Punate Weerateerangkul

Low-amplitude, left vagus nerve stimulation significantly attenuates ventricular dysfunction and infarct size through prevention of mitochondrial dysfunction during acute ischemia-reperfusion injury

BACKGROUND Right cervical vagus nerve stimulation (VNS) provides cardioprotective effects against acute ischemia-reperfusion injury in small animals. However, inconsistent findings have been reported. OBJECTIVE To determine whether low-amplitude, left cervical VNS applied either intermittently or continuously imparts cardioprotection against acute ischemia-reperfusion injury. METHODS Thirty-two isoflurane-anesthetized swine (25-30 kg) were randomized into 4 groups: control (sham operated, no VNS), continuous-VNS (C-VNS; 3.5 mA, 20 Hz), intermittent-VNS (I-VNS; continuously recurring cycles of 21-second ON, 30-second OFF), and I-VNS + atropine (1 mg/kg). Left cervical VNS was applied immediately after left anterior descending artery occlusion (60 minutes) and continued until the end of reperfusion (120 minutes). The ischemic and nonischemic myocardium was harvested for cardiac mitochondrial function assessment. RESULTS VNS significantly reduced infarct size, improved ventricular function, decreased ventricular fibrillation episodes, and attenuated cardiac mitochondrial reactive oxygen species production, depolarization, and swelling, compared with the control group. However, I-VNS produced the most profound cardioprotective effects, particularly infarct size reduction and decreased ventricular fibrillation episodes, compared to both I-VNS + atropine and C-VNS. These beneficial effects of VNS were abolished by atropine. CONCLUSIONS During ischemia-reperfusion injury, both C-VNS and I-VNS provide significant cardioprotective effects compared with I-VNS + atropine. These beneficial effects were abolished by muscarinic blockade, suggesting the importance of muscarinic receptor modulation during VNS. The protective effects of VNS could be due to its protection of mitochondrial function during ischemia-reperfusion.

Roles of the nitric oxide signaling pathway in cardiac ischemic preconditioning against myocardial ischemia-reperfusion injury

Summary Nitric oxide (NO), a vasoactive gas that can freely diffuse into the cell, has many physiological effects in various cell types. Since 1986, numerous studies of ischemic preconditioning against ischemia-reperfusion (I/R) injury have been undertaken and the roles of the NO signaling pathway in cardioprotection have been explored. Many studies have confirmed the effect of NO and that its relative signaling pathway is important for preconditioning of the cardioprotective effect. The NO signaling against I/R injury targeted on the mitochondria is believed to be the end-target for cardioprotection. If the NO signaling pathway is disrupted or inhibited, cardioprotection by preconditioning disappears. During preconditioning, signaling is initiated from the sarcolemmal membrane, and then spread into the cytoplasm via many series of enzymes, including nitric oxide synthase (NOS), the NO-producing enzyme, soluble guanylyl cyclase (sGC), and protein kinase G (PKG). Finally, the signal is transmitted into the mitochondria, where the cardioprotective effect occurs. It is now well established that mitochondria act to protect the heart against I/R injury via the opening of the mitochondrial ATP-sensitive K+ channel and the inhibition of mitochondrial permeability transition (MPT). This knowledge may be useful in developing novel strategies for clinical cardioprotection from I/R injury.

Mechanisms responsible for beneficial and adverse effects of rosiglitazone in a rat model of acute cardiac ischaemia–reperfusion

•  What is the central question of this study? Controversy exists regarding the beneficial and adverse effects of rosiglitazone. We sought to determine the effects of rosiglitazone in the heart during ischaemia–reperfusion injury. •  What is the main finding and what is its importance? We demonstrated that rosiglitazone simultaneously exerted both beneficial and adverse effects on the heart during ischaemia–reperfusion. These findings provided new mechanistic insights into the effects of this drug, and elucidate the possibility of its undesirable effects in patients taking this drug.

Effect of rosiglitazone on cardiac electrophysiology, infarct size and mitochondrial function in ischaemia and reperfusion of swine and rat heart

Rosiglitazone, a peroxisome proliferator‐activated receptor γ agonist, has been used to treat type 2 diabetes. Despite debates regarding its cardioprotection, the effects of rosiglitazone on cardiac electrophysiology are still unclear. This study determined the effect of rosiglitazone on ventricular fibrillation (VF) incidence, VF threshold (VFT), defibrillation threshold (DFT) and mitochondrial function during ischaemia and reperfusion. Twenty‐six pigs were used. In each pig, either rosiglitazone (1 mg kg−1) or normal saline solution was administered intravenously for 60 min. Then, the left anterior descending coronary artery was ligated for 60 min and released to promote reperfusion for 120 min. The cardiac electrophysiological parameters were determined at the beginning of the study and during the ischaemia and reperfusion periods. The heart was removed, and the area at risk and infarct size in each heart were determined. Cardiac mitochondria were isolated for determination of mitochondrial function. Rosiglitazone did not improve the DFT and VFT during the ischaemia–reperfusion period. In the rosiglitazone group, the VF incidence was increased (58 versus 10%) and the time to the first occurrence of VF was decreased (3 ± 2 versus 19 ± 1 min) in comparison to the vehicle group (P < 0.05). However, the infarct size related to the area at risk in the rosiglitazone group was significantly decreased (P < 0.05). In the cardiac mitochondria, rosiglitazone did not alter the level of production of reactive oxygen species and could not prevent mitochondrial membrane potential changes. Rosiglitazone increased the propensity for VF, and could neither increase defibrillation efficacy nor improve cardiac mitochondrial function.

Granulocyte colony-stimulating factor stabilizes cardiac electrophysiology and decreases infarct size during cardiac ischaemic/reperfusion in swine

Aim:  Effects of granulocyte colony‐stimulating factor (G‐CSF) on cardiac electrophysiology during ischaemic/reperfusion (I/R) period are unclear. We hypothesized that G‐CSF stabilizes cardiac electrophysiology during I/R injury by prolonging the effective refractory period (ERP), increasing the ventricular fibrillation threshold (VFT) and decreasing the defibrillation threshold (DFT), and that the cardioprotection of G‐CSF is via preventing cardiac mitochondrial dysfunction.

Effects of Kaempferia parviflora Wall. Ex. Baker and sildenafil citrate on cGMP level, cardiac function, and intracellular Ca2+ regulation in rat hearts.

Abstract: Although Kaempferia parviflora extract (KPE) and its flavonoids have positive effects on the nitric oxide (NO) signaling pathway, its mechanisms on the heart are still unclear. Because our previous studies demonstrated that KPE decreased defibrillation efficacy in swine similar to that of sildenafil citrate, the phosphodiesterase-5 inhibitor, it is possible that KPE may affect the cardiac NO signaling pathway. In the present study, the effects of KPE and sildenafil citrate on cyclic guanosine monophosphate (cGMP) level, modulation of cardiac function, and Ca2+ transients in ventricular myocytes were investigated. In a rat model, cardiac cGMP level, cardiac function, and Ca2+ transients were measured before and after treatment with KPE and sildenafil citrate. KPE significantly increased the cGMP level and decreased cardiac function and Ca2+ transient. These effects were similar to those found in the sildenafil citrate–treated group. Furthermore, the nonspecific NOS inhibitor could abolish the effects of KPE and sildenafil citrate on Ca2+ transient. KPE has positive effect on NO signaling in the heart, resulting in an increased cGMP level, similar to that of sildenafil citrate. This effect was found to influence the physiology of normal heart via the attenuation of cardiac function and the reduction of Ca2+ transient in ventricular myocytes.

Amyloid peptide regulates calcium homoeostasis and arrhythmogenesis in pulmonary vein cardiomyocytes

Eur J Clin Invest 2012; 42 (6): 589–598

Apelin regulates the electrophysiological characteristics of atrial myocytes

Eur J Clin Invest 2012

Early testosterone replacement attenuates intracellular calcium dyshomeostasis in the heart of testosterone-deprived male rats

BACKGROUND Testosterone deficiency in elderly men increases the risk of cardiovascular disease. In bilateral orchiectomized (ORX) animals, impaired cardiac Ca2+ regulation was observed, and this impairment could be improved by testosterone replacement, indicating the important role of testosterone in cardiac Ca2+ regulation. However, the temporal changes of Ca2+ dyshomeostasis in testosterone-deprived conditions are unclear. Moreover, the effects of early vs. late testosterone replacement are unknown. We hypothesized that the longer the deprivation of testosterone, the greater the impairment of cardiac Ca2+ homeostasis, and that early testosterone replacement can effectively reduce this adverse effect. METHODS Male Wistar rats were randomly divided into twelve groups, four sets of three. The first set were ORX for 2, 4 and 8 weeks, the second set were sham-operated groups of the same periods, the third set were ORX for 8 weeks coupled with a subcutaneous injection of vehicle (control), testosterone during weeks 1-8 (early replacement) or testosterone during weeks 5-8 (late replacement), and finally the 12-week sham-operated, ORX and ORX treated with testosterone groups. Cardiac Ca2+ transients (n=4-5/group), L-type calcium current (ICa-L) (n=4/group), Ca2+ regulatory proteins (n=6/group) and cardiac function (n=5/group) were determined. RESULTS In the ORX rats, impaired cardiac Ca2+ transients and reduced ICa-L were observed initially 4 weeks after ORX as shown by decreased Ca2+ transient amplitude, rising rate and maximum and average decay rates. No alteration of Ca2+ regulatory proteins such as the L-type Ca2+ channels, ryanodine receptor type 2, Na+-Ca2+ exchangers and SERCA2a were observed. Early testosterone replacement markedly improved cardiac Ca2+ transients, whereas late testosterone replacement did not. The cardiac contractility was also improved after early testosterone replacement. CONCLUSIONS Impaired cardiac Ca2+ homeostasis is time-dependent after testosterone deprivation. Early testosterone replacement improves cardiac Ca2+ transient regulation and contractility, suggesting the necessity of early intervention in conditions of testosterone-deprivation.

LEFT VAGUS NERVE STIMULATION SIGNIFICANTLY ATTENUATES VENTRICULAR DYSFUNCTION AND INFARCT SIZE THROUGH PREVENTION OF MITOCHONDRIAL DYSFUNCTION DURING ACUTE ISCHEMIA-REPERFUSION INJURY IN SWINE

Right cervical vagus nerve stimulation (VNS) provides cardioprotective effects against acute ischemia-reperfusion injury (IRI) in small animals. We determined whether left cervical (LC) VNS applied either intermittently or continuously imparts cardioprotection against acute IRI in swine. Thirty-two