.

Vanillylmandelic acid, a catecholamine end-metabolite, has been shown to have several biological properties in previous studies, despite considered biologically inactive. We examined the potential effects of vanillylmandelic acid on the ischemic heart following myocardial infarction and reperfusion on a rat model. Thirty-four female Wistar rats were randomized into two groups, control and experimental. They were anesthetized and subjected to myocardial infarction through left anterior descending artery ligation. A previously studied dose of vanillylmandelic acid (10 mg/kg) was administered and the following parameters were studied during ischemia and reperfusion: a) mortality b) severity of ventricular tachyarrhythmias c) premature ventricular contractions and d) heart rate. Administration of vanillymandelic acid significantly reduced the severity of ventricular tachyarrhythmias and mortality rate during reperfusion, while it did not affect any other of the parameters studied. In conclusion, reperfusion injury was blunted through vanillylmandelic acid administration, which seems to be mediated by parasympathetic activation. [ABSTRACT FROM AUTHOR]

We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, n = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) (n = 9), or AMI-PostC (n = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs.

MiRNA-1 may participate in regulating ischemia–reperfusion injury (IRI) by affecting the expression and distribution of connexin 43 (Cx43). The aim of this study is to investigate miR-1 expression and its potential role in regulating Cx43 during ischemic postconditioning (IPOST) in a rat model. Fifty-five Wistar male rats were randomly divided into five groups: N, IR, IPOST, agomir-1, and antagomir-1 group. The hearts were perfused with the Langendorff system. The reperfusion arrhythmia (RA) and myocardial infarct size were observed and recorded. The miRNA-1 expression and the Cx43 expression and distribution were assessed by RT-PCR, immunoblotting, and immunohistochemistry. First, the RA score in the IR group was higher than that in the control group, whereas there was no difference between the IPOST and antagomir-1 groups. Second, the myocardial infarct size was larger in the agomir-1 than in the IPOST group; there was no difference between the antagomir-1 and the IPOST group. Third, the miRNA-1 expression increased by 78% in the agomir-1 group but decreased by 32% in the antagomir-1 group compared with the IPOST group. Fourth, compared with the Control group, the Cx43 expression in the IR group decreased, the Cx43 expression decreased in the agomir-1 group compared with the IPOST group. Fifth, the distribution of Cx43 was irregular and disorganized in the IR and agomir-1 groups. In the IPOST and antagomir-1 groups, Cx43 was neatly distributed in the intercalated disk area. Our findings suggest that IPOST can inhibit the up-regulation of miRNA-1 induced by ischemia–reperfusion and that the down-regulation of miRNA-1 can prevent the decrease and redistribution of Cx43, which will protect the heart from IRI. [ABSTRACT FROM AUTHOR]

We investigated the direct action of angiotensin II (Ang II) on myocardial conduction and transmembrane action potential immediately after reoxygenation. Method: After superfusion in a simulated ischemic solution, ventricular papillary muscle preparations of rat heart were washed with oxygenated Tyrode solution containing Ang II, Ang II plus CV-11974 (an AT1 receptor blocker), or Ang II plus 5-hydroxydecanoic acid (mito-KATP blocker), under rapid electrical stimulation (RES) for 60 s. Results: In the control experiments, the incidence of conduction delay and block was the highest within the first 10 s, and subsequently, 1:1 conduction was established after 40 s. Ang II significantly enhanced the 2:1 conduction block during the later phase of RES (40–60 s after reoxygenation). This effect of Ang II was abolished by either CV-11974 (P

Variant angina pectoris, also called Prinzmetal’s angina, is a syndrome caused by vasospasms of the coronary arteries. It can lead to myocardial infarction, ventricular arrhythmias, atrioventricular block and even sudden cardiac death. We report the case of a 53 year-old male patient with recurrent episodes of chest pain and arrhythmias in the course of related variant angina pectoris. It is likely that the reperfusion following myocardial ischemia was responsible for the ventricular fibrillation while the ST-segment returned to the baseline. This case showed that potential lethal arrhythmias could arise due to variant angina pectoris. It also indicated that ventricular fibrillation could be self-terminated. [ABSTRACT FROM AUTHOR]

Abstract: Pervious biochemical and hemodynamic studies have highlighted the important role of εPKC in cardioprotection during ischemic preconditioning. However, little is known about the electrophysiological consequences of εPKC modulation in ischemic hearts. Membrane permeable peptide εPKC selective activator and inhibitor were used to investigate the role of εPKC modulation in reperfusion arrhythmias. Methods: Protein transduction domain from HIV-TAT was used as a carrier for peptide delivery into intact Langendorff perfused guinea pig hearts. Action potentials were imaged and mapped (124 sites) using optical techniques and surface ECG was continuously recorded. Hearts were exposed to 30min stabilization period, 15min of no-flow ischemia, followed by 20min reperfusion. Peptides (0.5μM) were infused as follows: (a) control (vehicle-TAT peptide; TAT-scrambled ψεRACK peptide); (b) εPKC agonist (TAT-ψεRACK); (c) εPKC antagonist (TAT-εV1). Results: Hearts treated with εPKC agonist ψεRACK had reduced incidence of ventricular tachycardia (VT, 64%) and fibrillation (VF, 50%) compared to control (VT, 80%, P <0.05) and (VF, 70%, P <0.05). However, the highest incidence of VT (100%, P <0.05) and VF (80%) occurred in hearts treated with εPKC antagonist peptide εV1 compared to control and to εPKC agonist ψεRACK. Interestingly, at 20min reperfusion, 100% of hearts treated with εPKC agonist ψεRACK exhibited complete recovery of action potentials compared to 40% (P <0.05) of hearts treated with εPKC antagonist peptide, εV1 and 65% (P <0.5) of hearts in control. At 20min reperfusion, maps of action potential duration from εPKC agonist ψεRACK showed minimal dispersion (48.2±9ms) compared to exacerbated dispersion (115.4±42ms, P <0.05) in εPKC antagonist and control (67±20ms, P <0.05). VT/VF and dispersion from hearts treated with scrambled agonist or antagonist peptides were similar to control. Conclusion: The results demonstrate that εPKC activation by ψεRACK peptide protects intact hearts from reperfusion arrhythmias and affords better recovery. On the other hand, inhibition of εPKC increased the incidence of arrhythmias and worsened recovery compared to controls. The results carry significant therapeutic implications for the treatment of acute ischemic heart disease by preconditioning-mimicking agents. [Copyright &y& Elsevier]

Abstract: Aims: Oxytocin (OXT) pretreatment protects the heart during ischemia–reperfusion injury by activating ATP-dependent potassium (KATP) channels. The aim of the current study was to elucidate the roles of nitric oxide synthaseNOS and myocardial biochemistry in the cardioprotective effects of OXT and ischemic preconditioning (IPC). Main methods: Male New Zealand White anesthetized rabbits (13 groups) were subjected to 30min of occlusion of the left coronary artery and 120min of reperfusion with or without IPC. Key findings: IPC (1cycle), OXT (0.03μg/kg, i.p.) or IPC+OXT yield significant infarct size reductions (21.8±1.5%, 20.5±1.2% and 19.4±1.4%, respectively, versus 38.9±3.5% in the S-CONT group; P<0.01) and antiarrhythmic effects, including VF (0%, 0% and 0%, versus 50% in S-CONT group; P<0.05) sustained VT (13%, 13% and 13%, versus 100% in S-CONT group; P<0.005) and other arrhythmias (25%, 13% and 25%, versus 100% in S-CONT group; P<0.005, P<0.01 and P<0.005, respectively). Atosiban (ATO, a selective OXT receptor antagonist), 5-HD and l-NAME (a nonspecific NOS inhibitor) abolished the beneficial effects of IPC and OXT, suggesting that the benefits are achieved via selective activation of OXT receptors, mitochondrial KATP channels and NO. An iNOS inhibitor (1400W) blocked the beneficial effects of IPC but not OXT. The IPC, OXT, IPC+OXT and 1400W+OXT interventions significantly preserved ATP levels in the heart. Significance: This study demonstrates similarities between acute OXT pretreatment and IPC in terms of infarct size reduction, antiarrhythmic activity, and metabolic status. [Copyright &y& Elsevier]

Abstract: We investigated the direct action of angiotensin II (Ang II) on myocardial conduction and transmembrane action potential immediately after reoxygenation. Method: After superfusion in a simulated ischemic solution, ventricular papillary muscle preparations of rat heart were washed with oxygenated Tyrode solution containing Ang II, Ang II plus CV-11974 (an AT1 receptor blocker), or Ang II plus 5-hydroxydecanoic acid (mito-KATP blocker), under rapid electrical stimulation (RES) for 60s. Results: In the control experiments, the incidence of conduction delay and block was the highest within the first 10s, and subsequently, 1:1 conduction was established after 40s. Ang II significantly enhanced the 2:1 conduction block during the later phase of RES (40–60s after reoxygenation). This effect of Ang II was abolished by either CV-11974 (P<0.001) or 5-HD (P<0.001). Conclusion: RES-induced conduction delay and block immediately after reoxygenation were accelerated by Ang II, which could be relevant to the maintenance of reperfusion arrhythmias. The mito-KATP channel may participate in the mechanism underlying this phenomenon. [Copyright &y& Elsevier]

Abstract: Background: Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Levosimendan (LEV) is a new inodilator, whose mechanism of action includes calcium sensitization of contractile proteins and the opening of ATP-dependent potassium channels. Objectives and methods: The aim of this investigation was to test whether the administration of LEV has cardioprotective and antiarrhythmic effects against ischemia and reperfusion injury in a manner similar to ischemic preconditioning (IPC) in a well-standardized model of reperfusion arrhythmias in anesthetized adult male rabbits (n =122) subjected to 30 min occlusion of the left coronary artery followed by 120 min of reperfusion. Results: Pretreatment with either 1 cycle of IPC, LEV (0.1 μmol/kg, i.v.), or IPC+LEV prior to the period of coronary occlusion offers significant infarct size reduction (21.6±1.6%, 22.1±2.2%, and 21.4±1.4%, respectively vs 38.7±3.6% in saline control group; P <0.01) and antiarrhythmic effects. IPC, LEV and IPC+LEV treatment significantly attenuated the incidence of life-threatening arrhythmias like sustained VT (13%, 13% and 13%, respectively vs 100% in saline control group; P <0.005) and other arrhythmias (25%, 25% and 13%, respectively vs 100% in saline control group; P <0.005), and increased the number of surviving animals without arrhythmias. Pretreatment with 5-HD, N ω-nitro-l-arginine methyl ester (l-NAME, a nonspecific NOS inhibitor) and the specific iNOS inhibitor 1400W [N-(-3-(aminomethyl)benzyl) acetamidine] abolished the beneficial effects of IPC, and LEV on reperfusion induced arrhythmias and cardioprotection suggesting that benefits have been achieved via both the selective activation of cardiomyocyte mitochondrial KATP channels and NO. One cycle of IPC and LEV pretreatment significantly preserved the level of ATP in the 30 min ischemic heart and 120 min reperfused heart. Conclusions: The present study demonstrates similarities between acute LEV treatment and IPC of the rabbit myocardium in terms of survival, cardioprotection, antiarrhythmic activity, and metabolic status. [Copyright &y& Elsevier]

Border zones between normal and ischemic tissue have been implicated as a cause of arrhythmic cardiac activity. A variety of experiments with coupled cells and strips of tissue has been designed to understand the arrhythmogenic effects of border zone currents. In this paper, we use systems of differential equations to model an ischemic (depolarized) cell (or region) coupled to a normal cell under a variety of conditions. For two ionic models (reduced Hodgkin--Huxley and Luo--Rudy I), we find the boundary in parameter space between oscillatory and nonoscillatory solutions. We find that there are regions in parameter space for which the ischemic cell (region) is stable and inexcitable when uncoupled, but when coupled to a normal, excitable cell the cells oscillate. We state a general principle that relates the oscillation of a forced single cell to oscillations of the coupled system. Furthermore, in modeling drug-modified experimental dynamics we are able to reproduce early after depolarization (EAD)--like phenomena, which has implications in locating oscillations in the drug-free experiment. Finally, we describe a mechanism by which oscillations in the transmembrane potential may be encountered during reperfusion. [ABSTRACT FROM AUTHOR]

Abstract: The relative contributions of cardiomyocyte sarcolemmal ATP-sensitive K+ (KATP) and mitochondrial KATP channels in the cardioprotection and antiarrhythmic activity induced by KATP channel openers remain obscure, though the mitochondrial KATP channels have been proposed to be involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we sought to investigate the effects of administration of ATP-sensitive K+ channel (KATP) openers (nicorandil and minoxidil), a specific mitochondrial KATP channel blocker (5-hydroxydecanoate (5-HD)) and a specific sarcolemmal KATP channel blocker (HMR 1883; (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea) prior to coronary occlusion as well as prior to post-ischemic reperfusion on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n =88), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias was achieved by tightening a previously placed loose silk ligature for 30 min. In Group II (n =206), arrhythmias were induced by reperfusion following a 20-min ligation of the left main coronary artery. Both in Group I and Group II, intravenous (i.v.) administration of nicorandil (0.47 mg/kg), minoxidil (0.5 mg/kg), HMR 1883 (3 mg/kg)/nicorandil and HMR 1883 (3 mg/kg)/minoxidil before coronary artery occlusion increased survival rate (86%, 75%, 75% and 86% vs. 55% in the control subgroup in Group I; 75%, 67%, 67% and 75% vs. 46% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias. In Group II, i.v. administration of nicorandil and minoxidil before coronary artery occlusion significantly decreased myocardial infarct size. However, i.v. administration of nicorandil or minoxidil before reperfusion did neither increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and minoxidil were abolished by pretreating the rabbits with 5-HD (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker but not by HMR 1883 (3 mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in necrotic zone of myocardium in all the 16 subgroups in Group II suggest little anti-free radical property of nicorandil and minoxidil. We conclude that intervention by intravenous administration of nicorandil and minoxidil (through the selective activation of mitochondrial KATP channels) increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to coronary occlusion. The cardiomyocyte mitochondrial KATP channel may be a pharmacologically modulable target of cardioprotection and antiarrhythmic activity. [Copyright &y& Elsevier]

The roles of cardiomyocyte sarcolemmal ATP-sensitive K+ (KATP) and mitochondrial KATP channels in the cardioprotection and antiarrhythmic activity induced by KATP channel openers remain obscure, though the mitochondrial KATP channels have been proposed to be involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and cromakalim), a specific mitochondrial KATP channel blocker (5-hydroxydecanoate (5-HD)) and a specific sarcolemmal KATP channel blocker (HMR 1883; (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits.The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n=80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Group II (n=184), arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery.Both in Groups I and II, early intravenous infusion of nicorandil (100 μg/kg bolus+10 μg/kg/min), cromakalim (0.2 μg/kg/min), HMR 1883 (3 mg/kg)/nicorandil and HMR 1883 (3 mg/kg)/cromakalim just prior to and during ischemia increased survival rate (75%, 67%, 86% and 75% versus 60% in the control subgroup in Group I; 75%, 75%, 75% and 67% versus 50% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or cromakalim at the onset and during reperfusion did neither increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and cromakalim were abolished by pretreating the rabbits with 5-HD (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker but not by HMR 1883 (3 mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in necrotic zone of myocardium in all the 16 subgroups in Group II suggest little anti-free radical property of nicorandil and cromakalim.We, therefore, conclude that intervention by intravenous administration of nicorandil and cromakalim (through the selective activation of mitochondrial KATP channels), increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion. The mitochondrial KATP channel may be a potential site of cardioprotection and antiarrhythmic activity. [Copyright &y& Elsevier]

We investigated the effects of administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and aprikalim), and a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia/reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. Arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery with a releaseable silk ligature. Early intervention by intravenous infusion of nicorandil (100 μg/kg bolus+10 μg/kg/min) or aprikalim (10 μg/kg bolus+0.1 μg/kg/min) just before and during ischemia increased survival rate (86% and 75% vs. 55% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and myocardial infarct size. The antiarrhythmic and cardioprotective effects of both nicorandil and aprikalim were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus). In conclusion, intervention by intravenous administration of nicorandil and aprikalim (through the selective activation of mitochondrial KATP channels) increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion. [Copyright &y& Elsevier]

We investigated the effects of administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and bimakalim), and a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left fourth intercostal space and after pericardiotomy the heart was exposed. In Part I, occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Part II, arrhythmias were induced by reperfusion following a 20-min ligation of the left main coronary artery. In Part I, early intravenous infusion of nicorandil (100 µg/kg bolus + 10 µg/kg per min) or bimakalim (3 µg/kg bolus + 0.1 µg/kg per min) just prior to and during ischemia increased survival rate (75% and 67% vs. 60% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. In Part II also, early intervention by intravenous infusion of nicorandil (100 µg/kg bolus + 10 µg/kg per min) or bimakalim (3 µg/kg bolus + 0.1 µg/kg per min) just before and during ischemia increased survival rate (86% and 75% vs. 55% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or bimakalim at the onset and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and bimakalim were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker. In conclusion, intervention by intravenous administration of nicorandil and bimakalim (through the activation of mitochondrial KATP channels), increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion. [ABSTRACT FROM AUTHOR]

The aim was to study the effects of nicorandil (an ATP-sensitive K[sup +] channel opener) and tolbutamide (an ATP-sensitive K[sup +] channel blocker) on reperfusion-induced arrhythmias in pentobarbitone and ketamine anesthetized rabbits. Arrhythmias were induced by reperfusion for 20 min following a 15-min ligation of the left main coronary artery with a silk ligature. Rabbits were pretreated with nicorandil (0.47, 0.93 or 1.86 mg/kg i.v.) or tolbutamide (180 mg/kg i.p.) or vehicle (dimethylsulfoxide/saline) before the coronary artery occlusion. In the control group (n = 10), only 60% of the animals survived during reperfusion. Intravenous pretreatment with 0.47, 0.93 or 1.86 mg/kg of nicorandil increased the survival rate to 86% (n = 7), 75% (n = 8) and 86% (n = 7), respectively. Nicorandil pretreatment significantly decreased the incidence and duration of reperfusion-induced life-threatening arrhythmias and increased the number of animals that survived without developing any arrhythmia. Tolbutamide pretreatment was associated with a decreased survival rate of 50% (n = 12) and an increase in the incidence and duration of reperfusion-induced arrhythmias. Pretreatment with nicorandil may result in protection against reperfusion-induced arrhythmias and increased survival in anesthetized rabbits. [ABSTRACT FROM AUTHOR]

Magnesium sulfate (Mg) has been widely used for the treatment of ventricular arrhythmias (VF) in patients with coronary artery disease. However, the mechanisms of prevention on the incidence of VF have not been defined. The aim of study was to investigate the role of Mg in the prevention of VF and the mechanism of those effects. Series 1 studied antiarrhythmic effects on VF. Isolated rat hearts were perfused in the working heart mode with Krebs'-Henseleit bicarbonate buffer (KHB). Whole heart ischemia was induced by a one-way ball valve with 300 beats/min electrical pacing for 10 minutes followed by 20 minutes of aerobic reperfusion. After control perfusion, Mg was added from 5 minutes before ischemia and was continued to the end of ischemia (1.2 mM for the control group and 2.4, 3.6, 4.8, and 9.6 mM for the study animals) or during reperfusion (3.6 mM). Left ventricular pressure, aortic flow, and ECG were monitored. Series 2 studied the effect of Mg on [Ca2+]i. Hearts were perfused by the Langendorff mode and were loaded with 4 μM of Fura 2/AM as a [Ca2+]i indicator. Ca2+ was monitored using the ratio of Fura-2 fluorescence intensity at excitation wavelengths of 340 and 380 nm. The hearts were subjected to a 20 minutes of low-flow ischemia followed by 20 minutes of aerobic reperfusion. Then 3.6 mM Mg was added to the KHB medium during ischemia. The duration of VF was significantly suppressed in the 2.4, 3.6, and 4.8 mM/L Mg-added groups (472 ± 173, 779 ± 159, and 525 ± 202 second, respectively) when compared with the control group (1200 seconds). Magnesium sulfate suppressed the fluorescence ratio of the diastolic Ca2+ level at the end of 20 minutes of ischemia from 40.5 ± 3.6% to 9.0 ± 1.0% ( P ≤0.05 vs. control hearts). These results suggested that Mg had a beneficial effect on VF and that the optimal Mg concentration was between 2.4 and 4.8 mM. The mechanism of the prevention of VF by Mg could be through the inhibition of [Ca2+]i retention during ischemia. [ABSTRACT FROM AUTHOR]

We investigated the electrophysiological effect and antiarrhythmic potential of cinnamophilin (Cinn), a thromboxane A[sub 2] antagonist isolated from Cinnamomum philippinense, on rat cardiac tissues. Action potential and ionic currents in single rat ventricular cells were examined by current clamp or voltage clamp in a whole-cell configuration. In 9 episodes of ischemia-reperfusion arrhythmia, 10 μM Cinn converted 6 of them to normal sinus rhythm. Cinn suppressed the maximal rate of rise of the action potential upstroke (V[sub max] ) and prolonged the action potential duration at 50% repolarization (APD[sub 50] ). Voltage clamp study showed that the suppression of V[sub max] by Cinn was associated with an inhibition of sodium inward current (I[sub Na] , IC[sub 50] = 10.0 ± 0.4 μM). At 30 μM, V[sub 1/2] for the steady-state inactivation curve of I[sub Na] was shifted from –84.1 ± 0.2 to –93.0 ± 0.5 mV. Cinn also reduced calcium inward current (I[sub Ca] ) dose-dependently with an IC[sub 50] value of 9.5 ± 0.3 μM. Cinn (10 μM) reduced the I[sub Ca] with a negative shift of V[sub 1/2] for the steady-state inactivation curve of I[sub Ca] from –32.2 ± 0.3 to –50.7 ± 0.4 mV. The prolongation of APD[sub 50] was associated with an inhibition of the integral of potassium outward current with IC[sub 50] values between 4.8 and 7.1 μM. At 10 μM, Cinn reduced I[sub Na] without a negative shift of its voltage-dependent steady-state inactivation curves. The inhibition of transient outward current (I[sub to] ) by Cinn (3–30 μM) was associated with an acceleration of its time constant of inactivation and negative shift of its potential-dependent steady-state inactivation curves. The equilibrium dissociation constant (K[sub d] ) of Cinn to inhibit open state I[sub to] channels, as calculated from the time constant of developing block, was 18.3 μM. The time constant of recovery of I[sub to] from inactivation state was unaffected by Cinn. The rate constant for the relief from the depolarization-dependent block of I[sub to] was calculated to be 23.9 ms. As compared with its effect on I[sub to] , Cinn exerted about half the potency to block I[sub Na] and I[sub Ca] . These results indicate that the inhibition of I[sub Na] , I[sub Ca] and I[sub to] may contribute to the antiarrhythmic activity of Cinn against ischemia-reperfusion arrhythmia. [ABSTRACT FROM AUTHOR]

Membrane lipid peroxidation is known to play a pivotal role in the genesis of coronary reperfusion arrhythmias in both experimental and clinical settings. To elucidate the electrophysiological mechanisms underlying these arrhythmias, the effects of tert butyl hydroperoxide (TBH) on the Na current (I) in isolated feline ventricular myocytes were studied using whole-cell patch clamp techniques under 100% O bubbling. This agent at 20 mM inhibited I from 2.2 ± 1.3 to 1.7 ± 1.0nA ( P < 0.01, n = 7) without changing time courses of I inactivation. Twenty millimoles TBH shifted the steady-state inactivation curve for I from −77.4 ± 1.7 to −81.3 ± 1.8mV when measured at I half inhibition voltage ( P < 0.01, n = 7), but did not affect the slope factor. The kinetics of I recovery from inactivation remained unchanged. These findings suggest that lipid peroxidation in the membrane by TBH reduces I conductance and voltage-dependent I availability, most likely as a result of structural damage to the Na channels. [ABSTRACT FROM AUTHOR]

Alpha-adrenoceptors mediating positive inotropic effects are well established in the heart of various species including human heart. The mechanism by which alpha-adrenoceptor stimulation increases force of contraction is not known. cAMP is unlikely to be involved as a mediator. Evidence has been presented that an increase in magnitude and duration of the slow Ca inward current may be partly responsible for the positive inotropic efffect. In addition, stimulation of alpha-adrenoceptors may increase Ca sensitivity of the contractile proteins. Stimulation of alpha-adrenoceptors by endogenous catecholamines may serve as a reserve mechanism under various conditions of impaired beta-adrenergic influence, e.g. hypothyroidism, bradycardia or ischemia. Furthermore, alpha-adrenoceptors may be involved in the genesis of reperfusion arrhythmias in ischemic heart. [ABSTRACT FROM AUTHOR]

The mechanism for the suppression of reperfusion arrhythmia by preconditioning (PC) remains unknown. This study aimed to examine the roles of the adenosine receptor, prostaglandin (PG), and bradykinin (BK) receptor in PC. Under pentobarbital anesthesia, the coronary artery of the rat was occluded for 5 min and then reperfused. In untreated controls, this protocol induced ventricular tachycardia (VT) in 100% of the rats and ventricular fibrillation (VF) in 60%. PC with 2 min ischemia/5 min reperfusion prior to the 5 min coronary occlusion significantly reduced the incidence of reperfusion VT and VF to 30% and 0%, respectively. This antiarrhythmic effect of the PC was not blocked when rats were pretreated with 8-phenyltheophylline (8-PT, 10 mg/kg), aspirin-DL-lysin (18 mg/kg), or a specific BK receptor antagonist, Hoe 140 (20 nmol/kg). None of these agents alone significantly modified the incidence of reperfusion VT or VF. These results suggest that neither the adenosine receptor, endogenous PG, nor BK receptor play a major role in the mechanism of suppression of perfusion arrhythmias by PC in the rat heart. [ABSTRACT FROM AUTHOR]

Losartan, an angiotensin II receptor antagonist with no bradykinin potentiating property, provides the opportunity to study the consequences of blocking angiotensin II. The objective of this study was to evaluate the antiarrhythmic responses of reperfusion arrhythmia to losartan in dogs. The effects of losartan on ventricular tachyarrhythmias induced during occlusion and reperfusion of the left anterior descending coronary artery were investigated in 30 dogs. The animals were randomized to receive either losartan (n = 15) or saline (n = 15). The VF inducing threshold was measured before occlusion and after reperfusion. Losartan (50 μg/kg per min) or saline was intravenously administered 5 minutes before occlusion and continued throughout the entire study period. The incidence of ventricular tachyarrhythmias during reperfusion was lower in the losartan group than in the control group (4/15 vs 6/15). There was no significant change in VF inducing threshold between the period before occlusion and during reperfusion in the losartan group (10.9 ± 5.7 vs 11.1 ± 5.7 mA, P = NS), whereas there was a significant decrease in the control group (15.5 ± 4.4 vs 7.7 ± 3.9 mA, P < 0.01). Blockade of the angiotensin II receptor has beneficial effects on reperfusion arrhythmias. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia-reperfusion (I/R) injury is still thought to be an unsolved puzzle that may lead to reperfusion arrhythmias and sudden cardiac death. Inflammation plays a key role in myocardial I/R. Studies have indicated that purinoceptor 2Y12 (P2Y12) antagonists have anti-inflammatory properties that are cardioprotective., Objectives: In this study, we explored whether inhibition of P2Y12 in macrophages could reduce cardiac inflammation and attenuate reperfusion arrhythmias after myocardial I/R., Material and Methods: Rats were randomly divided into 4 groups: group A (control + vehicle); group B (control + P2Y12 shRNA lentiviral vector); group C (myocardial I/R + vehicle); and group D (myocardial I/R + P2Y12 shRNA lentiviral vector). Infarct size, reperfusion arrhythmias, and P2Y12 and platelet endothelial cell adhesion molecule-1 (CD31) protein expression were measured., Results: The incidence of reperfusion ventricular tachycardia and fibrillation (VT/VF) was 90% in the I/R group, while it was reduced to 50% by P2Y12 shRNA treatment. Ionized calcium binding adapter molecule 1 and P2Y12 immunoreactivity in the myocardial I/R + P2Y12 shRNA group was lower compared to the myocardial I/R group. P2Y12 shRNA treatment increased α-smooth muscle actin (α-SMA) and CD31 protein expression, as evidence by western blot and immunohistochemistry analyses (0.31 ±0.01 compared to 0.26 ±0.008, group D compared to group C, p < 0.05)., Conclusions: Inhibition of P2Y12 in macrophages improved reperfusion arrhythmias in our rat I/R model, suggesting that blocking P2Y12 could decrease the inflammatory response after cardiac perfusion.

We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, n = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) (n = 9), or AMI-PostC (n = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs. [ABSTRACT FROM AUTHOR]