Ischemia-induced Ventricular Arrhythmias Research Articles

Neuroimmune modulation mediated by IL-6: A potential target for the treatment of ischemia-induced ventricular arrhythmias

BackgroundNeural remodeling in the left stellate ganglion (LSG), as mediated by neuroimmune reactions, promotes cardiac sympathetic nerve activity (SNA) and thus increases the incidence of ventricular arrhythmias (VAs). Interleukin-6 (IL-6) is an important factor of the neuroimmune interaction. ObjectiveThe present study explored the effects of IL-6 on LSG hyperactivity and the incidence of VAs. MethodsEighteen beagles were randomly allocated to a control group (saline with myocardial infarction [MI], n = 6), adeno-associated virus (AAV) group (AAV with MI, n = 6), and IL-6 group (overexpression of IL-6 via AAV vector with MI, n = 6). Ambulatory electrocardiography was performed before and 30 days after AAV microinjection into the LSG. LSG function and ventricular electrophysiology were assessed at 31 days after surgery, and a canine MI model was established. Samples of the LSG were collected for immunofluorescence staining and molecular biological evaluation. Blood samples and 24-hour Holter data were obtained from 24 patients with acute MI on the day after they underwent percutaneous coronary intervention to assess the correlation between IL-6 levels and SNA. ResultsIL-6 overexpression increased cardiac SNA and worsened postinfarction VAs. Furthermore, sustained IL-6 overexpression enhanced LSG function, promoted expression of nerve growth factor, c-fos, and fos B in the LSG, and activated the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway. Clinical sample analysis revealed a correlation between serum IL-6 levels and heart rate variability frequency domain index as well as T-wave alternans. ConclusionIL-6 levels are correlated with cardiac SNA. Chronic overexpression of IL-6 mediates LSG neural remodeling through the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway, elevating the risk of VA after MI.

Targeted ablation of the left middle cervical ganglion prevents ventricular arrhythmias and cardiac injury induced by AMI.

Cardiac sympathetic overactivation is a critical driver in the progression of acute myocardial infarction (AMI). The left middle cervical ganglion (LMCG) is an important extracardiac sympathetic ganglion. However, the regulatory effects of LMCG on AMI have not yet been fully documented. In the present study, we detected that the LMCG was innervated by abundant sympathetic components and exerted an excitatory effect on the cardiac sympathetic nervous system in response to stimulation. In canine models of AMI, targeted ablation of LMCG reduced the sympathetic indexes of heart rate variability and serum norepinephrine, resulting in suppressed cardiac sympathetic activity. Moreover, LMCG ablation could improve ventricular electrophysiological stability, evidenced by the prolonged ventricular effective refractory period, elevated action potential duration, increased ventricular fibrillation threshold, and enhanced connexin43 expression, consequently showing antiarrhythmic effects. Additionally, compared with the control group, myocardial infarction size, circulating cardiac troponin I, and myocardial apoptosis were significantly reduced, accompanied by preserved cardiac function in canines subjected to LMCG ablation. Finally, we performed the left stellate ganglion (LSG) ablation and compared its effects with LMCG destruction. The results indicated that LMCG ablation prevented ventricular electrophysiological instability, cardiac sympathetic activation, and AMI-induced ventricular arrhythmias with similar efficiency as LSG denervation. In conclusion, this study demonstrated that LMCG ablation suppressed cardiac sympathetic activity, stabilized ventricular electrophysiological properties and mitigated cardiomyocyte death, resultantly preventing ischemia-induced ventricular arrhythmias, myocardial injury, and cardiac dysfunction. Neuromodulation therapytargeting LMCG represented a promising strategy for the treatment of AMI.

PS-B02-5: NICORANDIL SUPPRESSES ISCHEMIA-INDUCED CARDIAC NOREPINEPHRINE ENHANCEMENT AND VENTRICULAR ARRHYTHMIAS IN PRESSURE OVERLOAD-INDUCED HYPERTROPHIC HEARTS.

Objective: Ventricular arrhythmias are a common cause of sudden death in acute myocardial infarction (MI) and hypertension is a major risk factor of MI. Nicorandil, an ATP sensitive potassium channel (KATP) opener, is usually used in the treatment of acute MI. KATP expresses in nerve terminals as well as cardiomyocytes and KATP in nerve terminals regulates norepinephrine release. The effects of nicorandil on ischemic myocyte are fully defined. On the other hand, the roles of nicorandil on ischemic norepinephrine release in hypertrophic cardiac tissue has remained unexplored. We examined whether nicorandil suppressed interstitial norepinephrine level and ventricular arrhythmia during acute ischemia in chronic pressure overload-induced hypertrophic hearts. Design and Methods: Rats were divided into two groups: abdominal aortic constriction (AAC) group and sham-operated (Sham) group. Four weeks after constriction, cardiac geometry and function were examined using echocardiography and hemodynamic measurements, and cardiac tissues were stained with hematoxylin and eosin and Sirius Red for histological examinations. In other rats, 4 weeks after constriction myocardial ischemia was induced by the left anterior descending artery occlusion for 100 minutes in the presence or absence of intravenous infusion of nicorandil. Cardiac interstitial norepinephrine concentration in ischemic region was measured using the microdialysis method. Ventricular arrhythmias were monitered by ECG during whole ischemic period. Results: Four weeks after constriction, remarkable left ventricular wall thickening and diastolic dysfunction were observed in AAC group. In histological examination, remarkable myocyte hypertrophy and interstitial fibrosis were observed in AAC group. Before ischemia, ventricular arrhythmia was not found in both groups. Number of ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, was increased in early ischemic period (−20 min) in both groups, and was grater in AAC group. Before ischemia, interstitial norepinephrine concentration in cardiac tissue was higher level in AAC group than in Sham group, and ischemia increased norepinephrine concentration in both groups. Nicorandil administration in ischemic period significantly suppressed the number of ventricular arrhythmias and abolished the ventricular tachycardia and fibrillation without hemodynamic alterations in hypertrophic hearts. Nicorandil also attenuated epinephrine enhancement in acute ischemic period in hypertrophic hearts. Conclusion: Ischemia-induced ventricular arrhythmias were more frequent and severe in hypertrophic hearts and associated with high interstitial norepinephrine concentration. Nicorandil suppressed ischemia-induced interstitial norepinephrine release by neuronal KATP opening, which attenuated ventricular arrhythmias in pressure overload-induced hypertrophic hearts.

Bmal1 knockdown in the left stellate ganglion inhibits neural activity and prevents ventricular arrhythmias after myocardial ischemia.

ObjectivesThe neural activity of the left stellate ganglion (LSG) is closely related to the occurrence of ventricular arrhythmias (VAs). Bmal1 modulates genes associated with neural activity in the central nervous system. However, few studies indicated the role of Bmal1 in the LSG and the subsequent effect on the heart. Therefore, we aimed to investigate the influence of Bmal1 knockdown in the LSG on its neural activity and cardiac electrophysiology and to explore the mechanisms.Materials and methodsWe used adeno-associated virus (AAV) to knock down Bmal1 in the LSG. Male beagles were randomized into the Bmal1 knockdown group and the control group. After 4 weeks of injection, the LSG function, neural activity, left ventricular effective refractory period (ERP), and action potential duration (APD) were measured. Electrocardiography for 1 h was recorded for VAs analysis after myocardial ischemia. Nerve growth factor (NGF) and c-fos in the LSG were quantified by immunofluorescence. Transcriptomic analysis was performed to assess the gene expression in the LSG.ResultsBmal1 was sufficiently knocked down by AAV. Compared with the control group, heart rate variability (HRV) in the knockdown group was altered. Bmal1 knockdown inhibited neural activity and function of LSG. It also prolonged ERP as well as APD90. Ischemia-induced VAs were significantly reduced. Nerve growth factor (NGF) and c-fos in the LSG were reduced. Bmal1 knockdown led to the expression changes of genes associated with neural activity in the LSG.ConclusionBmal1 knockdown in the LSG suppresses neural activity and prevents ventricular arrhythmias after myocardial ischemia.

Cardioprotective properties of the platelet P2Y12 receptor inhibitor prasugrel on cardiac ischemia/reperfusion injury.

The effects of prasugrel, a third-generation thienopyridine, on myocardial infarction, and ischemia-induced ventricular arrhythmias was evaluated in open-chest anesthetized rats. The role of protein kinase C and phosphoinositide 3-kinase pathways in these effects was also examined. The effect of P2Y12 receptor inhibition by prasugrel (3-10mg/kg, po) on infarct size after 30-min coronary artery occlusion and 120-min reperfusion or on arrhythmias after 7-min coronary occlusion and 7-min reperfusion was evaluated. In the control group, 31.25 ± 3.01% of the risk zone infarcted. At both prasugrel doses, infarct size was significantly smaller than that in the control group: 5.03 ± 0.81% for 3mg/kg (p < 0.0001), and 8.78 ± 2.04% for 10mg/kg (p < 0.0001). The protein kinase C antagonist chelerythrine abolished the anti-infarct effect of prasugrel at 24.77 ± 1.73% as did the phosphoinositide 3-kinase antagonist wortmannin abolished the anti-infarct effect of prasugrel at 27.45 ± 2.74%. Ten mg/kg prasugrel reduced the duration of VT (p = 0.0152 vs control), and wortmannin, but not chelerythrine, reversed the effect of prasugrel on arrhythmias (p = 0.0295). The selective P2Y12 inhibitor prasugrel provides effective protection against myocardial infarction and ischemia-induced ventricular arrhythmias in rats. As in ischemic postconditioning, protein kinase C and phosphoinositide 3-kinase signaling pathways play a role in this protection.

Selective chemical ablation of transient receptor potential vanilloid 1 expressing neurons in the left stellate ganglion protects against ischemia-induced ventricular arrhythmias in dogs

ObjectivesFindings from prior investigations show that left stellate ganglion (LSG) inhibitory approaches protect the heart from ventricular arrhythmias (VAs) caused by acute myocardial infarction (AMI), which still remain many side effects. Targeted transient receptor potential vanilloid 1/tyrosine hydroxylase (TRPV-1/TH) expressing sympathetic neurons ablation is a novel neuro-ablative strategy. The aim of this investigation was to explore if targeted molecular neuro-ablative strategy by resiniferatoxin (RTX) stellate microinjection could protect against ischemia-induced VAs. MethodsTwenty-four anesthetized beagles were assigned to a control group (n = 12) and RTX group (n = 12) in a random manner. Targeted molecular neuro-ablative was produced by RTX stellate microinjection and DMSO was microinjected into LSG in the same way as control. Plasma norepinephrine (NE) level, heart rate variability (HRV), Tpeak-Tend interval (Tp-Te), LSG neural activity and function, ventricular effective refractory period (ERP), beat-to-beat variability of repolarization (BVR) and ventricular action potential duration (APD) were measured at baseline and 60 min after RTX or DMSO microinjection. AMI model was established by the ligation of left anterior descending coronary artery and 60-minute electrocardiography was continuously recorded for VAs analysis. Subsequently, HRV, Tp-Te, plasma NE level from jugular vein and coronary sinus, LSG neural activity and function, ventricular ERP, ventricular APD, BVR, action potential duration alternans (APDA) cycle length and ventricular fibrillation threshold (VFT) were evaluated after AMI. Finally, tissue collection of LSG was performed for examining the TRPV-1, nerve growth factor (NGF) protein and c-fos protein. ResultsTRPV-1 was highly expressed in the TH-expressing neurons and RTX injection significantly ablated TRPV-1/TH-positive neurons in LSG. Compared with baseline, RTX stellate microinjection significantly reduced plasma NE level, the sympathetic component of HRV, LSG neural activity and LSG function, shortened Tp-Te, prolonged ventricular ERP and APD, but there were no remarkable differences existed for control group. AMI resulted in the significant raise in plasma NE level from jugular vein and coronary sinus, the sympathetic component of HRV, LSG neural activity and LSG function, the marked prolongation in Tp-Te and BVR, the significant decrease in ERP and APD from ischemia area, and the increase in APDA cycle length in the ischemic region of the control group, which were remarkably attenuated in the RTX group. RTX pretreatment markedly rose the VFT in the RTX group. Furthermore, the AMI-triggered VAs was significantly prevented by RTX injection in the RTX group. RTX microinjection down-regulated significantly TRPV-1, NGF and c-fos expression in the LSG compared with the control group. ConclusionTargeted ablation of TRPV-1/TH positive sympathetic neurons induced by RTX stellate microinjection could suppress ischemia-induced cardiac autonomic imbalances and cardiac electrophysiology instability to protect against AMI-induced VAs.

Single cell investigation of mechanically-induced arrhythmias during acute ischemia

Introduction: Ischemia-induced ventricular arrhythmias are a major cause of sudden death. We have demonstrated a contribution of altered mechanics to ischemia-induced arrhythmias, which appear to be calcium-driven and facilitated by a ‘vulnerable window’ (VW) created by spatio-temporal differences in voltage-calcium dynamics. The aim of our current work is to test the hypothesis that mechanically-induced arrhythmias during acute ischemia are indeed calcium-driven, due to distinct changes in action potential (APD) and calcium transient (CaTD) duration.

Nitrite Reduces Ischemia-Induced Ventricular Arrhythmias by Attenuating Connexin 43 Dephosphorylation in Rats.

Ventricular arrhythmias induced by ischemic heart disease are the main cause of sudden cardiac death. Ischemia can cause life-threatening arrhythmias by modulating connexin 43 (Cx43), a principal cardiac gap junction channel protein. The present study investigates whether nitrite can attenuate ischemia-induced ventricular arrhythmias and dephosphorylation of Cx43 in a rat model. Rats were medicated with normal saline (control, n = 10), nitrite (0.015, 0.15, and 1.5 mg/kg, n = 9 or 10 each), and 0.15 mg/kg nitrite with either the nitric oxide scavenger 2-(4-carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (cPTIO; n = 9) or allopurinol (xanthine oxidoreductase inhibitor, n = 9). We determined the severity of ventricular arrhythmias based on arrhythmia scores and levels of phosphorylated Cx43. The median arrhythmia score may have been lower in the group given 0.15 mg/kg nitrite (4 [interquartile range {IQR}, 4-5]) than that in the control group (7.5 [IQR, 5.25-8]; P = 0.013). There was no difference among the control, the given 0.015 mg/kg nitrite (7 [IQR, 5-8]), and 1.5 mg/kg nitrite (7 [IQR, 5.5-7.75]; P = 0.95). The arrhythmia scores in the cPTIO (6 [IQR, 5-8]; P = 0.030) and allopurinol (7 [IQR, 5-8]; P = 0.005) groups may have been higher than that in 0.15 mg/kg nitrite group. Immunoblotting revealed that the level of phosphorylated Cx43 in the group given 0.15 mg/kg nitrite, but not in the other treated groups, was significantly higher compared with the control group (P = 0.007). Nitrite may have attenuated acute ischemia-induced ventricular arrhythmias and Cx43 dephosphorylation in rats. Nitric oxide, which might be generated by xanthine oxidoreductase via nitrite reduction, appears to play a crucial role in this antiarrhythmic effect.

Abstract 15493: Renal Sympathetic Denervation Reduces Ventricular Arrhythmias Inducibility in Dogs With Healed Myocardial Infarction

Introduction: Previous studies have suggested that renal sympathetic denervation (RSD) could suppress acute myocardial ischemia-induced ventricular arrhythmias (VAs), but the long-term effects of RSD in a post-infarction canine model is not fully established. Methods: Thirty dogs underwent embolization of the left anterior descending artery. After a 14-days of recovery period, all the dogs were equally randomized to the RSD, medicine (MED; carvedilol 12.5mg PO BID), or control (CTRL; no therapy) group. Animals were monitored for 3 months after interventions. The serum norepinephrine (NE), echocardiographic indices, heart rate variability (HRV), and VAs inducibility were measured at the end of 90-day follow-up. Tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43) expressions in the peri-infarcted zone were also determined immunohistochemically. The protein levels of metrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitor of matalloproteinases (TIMP-1) were also determined. Results: When compared with CTRL group, RSD significantly (1) decreased heart rate, serum NE, sympathetic nerve indices of HRV, and the density of both TH- and GAP43-positive nerves in the peri-infarcted zone; (2) increased left ventricular ejection fraction and reduced left ventricular dilatation; (3) decreased the protein levels of MMP-2, MMP-9 and TIMP-1 in left ventricular tissues; (4) decreased the inducibility of ventricular tachyarrhythmias. Beta-receptor blockade by carvedilol showed comparable effects. Conclusions: RSD could reduce VAs inducibility in a canine model of healed myocardial infarction. Inhibition of autonomic and structural remodeling by RSD may be responsible for this salutary result.

The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: the role of adenosine A1 receptors.

Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid with anti-inflammatory activity mediated by enhancing adenosine signaling. As the adenosine A1 receptor activation confers protection against ischemia/reperfusion (I/R)-induced ventricular arrhythmias, we hypothesized that CBD may have antiarrhythmic effect through the activation of adenosine A1 receptor. Cannabidiol has recently been shown to suppress ischemia-induced ventricular arrhythmias. We aimed to research the effect of CBD on the incidence and the duration of I/R-induced ventricular arrhythmias and to investigate the role of adenosine A1 receptor activation in the possible antiarrhythmic effect of CBD. Myocardial ischemia and reperfusion was induced in anesthetized male rats by ligating the left anterior descending coronary artery for 6 minutes and by loosening the bond at the coronary artery, respectively. Cannabidiol alone was given in a dose of 50 µg/kg, 10 minutes prior to coronary artery occlusion and coadministrated with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) in a dose of 100 µg/kg, 15 minutes prior to coronary artery occlusion to investigate whether the antiarrhythmic effect of CBD is modified by the activation of adenosine A1 receptors. The experimental groups were as follows: (1) vehicle control (n = 10), (2) CBD (n = 9), (3) DPCPX (n = 7), and (4) CBD + DPCPX group (n = 7). Cannabidiol treatment significantly decreased the incidence and the duration of ventricular tachycardia, total length of arrhythmias, and the arrhythmia scores compared to control during the reperfusion period. The DPCPX treatment alone did not affect the incidence and the duration of any type of arrhythmias. However, DPCPX aborted the antiarrhythmic effect of CBD when it was combined with it. The present results demonstrated that CBD has an antiarrhythmic effect against I/R-induced arrhythmias, and the antiarrhythmic effect of CBD may be mediated through the activation of adenosine A1 receptor.

Heptanol decreases the incidence of ischemia-induced ventricular arrhythmias through altering electrophysiological properties and connexin 43 in rat hearts.

Heptanol is a type of gap junction inhibitor that decreases electrical conduction velocity. However, little is known regarding the effects of heptanol on the arrhythmias induced by regional myocardial ischemia. This study aimed to investigate the effects of heptanol on ventricular arrhythmias and the underlying mechanisms. On the Langendorff apparatus, isolated hearts of Sprague-Dawley rats underwent 30 min of ischemia, with or without pretreatment with heptanol (0.1, 0.3 or 0.5 mM), 15 min prior to the induction of regional ischemia through ligation of the left anterior descending coronary artery. The incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) were recorded after ligation. Heptanol decreased the incidence of ventricular arrhythmias (45% in the control group vs. 10% in the 0.1 mM group, 0% in the 0.3 mM group and 0% in the 0.5 mM group, P<0.05), whereas it prolonged the PR interval, QT interval and monophasic action potential duration at 90% repolarization (MAPD90). As evaluated with immunofluorescence microscopy, heptanol was able to partly reverse the downregulation of connexin 43 (Cx43) induced by ischemia. The results of the reverse transcription-polymerase chain reaction were consistent with those of immunofluorescence. In conclusion, heptanol significantly decreased the incidence of VT and VF induced by regional ischemia and prolonged the PR interval, QT interval and MAPD90. Heptanol also partly reversed the downregulation of Cx43 induced by ischemia.

Exendin-4 attenuates ischemia-induced ventricular arrhythmias in rats

Glucagon-like peptide-1 and its receptor agonist-exendin-4 (Ex-4) have been shown to provide beneficial effects for cardiovascular diseases. This study investigated the effects of Ex-4 on ischemia-induced ventricular arrhythmias in rats. Anesthetized male rats were once treated with Ex-4 (5 μg/kg, i.v.) 1 h before ischemia in the absence and/or presence of 5-hydroxydecanoic acid (5-HD, 10 mg/kg, i.v., a specific inhibitor of mitochondrial ATP-sensitive potassium [KATP] channels) which were once injected 10 min before ischemia. And then subjected to ischemia for 30 min. Ventricular arrhythmias were assessed. During the 30-min ischemia, Ex-4 significantly reduced the incidence of ventricular fibrillation (VF) (p < 0.05). The duration of ventricular tachycardia (VT) + VF, the number of VT + VF episodes and the severity of arrhythmias were all significantly reduced by Ex-4 compared to those in myocardial ischemia group (p < 0.05 for all). Administration of 5-HD abolished the protective effects of Ex-4 on VF incidence, the duration of VT + VF, the number of VT + VF episodes and the severity of arrhythmias (p < 0.05 for all). This study suggested that Ex-4 could attenuate ischemia-induced ventricular arrhythmias in rats in which mitochondrial KATP channels may be involved.

Wenxin Keli attenuates ischemia-induced ventricular arrhythmias in rats: Involvement of L-type calcium and transient outward potassium currents

Wenxin Keli is the first state‑sanctioned traditional Chinese medicine (TCM)-based antiarrhythmic drug. The present study aimed to examine whether long‑term treatment with Wenxin Keli reduces ischemia‑induced ventricular arrhythmias in rats in vivo, and if so, which mechanisms are involved. Male rats were treated with either saline (control group) or Wenxin Keli for 3 weeks and were subjected to myocardial ischemia for 30 min with assessment of the resulting ventricular arrhythmias. The L‑type calcium current (ICa,L) and transient outward potassium current (Ito) were measured by the patch clamp technique in normal rat cardiac ventricular myocytes. During the 30‑min ischemia, Wenxin Keli significantly reduced the incidence of ventricular fibrillation (VF) (P<0.05). The number of ventricular tachycardia (VT)+VF episodes and the severity of arrhythmias were significantly reduced by Wenxin Keli administration compared to the control group (P<0.05). In addition, Wenxin Keli inhibited ICa,L and Ito in a concentration‑dependent manner. These results suggest that long‑term treatment with Wenxin Keli may attenuate ischemia‑induced ventricular arrhythmias in rats and that ICa,L and Ito may be involved in this attenuation.

The role of central oxytocin in stress-induced cardioprotection in ischemic-reperfused heart model

Background and purposeThere is growing evidence that stress contributes to cardiovascular disease and triggers the release of oxytocin. Moreover previous studies confirmed oxytocin mimics the protection associated with ischemic preconditioning. The present study was aimed to assess the possible cardioprotective effects of the centrally released oxytocin in response to stress and intracerebroventricular (i.c.v.) administration of exogenous oxytocin in ischemic-reperfused isolated rat heart. Methods and subjectsRats were divided in two main groups and all of them were subjected to i.c.v. infusion of vehicle or drugs: unstressed rats [control: vehicle, oxytocin (OT; 100ng/5μl), atosiban (ATO; 4.3μg/5μl) as oxytocin antagonist, ATO+OT] and stressed rats [St: stress, OT+St, ATO+St]. After anesthesia, hearts were isolated and subjected to 30min regional ischemia and 60min reperfusion (IR). Acute stress protocol included swimming for 10min before anesthesia. Myocardial function, infarct size, coronary flow, ventricular arrhythmia, and biochemical parameters such as creatine kinase and lactate dehydrogenase were measured. Ischemia-induced ventricular arrhythmias were counted during the occlusion period. ResultsThe plasma levels of oxytocin and corticosterone were significantly elevated by stress. Unexpectedly hearts of stressed rats showed a marked depression of IR injury compared to control group. I.c.v. infusion of oxytocin mimicked the cardioprotective effects of stress, yet did not elevate plasma oxytocin level. The protective effects of both stress and i.c.v. oxytocin were blocked by i.c.v. oxytocin antagonist. ConclusionsThese findings suggest that i.c.v. infusion of exogenous oxytocin and centrally released endogenous oxytocin in response to stress could play a role in induction of a preconditioning effect in ischemic-reperfused rat heart via brain receptors.

Effects of propofol on ischemia-induced ventricular arrhythmias and mitochondrial ATP-sensitive potassium channels

To investigate the potential of propofol in suppressing ventricular arrhythmias and to examine whether mitochondrial ATP-sensitive potassium channels are involved. Male Sprague-Dawley rats were pretreated with intravenous infusion of propofol (Prop), a selective mitochondrial KATP channel inhibitor 5-hydroxydecanoate (5-HD), propofol plus 5-HD (Prop+5-HD), a potent mitochondrial K(ATP) channel opener diazoxide (DZ) or NS, respectively. The dosage of each drug was 10 mg/kg. The animals then underwent a 30 min-ligation of the left anterior descending artery. The severity of arrhythmias, the incidence of ventricular fibrillation (VF), and the time of the first run of ventricular arrhythmias were documented using an arrhythmia scoring system. Mitochondrial membrane potential (ΔΨm) was measured in freshly isolated rat cardiomyocytes with a fluorescence microscope. The arrhythmia scores in the Prop and DZ group were 2.6(0-5) and 2.4(0-5), respectively, which were significantly lower than that in the control group [4.9(2-8)]. VF was not observed in both Prop and DZ groups. The first run of ventricular arrhythmias was significantly postponed in the Prop group (10.5±2.2 vs 7.3±1.9 min). Bracketing of propofol with 5-HD eliminated the anti-arrhythmic effect of propofol. In isolated rat cardiomyocytes, propofol (50 μmol/L) significantly decreased ΔΨm, but when propofol was co-administered with 5-HD, the effect on ΔΨm was reversed. Propofol preconditioning suppresses ischemia-induced ventricular arrhythmias in the rat heart, which are proposed to be caused by opening of mitochondrial K(ATP) channels.

Antiarrhythmic effect of prolonged morphine exposure is accompanied by altered myocardial adenylyl cyclase signaling in rats

BackgroundMorphine is often administered to patients for pain management, but it is also recommended to ameliorate some types of cardiovascular diseases. Nevertheless, there is a lack of information regarding the effect of prolonged morphine treatment on myocardial adenylyl cyclase (AC) signaling, which plays an important role in regulating heart function. MethodsThe present work has investigated the consequences of 10-day administration of high morphine doses (10mg/kg per day) to adult Wistar rats for functioning of the G-protein-mediated AC signaling system. ResultsMorphine treatment appreciably affected neither the number of myocardial β-adrenoceptors nor the content of selected subunits of trimeric G-proteins (Gsα, Gi/oα, Gzα, Gq/11α and Gβ) but the amount of the dominant myocardial AC isoform V/VI almost doubled. These alterations were accompanied by a marked AC supersensitization: the enzyme activity stimulated by manganese, fluoride, forskolin or isoproterenol was considerably increased (by about 50–100%). In contrast, the ability of opioid agonists to inhibit forskolin-stimulated AC activity was slightly but significantly decreased in both groups. Besides that, morphine markedly decreased the incidence of ischemic ventricular arrhythmias induced by coronary artery occlusion, but did not significantly influence infarct size and arrhythmias occurring during reperfusion. ConclusionsOverall, these results indicate that prolonged treatment of rats with high doses of morphine substantially alters the function of myocardial G-protein-regulated AC signaling. These alterations are accompanied by a reduced susceptibility to ischemia-induced ventricular arrhythmias.

Cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in conscious rats.

The response to myocardial ischemia is complex and involves the cardio-cardiac sympathetic reflex. Specifically, cardiac spinal (sympathetic) afferents are excited by ischemic metabolites and elicit an excitatory sympathetic reflex, which plays a major role in the genesis of ventricular arrhythmias. For example, brief myocardial ischemia leads to ATP release, which activates cardiac spinal afferents through stimulation of P2 receptors. Clinical work with patients and preclinical work with animals document that disruption of this reflex protects against ischemia-induced ventricular arrhythmias. However, the role of afferent signals in the initiation of sustained ventricular tachycardia has not been investigated. Therefore, we tested the hypothesis that cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in adult (12-15 wk of age), conscious, male Sprague-Dawley rats. To test this hypothesis, the susceptibility to ventricular tachyarrhythmias produced by occlusion of the left main coronary artery was determined in two groups of conscious rats: 1) deafferentation (bilateral excision of the T1-T5 dorsal root ganglia) and 2) control (sham deafferentation). The ventricular arrhythmia threshold (VAT) was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. Results document a significantly higher VAT in the deafferentation group (7.0 ± 0.7 min) relative to control (4.3 ± 0.3 min) rats. The decreased susceptibility to tachyarrhythmias with deafferentation was associated with a reduced cardiac metabolic demand (lower rate-pressure product and ST segment elevation) during ischemia.

Minocycline attenuates ischemia-induced ventricular arrhythmias in rats

Minocycline has been shown to protect against myocardial ischemia–reperfusion injury. This study investigated the effects of minocycline on ischemia-induced ventricular arrhythmias in rats. Anesthetized male rats were once treated with minocycline (45 mg/kg, i.p.) 1 h before ischemia in the absence and/or presence of 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002, 0.3 mg/kg, i.v., a PI3K inhibitor) and 5-hydroxydecanoic acid [5-HD, 10 mg/kg, i.v., a specific inhibitor of mitochondrial ATP-sensitive potassium (K ATP) channels] which were once injected 10 min before ischemia and then subjected to ischemia for 30 min. Ventricular arrhythmias were assessed. L-type Ca 2+ current was measured by the patch-clamp technique. During the 30-minute ischemia, minocycline significantly reduced the incidence of ventricular fibrillation (VF) (P < 0.05). The duration of VT + VF, the number of VT + VF episodes and the severity of arrhythmias were all significantly reduced by minocycline compared to those in myocardial ischemia group (P < 0.05 for all). Administration of LY294002 or 5-HD abolished the protective effects of minocycline on VF incidence, the duration of VT + VF, the number of VT + VF episodes and the severity of arrhythmias (P < 0.05 for all). In addition, minocycline inhibited L-type Ca 2+ currents of normal myocardial cell membrane in a dose-dependent manner. This study suggested that minocycline could attenuate ischemia-induced ventricular arrhythmias in rats in which PI3K/Akt signaling pathway, mitochondrial K ATP channels and L-type Ca 2+ channels may be involved .

Partial hindlimb occlusion reduced the susceptibility to sustained ventricular tachycardia in conscious rats.

Remote conditioning induced by ischemia in distant organs protects the heart from ischemia/reperfusion injury; however, its effect on ischemia-induced ventricular arrhythmias is unknown. Therefore, we tested the hypothesis that partial hindlimb occlusion during coronary artery occlusion increases the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion. Rats (n = 7) were instrumented with a radio-telemetry device for recording arterial pressure, electrocardiogram (ECG), and body temperature. A Doppler ultrasonic flow probe and vascular occluder were placed around the terminal aorta. Finally, a snare was placed around the left main coronary artery. The VAT was determined without and, on an alternate day, during partial hindlimb occlusion (remote conditioning) in conscious rats. Without remote conditioning, the VAT was 4.56 + 0.15 minutes. Importantly, remote conditioning significantly increased the VAT (6.29 + 0.49 minutes), suggesting that ischemia in a distant organ may delay the development of ischemia-induced ventricular arrhythmias.

Protection against ischemia-induced ventricular arrhythmias and myocardial dysfunction conferred by preconditioning in the rat heart: involvement of mitochondrial KATP channels and reactive oxygen species

Ischemic preconditioning (I-PC) induced by brief episodes of ischemia and reperfusion (I/R) protects the heart against sustained I/R. Although activation of mitochondrial K(ATP) channels (mitoK(ATP)) interacting with reactive oxygen species (ROS) has been proposed as a key event in this process, their role in the antiarrhythmic effect is not clear. This study was designed: 1) to investigate the involvement of mito K(ATP) opening in the effect of I-PC (1 cycle of I/R, 5 min each) on ventricular arrhythmias during test ischemia (TI, 30-min LAD coronary artery occlusion) in Langendorff-perfused rat hearts and subsequent postischemic contractile dysfunction, and 2) to characterize potential mechanisms of protection conferred by I-PC and pharmacological PC induced by mito K(ATP) opener diazoxide (DZX), with particular regards to the modulation of ROS generation. Lipid peroxidation (an indicator of increased ROS production) was determined by measurement of myocardial concentration of conjugated dienes (CD) and thiobarbituric acid reactive substances (TBARS) in non-ischemic controls, non-preconditioned and preconditioned hearts exposed to TI, I-PC alone, as well as after pretreatment with DZX, mito K(ATP) blocker 5-hydroxydecanoate (5-HD) and antioxidant N-acetylcysteine (NAC). Total number of ventricular premature beats (VPB) that occurred in the control hearts (518+/-71) was significantly (P<0.05) reduced by I-PC (195+/-40), NAC (290+/-56) and DZX (168+/-22). I-PC and NAC suppressed an increase in CD and TBARS caused by ischemia indicating lower production of ROS. On the other hand, I-PC and DZX themselves moderately enhanced ROS generation, prior to TI. Bracketing of I-PC with 5-HD suppressed both, ROS production during PC and its cardioprotective effect. In conclusion, potential mechanisms of protection conferred by mito K(ATP) opening in the rat heart might involve a temporal increase in ROS production in the preconditioning phase triggering changes in the pro/antioxidant balance in the myocardium and attenuating ROS production during subsequent prolonged ischemia.