Involvement of calcitonin gene-related peptide in nitroglycerin induced improvement of preservation with cardioplegic solution.
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AIM: To study improvement of preservation with cardioplegic solution induced by nitroglycerin was related to stimulation of calcitonin gene-related peptide (CG RP) release. METHODS: The isolated rat heart was arrested using St Thomas Hospital cardioplegic solution and then was reperfused with normothermic Krebs-Henseleit solution for 40 min after the 4-h hypothermic ischemic period. Hear t rate, coronary flow, left ventricular pressure (LVP), and its first derivative (+/- dp/dtmax) were recorded, and the calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) and the release of creatine kinase (CK) were measured. RESULTS: Nitroglycerin (0.1 or 1 micro;mol/L) or CGRP (5 or 10 nmol/L) caused an improvement of cardiac function (LVP and +/- dp/dtmax) and a decrease in the release of creatine kinase during reperfusion. The protection induced by nitroglycerin was abolished by CGRP(8-37), the selective CGRP receptor antagonist, or pretreatment wit h capsaicin to deplete sensory nerves neurotransmitter content, but was unaltered by treatment w ith glibenclamide, the blocker of the ATP-sensitive potassium channel (KATP). The protection induced by exogenous CGRP was not also blocked by glibenclamide. Levels of CGRP-LI in the coronary effluent were significantly increased in the hearts treated with nitroglycerin. However, the elevated level of CGRP-LI by nitroglycerin was abolished by pretreatment with capsaicin. CONCLUSION: The improvement of preservation with cardioplegic solution induced by nitroglycerin was related to stimulation of CGRP release in the rat heart, and the effect is not related to the activation of the KATP channel. (+info)
Restoration of deficient membrane proteins in the cardiomyopathic hamster by in vivo cardiac gene transfer.
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BACKGROUND: One of the most important problems in developing in vivo cardiac gene transfer has been low transfection efficiency. A novel in vivo technique was developed, tested in normal hamsters, and the feasibility of restoring a deficient structural protein (delta-sarcoglycan) in the cardiomyopathic (CM) hamster evaluated. METHODS AND RESULTS: Adenoviral (AdV) vectors encoding either the lacZ gene or delta-sarcoglycan gene were constructed. Hypothermia was achieved in hamsters by external body cooling to a rectal temperature of 18 to 25 degrees C. Through a small thoracotomy, the ascending aorta and the main pulmonary artery were occluded with snares, and cardioplegic solution containing histamine was injected into the aortic root; viral constructs were delivered 3 to 5 minutes later followed by release of the occluders and rewarming. Four days later, homogeneous beta-galactosidase expression was detected throughout the ventricles of the normal hearts (average 77.3+/-9.0% [SEM] of left ventricular myocytes). At 1 and 3 weeks after transfection, immunostaining showed extensive restoration of delta-sarcoglycan as well as alpha- and beta-sarcoglycan proteins to the myocyte membranes, despite loss of beta-galactosidase expression at 3 weeks. Also, at 3 weeks after gene transfer, there was significantly less progression of left ventricular dysfunction assessed as percent change in fractional shortening compared with controls. CONCLUSIONS: This study demonstrates the feasibility of high efficiency in vivo myocardial gene transfer and shows application in improving the level of a deficient cardiac structural protein and cardiac function in CM hamsters. The approach should be useful for assessing effects of expressing other genes that influence the structure or function of the normal and failing heart. (+info)
Selective opening of mitochondrial ATP-sensitive potassium channels during surgically induced myocardial ischemia decreases necrosis and apoptosis.
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OBJECTIVE: Mitochondrial ATP-sensitive potassium channels have been proposed to be myoprotective. The relevance and specificity of this mechanism in cardiac surgery was unknown. The purpose of this study was to examine the effects of the mitochondrial potassium ATP-sensitive channel opener diazoxide on regional and global myocardial protection using a model of acute myocardial infarction. METHODS: Pigs (n=19) were placed on total cardiopulmonary bypass and then subjected to 30 min normothermic regional ischemia by snaring the left anterior descending coronary artery (LAD). The aorta was then crossclamped and cold blood Deaconess Surgical Associates cardioplegia (DSA; n=6) or DSA containing 50 microM diazoxide (DZX; n=6) was delivered via the aortic root and the hearts subjected to 30 min hypothermic global ischemia. The crossclamp and snare were removed and the hearts reperfused for 120 min. RESULTS: No significant differences in preload recruitable stroke work relationship, Tau, proximal, distal or proximal/distal coronary flow, regional or global segmental shortening, systolic bulging or post-systolic shortening were observed within or between DSA and DZX hearts during reperfusion. Infarct was present only in the region of LAD occlusion in both DSA and DZX hearts. Infarct size (% of area at risk) was 33.6+/-2.9% in DSA and was 16.8+/-2.4% in DZX hearts (P<0.01 versus DSA). Apoptosis as estimated by TUNEL positive nuclei was 120.3+/-48.8 in DSA and was significantly decreased to 21.4+/-5.3 in DZX hearts. Myocardial infarct was located centrally within the area at risk in both DSA and DZX hearts but was significantly increased at borderline zones within the area at risk in DSA hearts. CONCLUSIONS: The addition of diazoxide to cardioplegia significantly decreases regional myocardial cell necrosis and apoptosis in a model of acute myocardial infarction and represents an additional modality for achieving myocardial protection. (+info)
Glucose, insulin and potassium for heart protection during cardiac surgery.
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BACKGROUND: Coronary artery bypass grafting with hypothermic cardiac arrest and cardiopulmonary bypass (CPB) is associated with myocardial injury. Our study investigated whether an infusion of glucose, insulin and potassium (GIK) during elective coronary artery bypass surgery decreases myocardial cell death. METHODS: We measured cardiac troponin I (cTnI), a myofibrillar structural protein, which is a sensitive and specific indicator of myocytic injury. With ethics committee approval, 42 patients were enrolled into a randomized, prospective, double-blinded study. In the GIK group, 500 ml of 50% dextrose solution containing 100 IU insulin and potassium 80 mmol was infused at the rate of 0.75 ml kg(-1) h(-1). Patients in the non-GIK group received 5% dextrose solution at the same rate. Arterial blood samples were taken before induction of anaesthesia, after removal of the aortic clamp and 6 and 12 h after CPB. RESULTS: In both groups there was an increase in cTnI concentration (P<0.05), which was greatest about 6 h after CPB. At no time did the cTnI concentration differ between the two groups. CONCLUSION: The results suggest that GIK does not decrease the irreversible myocardial damage associated with routine coronary artery bypass surgery. (+info)
Cardioprotection by sevoflurane against reperfusion injury after cardioplegic arrest in the rat is independent of three types of cardioplegia.
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BACKGROUND: Sevoflurane protects the heart against reperfusion injury even after cardioplegic arrest. This protection may depend on the cardioplegic solution. Therefore, we investigated the effect of sevoflurane on myocardial reperfusion injury after cardioplegic arrest with University of Wisconsin solution (UW), Bretschneider's cardioplegia (HTK), and St Thomas' Hospital solution (STH). METHODS: We used an isolated rat heart model where heart rate, ventricular volume, and perfusion pressure were constant. The hearts underwent 30 min of normothermic ischaemia followed by 60 min of reperfusion. Seven groups were studied (n = 9 each). Three groups received 7 degrees C cold cardioplegic solutions (UW, HTK, STH) during the first 2 min of ischaemia at a flow of 2 ml min-1. In three groups (UW + Sevo, HTK + Sevo, STH + Sevo), sevoflurane was additionally added to the perfusion medium (membrane oxygenator) at 3.8% (1.5 MAC) during the first 15 min of reperfusion after cardioplegic arrest. Nine hearts served as untreated control group (control). We measured left ventricular developed pressure (LVDP) and infarct size. RESULTS: LVDP was similar in all groups during baseline (130 (SEM 2) mm Hg). HTK and STH improved recovery of LVDP during reperfusion from 5 (1) (control) to 67 (7) (HTK) and 52 (8) mm Hg (STH, both P < 0.05), while UW had no effect on myocardial function (7 (2) mm Hg). In the sevoflurane-treated groups, LVDP at the end of the experiments was not significantly different from the respective group without anaesthetic treatment (UW + Sevo 11 (2); HTK + Sevo 83 (8); STH + Sevo 64 (8) mm Hg; P = ns). Infarct size was reduced in the HTK and STH groups (HTK 20 (4); STH 17 (3)%; P < 0.05) compared with controls (39 (5)%; P < 0.05), but not in the UW group (52 (4)%). Compared with cardioplegia alone, sevoflurane treatment during reperfusion reduced infarct size (UW + Sevo 31 (4); HTK + Sevo 8 (1); STH + Sevo 4 (1)%; P < 0.05). CONCLUSION: We conclude, that the protection against reperfusion injury offered by sevoflurane is independent of the three cardioplegic solutions used. (+info)
Effect of L-arginine on oxygen consumption and haemodynamic function of rat's heart exposed to cold cardioplegic ischaemia and reperfusion.
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BACKGROUND: Ischaemia--reperfusion damage causes injury of all heart cells. Loss of endothelium function and biologically active substances secreted by it can be essential to development of the damage. Ischaemia and reperfusion decreases the release of nitric oxide, which influences postischaemic coronary flow and return of ventricular function. Administration of L-arginine to cardioplegic and reperfusion solution can improve protection of heart and cause the return of left ventricular function after hypothermic ischaemia through preservation of endothelial cell functions and increase of release of nitric oxide. OBJECTIVE: How addition of L-arginine to cardioplegic solution influences oxygen consumption by myocardium and its postischaemic haemodynamic function. METHODS: The research was conducted on isolated heart model of 56 rats, divided into seven equal groups. The hearts were prepared with modified Neely method and were perfused with the use of apparatus in accordance with modified Langendorf method. The research was carried out in the following order: initial perfusion of the non-working and working heart, perfusion with cardioplegic solution, cold cardioplegic arrest and reperfusion of the non-working heart. RESULTS: During initial perfusion, oxygen consumption was comparable in all groups. During cardioplegic perfusion, oxygen consumption was reduced in every group. At the time of reperfusion of non-working heart model, consumption of oxygen was increased. During reperfusion of the working heart, the lowest oxygen consumption was noted in group P, the highest in group DI. The decrease in cardiac output during postischaemic period was noted in control group and groups where L-arginine was added to reperfusion solution. CONCLUSION: Addition of L-arginine to cardioplegic solution significantly decreases oxygen consumption by myocardium. L-arginine added to cardioplegic solution improves postischaemic haemodynamic function of heart. (+info)
Development and evaluation of a new apparatus for continuous perfusion of isolated perfused pig heart.
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To develop a better model of isolated perfused heart, a new apparatus of coronary artery cannula- fixed-in-aortic tube was developed for continuous normothermic perfusion and compared to the Casalis apparatus with cold ischemia. Eight mongrel pigs with the body weight of 18 to 24 kg were divided half into two groups. All the continuous perfusion experimental hearts resumed a spontaneous heart beat and stabilized earlier than the control hearts without the need of defibrillator or pacemaker, indicating no reperfusion injury on the heart. All the experimental hearts did not show fibrillation nor stopped beating during the entire experiment, whereas the control hearts fibrillated. Two control hearts stopped beating, and only one of the two survived with the help of pacemaker.The coronary systolic, diastolic, and mean pressures were more stable with low variation in the experimental hearts than the cold ischemic control hearts. The experimental hearts consumed more oxygen than the control hearts, indicating more cardiac output. According to these results, the continuous normothermic perfusion method by the new cannula, even though with a short-period of hypothermic perfusion, provided better myocardial protection than the cold ischemia. (+info)
Insulin therapy as an adjunct to reperfusion after acute coronary ischemia: a proposed direct myocardial cell survival effect independent of metabolic modulation.
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Reperfusion therapy has become a practical and effective strategy in the salvage of ischemic myocardium. The direct enhancement of cardiac cellular tolerance against ischemic and reperfusion injury should further improve patient outcome in acute coronary syndromes (ACS). This approach has been explored for many decades, and although we await mortality-weighted randomized clinical trials, the infusion of glucose-insulin-potassium (GIK) has shown promise in protecting post-infarct myocardium. The current dogma is that this cardioprotective effect of GIK acts via the modulation of cardiac and circulating metabolites to provide the heart with an optimal metabolic milieu to resist ischemia and reperfusion injury. This concept of metabolic modulation has gained favor in coronary heart disease, and its efficacy currently is being investigated in stable angina using the new class of partial fatty acid oxidation inhibitors, including trimetazidine and ranolazine. We contend that the mitogen insulin, itself, promotes tolerance against ischemic cell death via the activation of innate cell-survival pathways in the heart. To advance this viewpoint, we will present clinical data that support a dose-dependent effect of insulin's beneficial action in the management of acute myocardial infarction. Furthermore, we present experimental data that identify cell-survival programs that are directly activated by the administration of insulin. Finally, as intravenous insulin therapy is both labor intensive and associated with metabolic perturbations, we propose that the development of pharmaco-therapeutic agents that target downstream cell-survival insulin-activated signaling molecules may be an alternate approach to promote cardioprotection during ACS. (+info)