Preconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and the potential to provide novel therapeutic paradigms for cardioprotection. While many signaling pathways leading to endogenous cardioprotection have been elucidated in experimental studies over the past 30 years, no cardioprotective drug is on the market yet for that indication. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic preclinical evaluation of promising cardioprotective therapies prior to their clinical evaluation, since ischemic heart disease in humans is a complex disorder caused by or associated with cardiovascular risk factors and comorbidities.
View Article and Find Full Text PDFAims: Remote ischaemic preconditioning (RIPC) is a robust cardioprotective intervention in preclinical studies. To establish a working and efficacious RIPC protocol in our laboratories, we performed randomized, blinded in vivo studies in three study centres in rats, with various RIPC protocols. To verify that our experimental settings are in good alignment with in vivo rat studies showing cardioprotection by limb RIPC, we performed a systematic review and meta-analysis.
View Article and Find Full Text PDFThe morbidity and mortality from cardiovascular diseases (CVD) remain high. Metabolic diseases such as obesity, hyperlipidemia, diabetes mellitus (DM), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as well as hypertension are the most common comorbidities in patients with CVD. These comorbidities result in increased myocardial oxidative stress, mainly from increased activity of nicotinamide adenine dinucleotide phosphate oxidases, uncoupled endothelial nitric oxide synthase, mitochondria as well as downregulation of antioxidant defense systems.
View Article and Find Full Text PDFConditioning-like infarct limitation by enhanced level of hydrogen sulfide (HS) has been demonstrated in many animal models of myocardial ischemia/reperfusion injury (MIRI) in vivo. We sought to evaluate the effect of HS on myocardial infarction across in vivo pre-clinical studies of MIRI using a comprehensive systematic review followed by meta-analysis. Embase, Pubmed and Web of Science were searched for pre-clinical investigation of the effect of HS on MIRI in vivo.
View Article and Find Full Text PDFEthnopharmacological Relevance: Viscum album L. (European mistletoe) is a hemiparasitic plant belonging to Loranthaceae family and has been used in Turkish traditional medicine for the treatment of cardiovascular disorders and heart diseases such as hypertension, tachycardia and angina pectoris.
Aim Of The Study: The present study investigated the cardioprotective effects of V.
The natriuretic peptides, Atrial-, B-type and C-type natriuretric peptides (ANP, BNP, CNP), are regulators of many endocrine tissues and exert their effects predominantly through the activation of their specific guanylyl cyclase receptors (GC-A and GC-B) to generate cGMP. Whereas cGMP-independent signalling has been reported in response to natriuretic peptides, this is mediated via either the clearance receptor (Npr-C) or a renal-specific NPR-Bi isoform, which both lack intrinsic guanylyl cyclase activity. Here, we report evidence of GC-B-dependent cGMP-independent signalling in pituitary GH3 cells.
View Article and Find Full Text PDFBackground And Purpose: H S protects myocardium against ischaemia/reperfusion injury. This protection may involve the cytosolic reperfusion injury salvage kinase (RISK) pathway, but direct effects on mitochondrial function are possible. Here, we investigated the potential cardioprotective effect of a mitochondria-specific H S donor, AP39, at reperfusion against ischaemia/reperfusion injury.
View Article and Find Full Text PDFExogenous hydrogen sulfide (H2S) protects against myocardial ischemia/reperfusion injury but the mechanism of action is unclear. The present study investigated the effect of GYY4137, a slow-releasing H2S donor, on myocardial infarction given specifically at reperfusion and the signalling pathway involved. Thiobutabarbital-anesthetised rats were subjected to 30min of left coronary artery occlusion and 2h reperfusion.
View Article and Find Full Text PDFUnmodified reperfusion therapy for acute myocardial infarction (AMI) is associated with irreversible myocardial injury beyond that sustained during ischemia. Studies in experimental models of ischemia/reperfusion and in humans undergoing reperfusion therapy for AMI have examined potential beneficial effects of nitric oxide (NO) supplemented at the time of reperfusion. Using a rigorous systematic search approach, we have identified and critically evaluated all the relevant experimental and clinical literature to assess whether exogenous NO given at reperfusion can limit infarct size.
View Article and Find Full Text PDFThe protective effect of ischaemic postconditioning (short cycles of reperfusion and reocclusion of a previously occluded vessel) was identified over a decade ago commanding intense interest as an approach for modifying reperfusion injury which contributes to infarct size in acute myocardial infarction. Elucidation of the major mechanisms of postconditioning has identified potential pharmacological targets for limitation of reperfusion injury. These include ligands for membrane-associated receptors, activators of phosphokinase survival signalling pathways and inhibitors of the mitochondrial permeability transition pore.
View Article and Find Full Text PDFPre-, post-, and remote conditioning of the myocardium are well described adaptive responses that markedly enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and provide therapeutic paradigms for cardioprotection. Nevertheless, more than 25 years after the discovery of ischemic preconditioning, we still do not have established cardioprotective drugs on the market. Most experimental studies on cardioprotection are still undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of cardiovascular risk factors.
View Article and Find Full Text PDFLimiting the injurious effects of myocardial ischemia-reperfusion is a desirable therapeutic target, which has been investigated extensively over the last three decades. Here we provide an up to date review of the literature documenting the experimental and clinical research demonstrating the effects of manipulating cGMP for the therapeutic targeting of the injurious effects of ischemic heart disease. Augmentation of the cyclic nucleotide cGMP plays a crucial role in many cardioprotective signaling pathways.
View Article and Find Full Text PDFB-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), and (Cys-18)-atrial natriuretic factor (4-23) amide (C-ANF), are cytoprotective under conditions of ischemia-reperfusion, limiting infarct size. ATP-sensitive K(+) channel (KATP) opening is also cardioprotective, and although the KATP activation is implicated in the regulation of cardiac natriuretic peptide release, no studies have directly examined the effects of natriuretic peptides on cardiac KATP activity. Normoxic cardiomyocytes were patch clamped in the cell-attached configuration to examine sarcolemmal KATP (sKATP) activity.
View Article and Find Full Text PDFThe guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells.
View Article and Find Full Text PDFAims: Guanylyl cyclase-cyclic guanosine monophosphate signalling plays an important role in endogenous cardioprotective signalling. The aim was to assess the potential of direct pharmacological activation and stimulation of soluble guanylyl cyclase, targeting different redox states of the enzyme, to limit myocardial necrosis during early reperfusion.
Methods And Results: Rat isolated hearts were subjected to reversible left coronary artery occlusion (ischaemia-reperfusion) and infarct size was assessed by the tetrazolium staining technique.
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).
View Article and Find Full Text PDFNitric oxide (NO) and B-type natriuretic peptide (BNP) are protective against ischemia-reperfusion injury as they increase intracellular cGMP level via activation of soluble (sGC) or particulate guanylate cyclases (pGC), respectively. The aim of the present study was to examine if the cGMP-elevating mediators, NO and BNP, share a common downstream signaling pathway via cGMP-dependent protein kinase (PKG) in cardiac cytoprotection. Neonatal rat cardiac myocytes in vitro were subjected to 2.
View Article and Find Full Text PDFJ Cardiovasc Pharmacol Ther
March 2010
Hydrogen sulfide (H( 2)S) is a biological mediator produced by enzyme-regulated pathways from L-cysteine, which is a substrate for cystathionine-gamma-lyase (CSE). In myocardium, endogenously and exogenously administered H(2)S has been shown to protect against ischemia-reperfusion injury. We hypothesized that L-cysteine exerts its protective action through stimulation of H(2)S production.
View Article and Find Full Text PDFCell Biochem Funct
March 2010
Since the discovery of endogenously-produced hydrogen sulfide (H(2)S) in various tissues, there has been an explosion of interest in H(2)S as a biological mediator alongside other gaseous mediators, nitric oxide and carbon monoxide. The identification of enzyme-regulated H(2)S synthetic pathways in the cardiovascular system has led to a number of studies examining specific regulatory actions of H(2)S. We review evidence showing that endogenously-generated and exogenously-administered H(2)S exerts a wide range of actions in vascular and myocardial cells including vasodilator/vasoconstrictor effects via modification of the smooth muscle tone, induction of apoptosis and anti-proliferative responses in the smooth muscle cells, angiogenic actions, effects relevant to inflammation and shock, and cytoprotection in models of myocardial ischemia-reperfusion injury.
View Article and Find Full Text PDFWe demonstrated previously that adrenomedullin (AM), when given during early reperfusion, limited infarct size in rat heart. The present study was undertaken to provide direct evidence of the NO-dependency of AM's cardioprotective action by assessing NO biosynthesis and involvement of the soluble guanylyl cyclase (sGC) pathway. Perfused hearts from male CD-1 mice were subjected to 30-min left coronary occlusion and 60-min reperfusion.
View Article and Find Full Text PDFPostconditioning is an intervention in which controlled, brief, intermittent periods of ischaemia at the onset of reperfusion protect myocardium from the lethal consequences of reperfusion ('reperfusion injury'). Postconditioning has been demonstrated in humans with acute myocardial infarction and offers the possibility of further limiting infarct size in patients undergoing reperfusion therapy. We review current research that focuses on the molecular mechanisms of postconditioning.
View Article and Find Full Text PDFTherapeutic strategies to protect the ischemic myocardium have been studied extensively. Reperfusion is the definitive treatment for acute coronary syndromes, especially acute myocardial infarction; however, reperfusion has the potential to exacerbate lethal tissue injury, a process termed "reperfusion injury." Ischemia/reperfusion injury may lead to myocardial infarction, cardiac arrhythmias, and contractile dysfunction.
View Article and Find Full Text PDFApelin, the endogenous ligand of the G protein-coupled APJ receptor, is a peptide mediator with emerging regulatory actions in the heart. The aim of the present studies was to explore potential roles of the apelin/APJ system in myocardial ischaemia/reperfusion injury. To determine the cardiac expression of apelin/APJ and potential regulation by acute ischaemic insult, Langendorff perfused rat hearts were subjected to regional ischaemia (left coronary artery occlusion, 35 min) or ischaemia followed by reperfusion (30 min).
View Article and Find Full Text PDFBasic Res Cardiol
November 2007
Natriuretic peptides are regulatory autacoids in the mammalian myocardium whose functions, mediated via particulate guanylyl cyclase/cGMP, may include cytoprotection against ischaemia-reperfusion injury. Previous work has identified that B-type natriuretic peptide (BNP) limits infarct size when administered prior to and during coronary occlusion through a K(ATP) channel-dependent mechanism. The present study examined the hypothesis that the protection afforded by BNP is mediated specifically at reperfusion in a postconditioning-like manner.
View Article and Find Full Text PDFAlthough in experimental hypertension the cardioprotective effects of ischemic preconditioning (PC) appear to be maintained, most studies have examined the short-term hypertension in juvenile animals. However, aging may be an additional factor that influences the effectiveness of PC. The aim of this study was to characterise the effects on PC of LVH and aging simultaneously.
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