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Background and Purpose: Dysregulation of gap junction-mediated cell coupling contributes to development of arrhythmias and myocardial damage after ischaemia/reperfusion (I/R). Connexin 43 (Cx43) is present at ventricular gap junctions and also in the mitochondria of cardiomyocytes. The dipeptide (2S, 4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid (ZP1609) has antiarrhythmic properties and reduces infarct size when given at reperfusion. However, it is unclear, whether ZP1609 targets Cx43-containing mitochondria and affects cardiomyocyte hypercontracture following I/R., Experimental Approach: We studied the effects of ZP1609 on the function of murine sub-sarcolemmal mitochondria (SSM, containing Cx43) and interfibrillar mitochondria (IFM, lacking Cx43). Murine isolated cardiomyocytes were subjected to simulated I/R without and with ZP1609 (applied during I/R or at the onset of reperfusion only), and the number of cardiomyocytes undergoing hypercontracture was quantified. Biochemical pathways targeted by ZP1609 in cardiomyocytes were analysed., Key Results: ZP1609 inhibited ADP-stimulated respiration and ATP production in SSM and IFM. ROS formation and calcium retention capacities in SSM and IFM were not affected by ZP1609, whereas potassium uptake was enhanced in IFM. The number of rod-shaped cardiomyocytes was increased by ZP1609 (10 μM) when administered either during I/R or reperfusion. ZP1609 altered the phosphorylation of proteins contributing to the protection against I/R injury., Conclusions and Implications: ZP1609 reduced mitochondrial respiration and ATP production, but enhanced potassium uptake of IFM. Additionally, ZP1609 reduced the extent of cardiomyocytes undergoing hypercontracture following I/R. The protective effect was independent of mitochondrial Cx43, as ZP1609 exerts its effects in Cx43-containing SSM and Cx43-lacking IFM., (© 2017 The British Pharmacological Society.)

Simple Summary: Impaired coronary blood flow induces cardiac ischemia and can lead to myocardial infarction. Although revascularization therapy and medical treatment potentially restore cardiac function in ischemic hearts, loss of cardiomyocytes and replacement of the dead myocardium by a scar can lead to ischemic heart disease with impaired cardiac output, a condition called heart failure. Medical treatment of heart failure includes drugs such as ACE-inhibitors, beta-blockers, diuretics, mineralocorticoid receptor antagonists, and SGLT (sodium-glucose cotransporter) 2 inhibitors. In addition, dietary interventions may provide further benefits to slow down disease progression. Caloric restriction, the decrease in calorie intake without malnutrition, is a strategy for improving health and increasing lifespan. Caloric restriction reduces the risk factors for cardiovascular diseases, and it improves heart function in animals and humans. Our study investigated the impact of caloric restriction on heart failure progression in mice and rats with myocardial infarction. We show that caloric restriction inhibits progressive loss of heart function, even when started after heart failure is already established. Together, the findings help to deepen our understanding of the complex mechanisms involved in the cardioprotective effects of caloric restriction and how they could be therapeutically utilized to prevent disease progression. Background: Caloric restriction (CR) extends lifespan in many species, including mammals. CR is cardioprotective in senescent myocardium by correcting pre-existing mitochondrial dysfunction and apoptotic activation. Furthermore, it confers cardioprotection against acute ischemia-reperfusion injury. Here, we investigated the role of AMP-activated protein kinase (AMPK) in mediating the cardioprotective CR effects in failing, postinfarct myocardium. Methods: Ligation of the left coronary artery or sham operation was performed in rats and mice. Four weeks after surgery, left ventricular (LV) function was analyzed by echocardiography, and animals were assigned to different feeding groups (control diet or 40% CR, 8 weeks) as matched pairs. The role of AMPK was investigated with an AMPK inhibitor in rats or the use of alpha 2 AMPK knock-out mice. Results: CR resulted in a significant improvement in LV function, compared to postinfarct animals receiving control diet in both species. The improvement in LV function was accompanied by a reduction in serum BNP, decrease in LV proapoptotic activation, and increase in mitochondrial biogenesis in the LV. Inhibition or loss of AMPK prevented most of these changes. Conclusions: The failing, postischemic heart is protected from progressive loss of LV systolic function by CR. AMPK activation is indispensable for these protective effects. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) and the heart failure (HF) that often result remain the leading causes of death and disability worldwide. As such, new therapeutic targets need to be discovered to protect the myocardium against acute ischaemia/reperfusion (I/R) injury in order to reduce myocardial infarct (MI) size, preserve left ventricular function and prevent the onset of HF. Mitochondrial dysfunction during acute I/R injury is a critical determinant of cell death following AMI, and therefore, ion channels in the inner mitochondrial membrane, which are known to influence cell death and survival, provide potential therapeutic targets for cardioprotection. In this article, we review the role of mitochondrial ion channels, which are known to modulate susceptibility to acute myocardial I/R injury, and we explore their potential roles as therapeutic targets for reducing MI size and preventing HF following AMI. [ABSTRACT FROM AUTHOR]

Cardiac remodeling plays a crucial role in the development of heart failure after mycocardial infarction. Besides cardiomyocytes, endothelial cells are recognized to contribute to cardiac remodeling. We now investigated processes of endothelial mesenchymal transition (EndoMT) in microvascular endothelial cells of rat (MVEC) under hypoxia and paracrine effects on ventricular cardiomyocytes of adult rat. Exposure of MVECs to hypoxia/reoxygenation enhanced TGFβ/SMAD signaling, since phosphorylation, and thus activation, of SMAD1/5 and SMAD2 increased. This increase was blocked by inhibitors of TGFβ receptor types ALK1 or ALK5. Exposure of ventricular cardiomyocytes to conditioned medium from hypoxic/reoxygenated MVECs enhanced SMAD2 phosphorylation and provoked apoptosis in cardiomyoyctes. Both were blocked by ALK5 inhibition. To analyze autocrine effects of hypoxic TGFβsignaling we investigated EndoMT in MVECs. After 3 days of hypoxia the mesenchymal marker protein α-smooth muscle actin (α-SMA), and the number of α-SMA- and fibroblast specific protein 1 (FSP1)-positive cells increased in MVECs cultures. This was blocked by ALK5 inhibition. Similarly, TGFβ1 provoked enhanced expression of α-SMA and FSP1 in MVECs. In conclusion, hypoxia provokes EndoMT in MVECs via TGFβ1/SMAD2 signaling. Furthermore, release of TGFβ1 from MVECs acts in a paracrine loop on cardiomyocytes and provokes apoptotic death. Thus, in myocardial infarction hypoxic endothelial cells may contribute to cardiac remodeling and heart failure progression by promotion of cardiac fibrosis and cardiomyocytes death. [ABSTRACT FROM AUTHOR]

Whereas high amounts of reactive oxygen species (ROS) contribute to cardiac damage following ischemia and reperfusion (IR), low amounts function as trigger molecules in the cardioprotection by ischemic preconditioning (IPC). The mitochondrial translocation and contribution of the hydrogen peroxide-generating protein p66shc in the cardioprotection by IPC is unclear yet. In the present study, we investigated themitochondrial translocation of p66shc, addressed the impact of p66shc on ROS formation after IR, and characterized the role of p66shc in IR injury per se and in the cardioprotection by IPC. The amount of p66shc in subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) isolated from wildtype mouse left ventricles (LV) was determined after 40 min normoxic perfusion and after 30 min ischemia and 10 min reperfusion without and with IPC. The p66shc content in SSM (in % of normoxic controls, n = 5) was 174 ± 16% (n = 6, p < 0.05) after IR, and was reduced to 128 ± 13% after IPC (n = 6, p = ns). In IFM, the amount of p66shc remained unchanged (IR: 81 ± 7%, n = 6; IPC: 110 ± 5%, n = 6, p = ns). IR induced an increase in ROS formation in SSM and IFM isolated from mouse wildtype LV, which was more pronounced in SSM than in IFM (1.18 ± 0.18 vs. 0.81 ± 0.16, n = 6, p < 0.05). In mitochondria from p66shc-knockout mice (p66shc-KO), the increase in ROS formation by IR was not different between SSM and IFM (0.90 ± 0.11 vs. 0.73 ± 0.08, n = 6, p = ns). Infarct size (in % of the left ventricle) was 51.7 ± 2.9% in wildtype and 59.7 ± 3.8% in p66shc-KO hearts in vitro and was significantly reduced to 35.8 ± 4.4% (wildtype) and 34.7 ± 5.6% (p66shc-KO) by IPC, respectively. In vivo, infarct size was 57.8 ± 2.9% following IR (n = 9) and was reduced to 40.3 ± 3.5% by IPC (n = 11, p < 0.05) in wildtype mice. In p66shc-knockout mice, infarct sizes were similar to those measured in wildtype animals (IR: 56.2 ± 4.3%, n = 11; IPC: 42.1 ± 3.9%, n = 13, p < 0.05). Taken together, the mitochondrial translocation of p66shc following IR and IPC differs between mitochondrial populations. However, similar infarct sizes after IR and preserved infarct size reductions by IPC in p66shc-KO mice suggest that p66shc-derived ROS are not involved in the cardioprotection by IPC nor do they contribute to IR injury per se. [ABSTRACT FROM AUTHOR]

Connexins are widely distributed proteins in the body that are crucially important for heart and brain functions. Six connexin subunits form a connexon or hemichannel in the plasma membrane. Interactions between two hemichannels in a head-to-head arrangement result in the formation of a gap junction channel. Gap junctions are necessary to coordinate cell function by passing electrical current flow between heart and nerve cells or by allowing exchange of chemical signals and energy substrates. Apart from its localization at the sarcolemma of cardiomyocytes and brain cells, connexins are also found in the mitochondria where they are involved in the regulation of mitochondrial matrix ion fluxes and respiration. Connexin expression is affected by age and gender as well as several pathophysiological alterations such as hypertension, hypertrophy, diabetes, hypercholesterolemia, ischemia, post-myocardial infarction remodeling or heart failure, and post-translationally connexins are modified by phosphorylation/de-phosphorylation and nitros(yl)ation which can modulate channel activity. Using knockout/knockin technology as well as pharmacological approaches, one of the connexins, namely connexin 43, has been identified to be important for cardiac and brain ischemia/reperfusion injuries as well as protection from it. Therefore, the current review will focus on the importance of connexin 43 for irreversible injury of heart and brain tissues following ischemia/reperfusion and will highlight the importance of connexin 43 as an emerging therapeutic target in cardio- and neuroprotection. [ABSTRACT FROM AUTHOR]

Induction and activation of arginase is among the fastest responses of the heart to ischemic events. Induction of arginase expression and enzyme activation under ischemic conditions shifts arginine consumption from nitric oxide formation (NO) to the formation of ornithine and urea. In the heart such a switch in substrate utilization reduces the impact of the NO/cGMP-pathway on cardiac function that requires intact electromechanical coupling but at the same time it induces ornithine-dependent pathways such as the polyamine metabolism. Both effects significantly reduce the recovery of heart function during reperfusion and thereby limits the success of reperfusion strategies. In this context, changes in arginine consumption trigger cardiac remodeling in an unfavorable way and increases the risk of arrhythmia, specifically in the initial post-ischemic period in which arginase activity is dominating. However, during the entire ischemic period arginase activation might be a meaningful adaptation that is specifically relevant for reperfusion following prolonged ischemic periods. Therefore, a precise understanding about the underlying mechanism that leads to arginase induction as well as of it's mechanistic impact on post-ischemic hearts is required for optimizing reperfusion strategies. In this review we will summarize our current understanding of these processes and give an outlook about possible treatment options for the future. [ABSTRACT FROM AUTHOR]

Coronary heart disease (CHD) is the leading cause of death and disability worldwide. Despite current therapy, the morbidity and mortality for patients with CHD remains significant. The most important manifestations of CHD arise from acute myocardial ischaemia–reperfusion injury (IRI) in terms of cardiomyocyte death and its long-term consequences. As such, new therapeutic interventions are required to protect the heart against the detrimental effects of acute IRI and improve clinical outcomes. Although a large number of cardioprotective therapies discovered in pre-clinical studies have been investigated in CHD patients, few have been translated into the clinical setting, and a significant number of these have failed to show any benefit in terms of reduced myocardial infarction and improved clinical outcomes. Because of this, there is currently no effective therapy for protecting the heart against the detrimental effects of acute IRI in patients with CHD. One major factor for this lack of success in translating cardioprotective therapies into the clinical setting can be attributed to problems with the clinical study design. Many of these clinical studies have not taken into consideration the important data provided from previously published pre-clinical and clinical studies. The overall aim of this ESC Working Group Cellular Biology of the Heart Position Paper is to provide recommendations for optimizing the design of clinical cardioprotection studies, which should hopefully result in new and effective therapeutic interventions for the future benefit of CHD patients. [ABSTRACT FROM PUBLISHER]

The present review summarizes the experimental and clinical evidence for the anti-ischemic action of the selective bradycardic agent ivabradine. Improvements in myocardial blood flow and contractile function during experimental myocardial ischemia and the clinical anti-anginal effect are largely mediated by heart rate reduction. However, a significant reduction in infarct size by ivabradine persists in the absence of heart rate reduction, and such protection can also be recruited when ivabradine is given only during early reperfusion. The mechanisms for such pleiotropic action of ivabradine remain to be resolved. [ABSTRACT FROM PUBLISHER]

The article presents a study which aimed to quantify the release of vasoconstrictors during stent implantation into atherosclerotic plaques and to determine the efficacy of coronary dilators to attenuate their action. Results showed serotonin as the main coronary vasoconstrictor released after stenting with thromboxane and tumor necrosis factor (TNF)α potentiating the response. Nitroprusside and verapamil were found to be more potent than adenosine in attenuating the aspirate plasma-induced vasoconstriction.

Ischemic heart disease (IHD) is the leading cause of death worldwide. Novel cardioprotective strategies are therefore required to improve clinical outcomes in patients with IHD. Although a large number of novel cardioprotective strategies have been discovered in the research laboratory, their translation to the clinical setting has been largely disappointing. The reason for this failure can be attributed to a number of factors including the inadequacy of the animal ischemia-reperfusion injury models used in the preclinical cardioprotection studies and the inappropriate design and execution of the clinical cardioprotection studies. This important issue was the main topic of discussion of the UCL-Hatter Cardiovascular Institute 6th International Cardioprotection Workshop, the outcome of which has been published in this article as the 'Hatter Workshop Recommendations'. These have been proposed to provide guidance on the design and execution of both preclinical and clinical cardioprotection studies in order to facilitate the translation of future novel cardioprotective strategies for patient benefit. [ABSTRACT FROM AUTHOR]

Ischaemic postconditioning (brief periods of ischaemia alternating with brief periods of reflow applied at the onset of reperfusion following sustained ischaemia) effectively reduces myocardial infarct size in all species tested so far, including humans. Ischaemic postconditioning is a simple and safe manoeuvre, but because reperfusion injury is initiated within minutes of reflow, postconditioning must be applied at the onset of reperfusion. The mechanisms of protection by postconditioning include: formation and release of several autacoids and cytokines; maintained acidosis during early reperfusion; activation of protein kinases; preservation of mitochondrial function, most strikingly the attenuation of opening of the mitochondrial permeability transition pore (MPTP). Exogenous recruitment of some of the identified signalling steps can induce cardioprotection when applied at the time of reperfusion in animal experiments, but more recently cardioprotection was also observed in a proof-of-concept clinical trial. Indeed, studies in patients with an acute myocardial infarction showed a reduction of infarct size and improved left ventricular function when they underwent ischaemic postconditioning or pharmacological inhibition of MPTP opening during interventional reperfusion. Further animal studies and large-scale human studies are needed to determine whether patients with different co-morbidities and co-medications respond equally to protection by postconditioning. Also, our understanding of the underlying mechanisms must be improved to develop new therapeutic strategies to be applied at reperfusion with the ultimate aim of limiting the burden of ischaemic heart disease and potentially providing protection for other organs at risk of reperfusion injury, such as brain and kidney. [ABSTRACT FROM PUBLISHER]

Aims: Reperfusion is mandatory to salvage ischaemic myocardium from infarction, but also induces additional reperfusion injury and contributes to infarct size (IS). Gentle reperfusion (GR) has been proposed to attenuate reperfusion injury, but this remains contentious. We now investigated whether (i) GR reduces IS and (ii) GR is associated with the activation of reperfusion injury salvage kinases (RISK). [ABSTRACT FROM PUBLISHER]

Ischemic postconditioning, a simple mechanical maneuver at the onset of reperfusion, reduces infarct size after ischemia/reperfusion. After its first description in 2003 by Zhao et al. numerous experimental studies have investigated this protective phenomenon. Whereas the underlying mechanisms and signal transduction are not yet understood in detail, infarct size reduction by ischemic postconditioning was confirmed in all species tested so far, including man. We have now reviewed the literature with focus on experimental models and protocols to better understand the determinants of protection by ischemic postconditioning or lack of it. Only studies with infarct size as unequivocal endpoint were considered. In all species and models, the duration of index ischemia and the protective protocol algorithm impact on the outcome of ischemic postconditioning, and gender, age, and myocardial temperature contribute. [ABSTRACT FROM AUTHOR]

The article reports a study in pigs with sustained moderate ischemia inducible with nitric oxide synthase expression and cardiomyocyte dysfunction. It examines the involvement of an inflammatory signal cascade under a progressive dysfunction and on whether dysfunction is intrinsic to cardiomyocytes. According to the authors, research shows that sustained regional ischemia induces myocardial iNOS expression in pigs, which adds to contractile dysfunction at the level of cardiomyocyte.

The article analyzes whether or not ischemic postconditioning (iPoco) was effective in aged mice hearts and whether iPoco was dependent on signal transducer and activator of transcription 3 (STAT3). Reduced levels of STAT3 with increasing age was significant to the age-related loss of iPoco. Results of Western blot analysis was discussed.

Abstract: Objectives: Nitric oxide (NO) synthesis by NO synthases (NOS) requires oxygen. However, although counterintuitive, NO synthesis is increased in ischemic myocardium. Accordingly, mechanisms independent of the NOS pathway have been suggested to contribute to NO synthesis during ischemia. NO initiates detrimental as well as protective mechanisms in a concentration-dependent manner, thus aggravating or improving the outcome of ischemia. The aim of this study was to measure in situ interstitial NO concentrations in parallel to infarct size in anaesthetized pigs subjected to myocardial ischemia/reperfusion. The contribution of NOS-independent pathways to NO synthesis was studied using NOS blockade. Methods: Interstitial NO measurements, based on microdialysis combined with the oxyhemoglobin method, were made during 90 min of moderate or severe ischemia and subsequent reperfusion. To examine the effect of NOS inhibition, an initial 30-min ischemic period was followed 60 min later by a second 30-min ischemic period with intracoronary infusion of S-ethyl-isothiourea. Results: During ischemia, the interstitial NO concentration increased for about 30 min and then remained constant at this elevated level. The increase in NO concentration by 253±82 nmol/L during moderate and 565±169 nmol/L during severe ischemia correlated inversely with subendocardial blood flow (r =−0.76). NOS inhibition increased coronary arterial pressure and decreased the interstitial basal NO concentration and tissue nitrite content. However, it did not diminish the increase in interstitial NO concentration during ischemia. Conclusion: NOS-independent pathways are significantly involved in NO synthesis during myocardial ischemia. [Copyright &y& Elsevier]

Protection from a prolyl hydroxylase domain-containing enzyme (PHD) inhibitor, desferoxamine (DFO), was recently reported to be dependent on production of reactive oxygen species (ROS). Ischemic preconditioning triggers the protected state by stimulating nitric oxide (NO) production to open mitochondrial ATP-sensitive K+ (mitoKATP) channels, generating ROS required for protection. We tested whether DFO and a second PHD inhibitor, ethyl-3,4-dihydroxybenzoate (EDHB), might have similar mechanisms. EDHB and DFO increased ROS generation by 50-75% (P < 0.001) in isolated rabbit cardiomyocytes. This increase after EDHB exposure was blocked by Nω-nitro-L-arginine methyl ester (L-NAME), an NO synthase (NOS) inhibitor; ODQ, a guanylyl cyclase antagonist; and Rp-8-bromoguanosine-3' ,5'-cyclic monophosphorothioate Rp isomer, a PKG blocker, thus implicating the NO pathway in EDHB's signaling. Glibenclamide, a nonselective KATP channel blocker, or 5-hydroxydecanoate, a selective mitoKATP channel antagonist, also prevented EDHB's ROS production, as did blockade of mitochondrial electron transport with myxothiazol. NOS is activated by Akt. However, neither wortmannin, an inhibitor of phosphatidylinositol-3-kinase, nor Akt inhibitor blocked EDHB-induced ROS generation, indicating that EDHB initiates signaling downstream of Akt. DFO also increased ROS production, and this effect was blocked by ODQ, 5-hydroxydecanoate, and N-(2-mercaptopropionyl)glycine, an ROS scavenger. DFO increased cardiomyocyte production of nitrite, a metabolite of NO, and this effect was blocked by an inhibitor of NOS. DFO also spared ischemic myocardium in intact hearts. This infarct-sparing effect was blocked by ODQ, L-NAME, and N-(2-mercaptopropionyl)glycine. Hence, DFO and EDHB stimulate NO-dependent activation of PKG to open mitoKATP channels and produce ROS, which act as second messengers to trigger entrance into the preconditioned state. [ABSTRACT FROM AUTHOR]

Connexin 43 (Cx43) is the essential protein to form hemichannels and gap junctions in the myocardium. The phosphorylation status of Cx43 which is regulated by a variety of protein kinases and phosphatases determines hemichannel and/or gap junction conductance and permeability. Gap junctions are involved in cell–cell coupling while hemichannels contribute to cardiomyocyte volume regulation. Cx43-formed channels are involved in ischemia/reperfusion injury, since blockade of a large portion of Cx43-formed channels attenuates ischemic hypercontracture, infarct development and post myocardial infarction remodeling. Ischemic preconditioning''s protection also depends on functional Cx43-formed channels, since uncoupling of channels or genetic Cx43 deficiency abolishes infarct size reduction by ischemic preconditioning. The exact underlying mechanism(s) how Cx43 mediates protection remain to be established. [Copyright &y& Elsevier]

Responses of chronically hypoxic rat hearts to ischemia: KATP channel blockade does not abolish increased RV tolerance to ischemia. Am J Physiol Heart Circ Physiol 286:H545–H551, 2004. First published October 9, 2003; 10.1152/ajpheart.00022.2003.—Chronic hypoxia may precondition the myocardium and protect from ischemia-reperfusion damage. We therefore examined the recovery of left and right ventricular function after ischemia and reperfusion (15 min each) in isolated blood-perfused working hearts from normoxic (Norm) and hypoxic (Hypo; 14 days, 10.5% O2) adult rats. In addition, the mRNA expression of hypoxia-inducible factor (HIF)-lα and the protein expression of endothelial nitric oxide synthase (eNOS) were measured. Postischemic left ventricular function recovered to 66 ± 6% and 67 ± 5% of baseline in Norm and Hypo, respectively. In contrast, postischemic right ventricular function was 93 ± 2% of baseline in Hypo vs. 67 ± 3% in Norm (P < 0.05). Improved postischemic right ventricular function in Hypo (93 ± 2% and 96 ± 2% of baseline) was observed with 95% O2 or 21% O2 in the perfusate, and it was not attenuated by glibenclamide (5 and 10 μmol/1) (86 ± 4% and 106 ± 6% recovery). HIF-lot mRNA and eNOS protein expression were increased in both left and right hypoxic ventricles. In conclusion, postischemic right, but not left, ventricular function was improved by preceding chronic hypoxia. ATP-sensitive K+ channels are not responsible for the increased right ventricular tolerance to ischemia after chronic hypoxia in adult rat hearts. [ABSTRACT FROM AUTHOR]

1 Activation of ATP-dependent potassium channels (K[SUBATP]) is involved in ischaemic preconditioning (IP). In isolated buffer-perfused rabbit hearts, activation of mitochondrial K[SUBAP] - through a generation of free radicals - acted as a trigger rather than a mediator of IIP; the isolated buffer-perfused heart preparation, however, favours free radical generation. In contrast, in vivo studies in rats and dogs suggested that activation of K[SUBAP] acts as a mediator of IP's protection. A detailed analysis on the role of K[SUBATP] in IP's protection in vivo by varying the time and dose of K[SUBATP] blocker administration is, however, lacking. 2 In 54 influrane -anaesthetized pigs, the left anterior descending coronary artery was perfused by an extracorporeal circuit. Infarct size (IS, %, TTc) following 90 min sustained low-flow ischaemia and 120 min reperfusion was 26.6±3.5 (s.e.m.) (n=8). IP with one cycle of 10 min ischaemia and 15 min reperfusion reduced IS to 6.5±2.1 (n=7, P<0.05). Blockade of K[SUBATP] with glibenclamide (0.5 mg kg[SUP-1] i.v., 50 μgmin[SUP-1] continuous infusion) starting 10 min before or immediately a trigger role of K[SUBATP] in sustained ischaemia did not prevent IS reduction by IP (3.7±2.3, n=6), even when its bolus dose was increased to 1.5 mg kg[SUP-1] (26.6±3.8 with IP vs 37.5±2.9 without IP;n=7 and 6 respectively, P<0.05), thereby refuting a mediator role of K[SUBATP] in IP. 3 In conclusion, activation of K[SUBATP] in the immediate reperfusion following the preconditioning ischaemia is pivotal for triggering IP. [ABSTRACT FROM AUTHOR]

Pretreatment with tumor necrosis factor-α (TNF-α) antibodies abolishes myocardial infarct size reduction by late ischemic preconditioning (IP). Whether or not TNF-α is also important for myocardial infarct size reduction by classic IP is unknown. Anesthetized rabbits were untreated (group 1, n = 7), classically preconditioned by 5 min left coronary artery occlusion/10 min reperfusion (group 2, n = 6), or pretreated with TNF-α antibodies without (group 3, n = 6) or with IP (group 4, n = 6) before undergoing 30 min of occlusion and 180 min of reperfusion. Infarct size in group 1 was 44 ± 11 (means ± SD)% of the area at risk. With a comparable area at risk, infarct size was reduced to 13 ± 7%, 23 ± 8%. and 19 ± 12% (all P < 0.05) in groups 2, 3, and 4, respectively. The circulating TNF-α concentration was increased during ischemia in group 1 from 752 ± 403 to 1,542 ± 482 U/ml (P < 0.05) but remained unchanged in all other groups. Circulating TNF-α concentration during ischemia and infarct size correlated in all groups (r = 0.76). IP, TNF-α antibodies, and the combined approach reduced infarct size to a comparable extent. Therefore, the question of whether or not TNF-α is causally involved in the infarct size reduction by IP in rabbits could not be answered. [ABSTRACT FROM AUTHOR]

Discusses results of a study investigating the attenuation of ischemic preconditioning in pigs by scavenging of free oxyradicals with ascorbic acid. Measurement of infarct size; Ascorbyl radical concentration; Collateral blood flow to the ischemic region.

The effect of synthetic parathyroid hormone (PTH)related peptide [PTHrP(1-34)] on regional myocardial function was studied in 11 anesthetized pigs. Intracoronary infusion of PTHrP (cumulative dose: 14 ± 1 µg) decreased coronary resistance to 33 ± 2% of baseline (P < 0.05) and regional myocardial function to 90 ± 3% of baseline (not significant). Ischemia-reperfusion alters the activity of sew eral kinases and therefore possibly the myocardial effects of PTHrP. In stunned myocardium, induced by 20-min ischemia and 30-min reperfusion, the dose of PTHrP reducing coronary resistance to a minimum of 29 ± 2% was decreased to 8 ± 2 µg (P < 0.05). Regional myocardial function was no longer decreased but increased to 132 ± 9% (P < 0.05). The increase in regional myocardial function during PTHrP was inversely related to baseline function at 30-min reperfusion in vivo (r = 0.9) as well as in myocytes isolated from stunned pig hearts (r = 0.7). In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, blockade of endogenous PTHrP by D-Trp[sup 12]-Tyr[sup 34]-PTH(7-34) attenuated the recovery of left ventricular developed pressure by 30 ± 14% (P < 0.05). Thus endogenous and exogenous PTHrP impact on the function of stunned myocardium. [ABSTRACT FROM AUTHOR]

Objective: The role of p38MAPK in ischemic preconditioning (IP) is still equivocal, insofar as the p38MAPK-inhibitor SB203580 abolished IP in rats, rabbits and dogs, but not in pigs. Blockade of p38MAPK prior to the sustained ischemia also generated contradictory findings, insofar as p38MAPK acted as trigger in dogs but as mediator in rats. We have now tested whether the two structurally unrelated p38MAPK-inhibitors, BIX-645 and SB203580, abolished infarct size (IS) reduction by IP in pigs and whether their effects depended on the time of administration. Methods: Sixty-five enflurane-anesthetized pigs underwent 90 min low-flow ischemia and 120 min reperfusion without or with one preceding cycle of 10 min preconditioning ischemia and 15 min reperfusion. Pigs received BIX-645 (1 mg/kg, i.v.) or SB203580 (10 μM, i.c.) prior to either IP or the sustained ischemia. Results: IS (% TTC-staining) was reduced by IP [4.8±3.1(S.E.M.), P<0.05] compared to placebo (25.8±5.5). BIX-645 or SB203580 per se had no effect on IS (23.5±5.2 and 21.8±4.4, respectively). IS reduction by IP was abolished by BIX-645 (26.2±6.4 or 25.5±4.7) and SB203580 (19.9±4.3 or 16.7±4.7), given either prior to IP or the sustained ischemia, respectively. The supernatant of homogenized myocardial biopsies taken during the sustained ischemia from preconditioned pigs receiving either BIX-645 or SB203580 inhibited the anisomycin-stimulated ATF-2 phosphorylation in cultured Rat1 fibroblasts. This in vitro inhibition of ATF-2 phosphorylation correlated to the actual IS. Conclusion: The attenuation of the IS-reducing effect of IP depends on the effectiveness of blockade of p38MAPK activity. p38MAPK is a mediator of IP in pigs. [Copyright &y& Elsevier]

Objective: In pigs, the infarct size (IS) reduction achieved by a strong preconditioning stimulus (IPs) of 10 min ischemia and 15 min reperfusion is greater than that by a weaker preconditioning stimulus (IPw) of 3 min ischemia and 15 min reperfusion. The cardioprotection achieved by IPw is completely abolished by blockade of bradykinin-B2-receptors. Since activation of bradykinin-B2-receptors subsequently activates cyclooxygenase, we now tested whether or not inhibition of cyclooxygenase with indomethacin interferes with IS reduction by IP. Methods and results: In 42 enflurane-anesthetized pigs, the LAD coronary artery was cannulated, and subendocardial blood flow (ENDO, microspheres, ml/min/g) and IS (%, TTC-staining) were determined. Following 90 min ischemia and 120 min reperfusion, IS averaged 25.5±3.8 (S.E.M.) (ENDO: 0.05±0.01). IS was reduced by IPw to 6.3±2.1 (ENDO: 0.07±0.01) and further reduced by IPs to 2.4±1.0 (ENDO: 0.06±0.01). Indomethacin (10 mg/kg i.v.) did not alter IS per se (20.9±5.4, ENDO: 0.06±0.02), but completely abolished the IS reduction by IPw (23.2±5.9, ENDO: 0.06±0.01). In contrast, indomethacin abolished the IS reduction by IPs in only two of seven pigs (16.1±7.4, ENDO: 0.05±0.01). Conclusion: Prostaglandins are involved in IP. However, with stronger IP stimuli other triggers/mediators can compensate for the lack of prostaglandins. [Copyright &y& Elsevier]

Presents information on a study which tested whether endogenous nitric oxide attenuates beta-adrenergic inotropic responsiveness during ischemia. Measurement of arterial pressure in swine; Estimation of regional myocardial activity; Regional myocardial function in response to dobutamine or calcium.

Presents information on a study which analyzed the consequences of ischemic preconditioning on hepatic function and morphology and the animal's survival following either 120 or 200 min of normothermic ischemia in pigs. Information on ischemic preconditioning; Methodology; Results; Discussion.

The present article describes the concept of perfusion-contraction matching originally proposed by Ross, goes on to critically discuss the available techniques to measure both regional myocardial blood flow and function in the experimental and clinical setting, and finally analyzes the available evidence for perfusion-contraction match and mismatch during normoperfusion and various scenarios of myocardial ischemia/reperfusion, including acute and subacute ischemia, coronary microembolization, stunning and hibernation. [ABSTRACT FROM AUTHOR]

Examines the inconsistent relation of mitogen-activated protein kinase (MAPK) activation to infarct size reduction by ischemic preconditioning (IP) in pigs. Role of MAPK in IP; Phosphorylation of p38 and extracellular signal-regulated protein kinase after complete coronary occlusion.

Presents information on a study regarding endotoxin and ischemic preconditioning in relation to the concentration of tumor necrosis factor-alpha and myocardial infarct. Methodology; Results; Discussion on the results.

Presents a study on hibernation and ischemic preconditioning, endogenous protective mechanisms in coronary heart disease. Mechanics of hibernation and ischemic preconditioning; Limitations of the protective mechanisms; Clinical implications.

Increased vascular permeability is a hallmark of several cardiovascular anomalies, including ischaemia/reperfusion injury and inflammation. During both ischaemia/reperfusion and inflammation, massive amounts of various nucleotides, particularly adenosine 5′-triphosphate (ATP) and adenosine, are released that can induce a plethora of signalling pathways via activation of several purinergic receptors and may affect endothelial barrier properties. The nature of the effects on endothelial barrier function may depend on the prevalence and type of purinergic receptors activated in a particular tissue. In this review, we discuss the influence of the activation of various purinergic receptors and downstream signalling pathways on vascular permeability during pathological conditions. [ABSTRACT FROM AUTHOR]

In situ hearts and isolated cardiomyocytes from heterozygous connexin 43-deficient (Cx43+/−) mice cannot be protected by ischemic preconditioning or diazoxide. We have now addressed the role of connexin 43 in ischemic postconditioning (PC). Wild type (WT) and Cx43+/−mice were subjected to 30 min coronary occlusion and 120 min reperfusion, with and without a PC protocol of three cycles of 10 s coronary occlusion/10 s reperfusion. Infarct size (TTC staining) was reduced by PC from 54±5 to 37±3% of area at risk in WT. Likewise, infarct size was reduced by PC from 53±4 to 34±3% of area at risk in Cx43+/−. We conclude that connexin 43 is no prerequisite for PC’s protection. To this end, the signal transduction of ischemic preconditioning and postconditioning differs. [ABSTRACT FROM AUTHOR]

Examines the Ischemic Preconditioning (IP) in heterozygous connexin43-deficient mice. Contribution of colocalizes with and phosporylates connexin in rats and humans to IP in mice; Period for inducement of IP; Infarct size reduce by IP.