动物造模 z-bio 2021-09-23 446

　　Background: Volatile anesthetic gases are used to induce and maintain general anesthesia. This has the advantages of rapid deployment and rapid recovery. It has an acceptable effect on the peripheral organs of most patients. In 1275, Spanish physician Aymond Lullus created a volatile liquid. This was called "sweet ether sulfate" and was later used as an anesthetic. A few years later, American doctor Crawford W. Long said in 1842 that when a colleague used ether as an anesthetic for his first operation, the patient underwent cervical tumor resection, but reportedly there was no pain. Lang published a report in 1849. On October 16, 1846, William TG Morton was the first person to successfully publish ether anesthetics in the operating room of the Massachusetts General Hospital. During a stroke, VA slows the progression of brain damage. Many medical conditions have benefits. By reducing the number of cerebral ischemic injury, it provides a wide range of medical benefits for stroke patients, or as a kidney protectant to prevent ischemia and reperfusion injury, reduce plasma creatinine and reduce renal necrosis, other volatile anesthetic gases isoflurane, Desflurane and sevoflurane have been shown to protect the heart by reducing and preventing myocardial ischemia during and after surgery. However, myocardial depression and vasodilation are VA. The use of serotonin can cause symptoms of intraoperative hypotension during surgery. It disrupts the balance between oxygen supply and demand in the myocardium and causes myocardial ischemia. Therefore, many doctors choose to limit or avoid patients undergoing ischemic bypass surgery (CABG). For example, the Italian Heart Surgery Center uses 40 VA for heart disease patients and 25 VA for coronary artery bypass surgery (CABG). Similarly, in an analysis investigating the impact of VA, nearly half of patients received a full vein during cardiac surgery anesthesia.

　　In addition, the use of VA has proven to be more effective when patients have severe myocardial ischemia and cardiovascular instability before cardiac surgery. Serious consequences In addition, inhalation anesthesia for acute myocardial ischemia, the rapid introduction of drugs can prolong the QT interval, there is a risk of ventricular fibrillation during the operation, and patients need to pay more attention.

　　This recent review focused on obtaining laboratory and clinical data. Inhalation anesthetics have a protective effect on the myocardium, so isoflurane, desflurane, sevoflurane. Potential heart-related risks of inhalation anesthetics

　　Literature search strategy: The literature in this review focuses on volatile anesthetics: drugs isoflurane, desflurane, sevoflurane. Use the following search criteria for each volatile anesthetic: volatile anesthetics and cardiovascular protection, or myocardial ischemia, or heart injury or cardiotoxicity, or heart failure blood pretreatment, or cytotoxicity, or myocardial ischemia, hypoxia, or Cardiomyocytes, heart hemorrhage, or heart tolerance, or cardiac post-processing, or cardiac preconditioning, or cardiomyocyte apoptosis, or arrhythmia. The existing literature discusses important areas of cardioprotection research and clinical medicine.

　　Ischemic preconditioning: Ischemic injury is a pathological process of blood. When the supply of fluid to a particular tissue area is interrupted, the demand for oxygen may exceed the supply of oxygen. In the case of ischemia, the myocardium continues to act as a glycogen reservoir. But if hypoxia lasts for more than 15 minutes, necrosis of myocardial tissue will occur, causing irreversible damage. Pretreatment is a process that causes certain damage to organs and tissues, but this damage protects the tissues that are in the process of greater damage. By inducing short-term ischemia, "cardiomyocytes contract less frequently in a few seconds, and stop contracting in a few minutes" to save energy, protect myocardial tissue, and reduce tissue necrosis. Heart damage directly affects other parts of the body, causing the blood supply to all organ systems to be interrupted, which can lead to brain damage, kidney failure, and pulmonary edema. Therefore, preconditioning for cardiac ischemia may have fatal consequences. Clinical studies have shown that ischemic preconditioning can reduce the area of myocardial infarction after myocardial ischemia. This concept was first proposed in 1986. Murray and colleagues found that the area of myocardial infarction in the canine ischemic preconditioning group that received coronary artery occlusion decreased by 7? from 29 in the control group. The dog experienced a brief coronary artery occlusion (4-5 minutes) before the 40-minute arterial occlusion consisting of ischemic events. Murry et al. observed a reduction in infarct size 22. Promote the protective mechanism of ischemic preconditioning.

　　We have also studied the phenomenon of ischemic preconditioning related to several intracellular signaling pathways. The main target of all these pathways seems to be the adenosine triphosphate (ATP) sensitive potassium channel (KATP)? + ?. KATP channels are located in the mitochondria, cell membranes, and nuclear envelope of cardiomyocytes, and in the brain and pancreas β cells, bones, smooth muscles, and nerves. The open mitochondrial KATP channel leads to the production of reactive oxygen species (ROS), which activates downstream protein kinases and leads to myocardial protection. An early increase in OS has been shown to activate cytokine channels, such as protein kinase C (PKC) and tyrosine kinase (TK) channels. This opens the mitochondrial KATP channel and reduces OS. Therefore, the initial increase in reactive oxygen species caused by ischemic stimulation leads to the opening of the channel, thereby reducing OS. In addition, the activation and expression of the KATP channel shortens the action potential time and saves energy. This is a protective effect on the heart tissue.

　　Reperfusion injury: If blood flow accumulates in the ischemic area, the ischemic injury will lead to reperfusion injury. The reperfusion process leads to severe calcium accumulation due to cell membrane damage, which leads to the opening of mitochondrial permeability transition pores (mPTPs). This destroys the mitochondrial membrane, cleaves oxidative phosphorylation, and causes ATP depletion and cell death. Due to hypoxia, ischemia causes the conversion of xanthine dehydrogenase to xanthine oxidase in the metabolism of cardiomyocytes. Xanthine oxidase causes the accumulation of hypoxanthine. During reperfusion, hypoxanthine xanthine oxidase is metabolized, resulting in overproduction of OS. This phenomenon will cause the damaged tissue to produce superoxide free radicals, which will further damage the tissue and cause irreversible contractile dysfunction.

　　Volatile anesthetic preconditioning: The use of anesthetics activates some of the same channels, leading to the protective mechanism of ischemic preconditioning. Zauggetal. Shows that exposure to volatile anesthetics (isoflurane or sevoflurane) in a dose-dependent manner (similar to ischemic preconditioning) rather than myocardial ischemia is beneficial to reduce myocardial ischemic damage. I confirmed. By using the KATP blocker 5-HD (mitochondrial KATP blocker HMR-1098) and (cell membrane KATP blocker) and the KATP channel activator diazoxide, they proved that isoflurane and sevoflurane are the main mitochondria. KATP channel of the myocardial cell membrane. Zaugg et al. explained that sevoflurane and isoflurane cause the activation of mitochondrial KATP channels, similar to those seen in ischemic preconditioning. The same research team found that compared with placebo pretreatment, the use of sevoflurane coronary artery bypass surgery significantly improved outcomes and reduced the incidence of advanced cardiac ischemia and congestive heart failure. However, it is not clear whether the preconditioning effect of volatile anesthetics will increase the effect of obstructive cerebral ischemic preconditioning. Studies have shown that performing VA before and 15 minutes after coronary artery occlusion shows better myocardial recovery function. In this experiment, the dog was anesthetized with halothane or isoflurane, and myocardial function returned to baseline after 5 hours of reperfusion. The myocardial function of dogs without anesthesia preconditioning is 50? Further studies have shown that similar ischemic cardioplegia and the use of sevoflurane, desflurane and enflurane-type myocardial dysfunction. Rabbit myocardial studies have shown that desflurane is the most effective volatile anesthetic for pretreatment of myocardial injury, but sevoflurane does not have the same significant effect. Pretreatment with halothane and isoflurane also caused the same cardiac arrest. However, sevoflurane pretreatment can also protect the myocardium in other models.

　　seems to involve other mechanisms of cardiac arrest through ischemic preconditioning. These mechanisms include Akt, ERK, and OS signaling pathways. The channels involved have been identified as MPTP, myocardial KATP channel and mitochondrial KATP channel.

　　Mechanical pathway: Several important signaling mechanisms have been identified as intermediaries. Including KATP channel activation and pretreatment protection mediators and cytokine regulators, MPTP regulatory pathway (Akt/PI3K). In ischemic preconditioning, KATP has been identified as a cardiac arrest mediator, and volatile anesthetic preconditioning is being studied. The opening of the mitochondrial KATP channel has been shown to cause the production of OS. In a rat trabecular study, deRuijteretal showed that the cardioprotective effect of sevoflurane is due to PKC activation, which opens the mitochondrial KATP channel. After 60 minutes of trabecular ischemia and reperfusion in rats, the main recovery amount is used as a measure of cardiac function after myocardial infarction (MI). Sevoflurane increased the pillar recovery by 67 but only 28 in the control group. However, when KATP channel inhibitor (5-HD) is used in combination with sevoflurane, the main recovery rate is only 31? and when the active oxygen scavenger is used in combination with sevoflurane, the main recovery rate is only 33? This data shows that KATP channel and OS Both are involved in the cardiac arrest mechanism of sevoflurane. According to a report by Marinovicetal, the KATP channel of the myocardial cell membrane is the preconditioning effector, and the mitochondrial KATP channel is the sensor and effector. This is based on the management of KATP channel inhibitors in mitochondria and cell membranes in the isoflurane pretreatment group of rat cardiomyocytes. 5-HD administration in the sevoflurane pretreatment group reduced myocardial protection, but it was not observed in the HMR-1098 group. However, the application of HMR-1098 has no protective effect without pretreatment during the experiment.

　　Piriouetal. Point out that KATP channels are also related to MPTPs. This study showed that ischemic preconditioning and VA preconditioning delayed the initiation of MPTP channels. Delaying MPTP channel activation is to protect the mitochondrial matrix swelling caused by mPTP channel activation. This disrupts the mitochondrial membrane, disrupts the electron transport chain, and releases cytochrome C and other apoptotic factors such as Bax and caspase. 9 and ATP. The administration of 5-HD eliminated the calcium-induced increase in tolerance of MPTP channel openings. This indicates the possibility of a connection between the MPTP channel and the KATP channel.

　　"In other words, the Akt/PI3K signaling pathway that is clinically determined to have cardioprotective effects is the Akt/PI3K signaling pathway, which is an important intracellular signaling pathway for cell apoptosis. aphaeletal. The role of Akt/PI3K signaling pathway in VA cardioplegia was studied. Detection of DNA fragments by the TUNEL method showed that isoflurane pretreatment significantly reduced the percentage of apoptotic cells. In addition, the expression of Akt and phosphorylated Akt (active Akt) during ischemia-reperfusion showed that the expression of phosphorylated Akt was significantly higher than that of the ischemia-reperfusion and isoflurane preconditioning group. The use of LY294002 (PI3K inhibitor) and wortmannin inhibits Akt phosphorylation. It was also shown that the use of wortmannin and LY294002 eliminated the cardioplegia effect of pre-anaesthesia treatment, and phosphorylated Akt had cardioplegia effect.

　　The extracellular signal kinase (ERK) pathway is related to cardiac arrest caused by VA pretreatment. In the tomaetal rat myocardial ischemia-reperfusion experiment, desflurane preconditioning is ERK (the active form of ERK). Studies have shown that it can induce phosphorylation. In the desflurane pretreatment group, the MEK/ERK1/2 inhibitor PD98059 was used in combination with desflurane to eliminate its cardiac arrest function. This indicates that MEK/ERK1/2 is superior to injury as a modulator of VA cardioplegia. Western blot analysis showed that the use of desflurane increased early ERK phosphorylation 10 minutes after myocardial infarction. ERK1/2 has been identified as a downstream effector of PKC-mediated effects. And found that the phosphate of ERK does not depend on PKC. Western blotting showed that administration of calphophos protein C (PKC inhibitor) to rats did not affect the phosphorylation of ERK1/2. These results indicate that a single dose of ERK1/2 activator and desflurane is used for cardiac arrest, but the use of additional doses may reduce this cardiac arrest. Emphasize the VA pretreatment of cardioplegia. Finally, the literature shows that ERK1/2 activation is PKC-dependent.

　　In addition, VA pretreatment shows that Ca2 + flow is related to cardiac arrest function and the involvement of nuclear factor B (NF-κBκκ). Fluorescence detection of calcium ion concentration showed that the sevoflurane pretreatment group can improve coronary blood flow and reduce calcium ion load. In addition, Western blotting showed that sevoflurane pretreatment group can reduce the destruction of sarcoplasmic reticulum Ca2+? circulating proteins. Due to systolic Ca2+ depletion, reperfusion injury protects the myocardium and leads to irreversible Ca2+ excess. The accumulation of Ca2+ after ischemia-reperfusion leads to the activation of F-κB and the release of inflammatory mediators. Further studies have shown that calcineurin has a protective effect in myocardial ischemia-reperfusion model and Koniaetal myocardial ischemia-reperfusion model. Studies have shown that the NF-κB inhibitor parthenolide (IF-κB inhibitor) in the sevoflurane pretreatment group has been shown to be used for prevention. Activation of F-κB The conclusion is that F-κB inhibitors provide greater post-ischemic cardiac arrest than sevoflurane. The sevoflurane group shows 19. The control group showed that 59 participated in anesthesia preconditioning in terms of myocardial infarction. Further research and anesthesia preconditioning function is needed. The use of other anesthetics during surgery can also provide protection. It is not clear whether VA has clinical cardioprotective effects. For cardiac surgery patients undergoing VA pretreatment, especially coronary artery bypass graft (CABG) patients, they may support the beneficial effects of VA, such as reducing myocardial infarction, releasing cardiac troponin, and shortening the length of hospital stay. ...For example, in a study involving CABG patients, the increase in biomarkers of myocardial injury after Guarracinoetal and Mecoetal was lower in the desflurane group compared with general intravenous anesthesia. There are differences in the biochemical indicators of myocardial injury in patients. However, patients undergoing VA pretreatment have shorter hospital stays within 1 year and lower mortality rates. In a retrospective study of 10,000 patients undergoing cardiac surgery, VA had a good prognosis for patients undergoing cardiac surgery using preconditioning, but for patients with severe myocardial infarction before surgery, VA was more effective than general intravenous anesthesia for ischemia or cardiovascular failure. stable. The result is terrible.

　　Bignamietal provided additional evidence that pre-VA patients are beneficial for heart surgery. He said that heart surgery patients have good results after using VA. This analysis shows that the use of VA to precondition patients

　　There are certain benefits. Amretal. Both ischemic preconditioning and isoflurane lamp reconditioning in CABG patients are cold-blooded under general intravenous anesthesia. We found that it is superior to myocardial paralysis in terms of myocardial protection. In addition, VA preconditioning is beneficial to CABG patients, and the use of remote ischemic preconditioning and VA preconditioning has a protective function. The use of propofol will not affect the heart muscle, but the use of propofol will not. The international consensus meeting provides expert support: the pretreatment of VA for cardiac surgery patients is that it has a stabilizing effect on hemodynamics. Yes: Patients undergoing further diastolic surgery should use VA propofol.

　　The study also used human heart tissue to study the benefits of VA pretreatment and to identify similar mechanical pathways, including animal studies that caused it. Some important signaling mechanisms are drugs. It has been shown that the use of antagonistic ion channels is involved in the pretreatment anesthesia process. Jiangetal. Human ventricular myocytes are not suitable for transplantation to study the activity of mitochondrial KATP channels in human tissues. By providing 5-HD to cells, we show that mitochondrial KATP channels in human and animal cardiomyocytes are involved in the process of ischemic injury. In the treatment group, the use of 5-HD may weaken the activity of KATP ion channels. In the other group, isoflurane increased the activity of mitochondrial KATP channels and increased the peak current of the control group. It proves the function of the KATP channel after clinical VA pretreatment. Further clinical studies have shown that ROS is involved in cardiac arrest during pre-anesthesia treatment. Therefore, they studied the role of exogenous hydrogen peroxide in the device. First, ATP blocks the mitochondrial KATP channel. In addition, although ATP is retained, hydrogen peroxide administration activates the KATP channel. In vitro experiments have shown that OS affects the KATP channel in human mitochondria. in

　　In an in vitro study, Mioetal, an adult patient undergoing cardiac surgery using the right atrial appendage, studied the mechanical effects of VA preconditioning. They believe that the KATP channel is involved in the cardioprotective function of inhalation anesthesia preconditioning, and the results indicate that isoflurane inhibits stress-induced cell death and maintains mitochondrial function. Isoflurane maintains mitochondrial oxygen consumption, is stimulated by pyruvate, and is accelerated by adenosine diphosphate. The storage of oxygen-consuming mitochondria shows the protective effect of isoflurane on myocardial ischemia. In addition, they pointed out that isoflurane's cardiac arrest is due to the KATP mechanism of the myocardial cell membrane. The use of HMR-1098 reduces the cardiac arrest function of isoflurane from 21-cell mortality (without HMR-1098) and 41-cell mortality (with HMR-1098). KATP channels are involved in myocardial protection. Someone suggested that they were doing it.

　　Hanouzetal. Using human right atrium cultured in vitro, the effect of active oxygen pretreatment with sevoflurane and desflurane on cardioplegia was studied. In the study to observe the recovery of contraction, the control group, sevoflurane pretreatment group and desflurane pretreatment group. The shrinkage elasticity of the sevoflurane group (53 and 85) and the desflurane group (53 and 86) was significantly improved. Use MPG (ROS Scavenger) to prevent contraction recovery: the myocardial contractility of the desflurane?+?MPG group has 53 to 48 changes, and the sevoflurane?+?MPG group has 53 grades and 56 changes. (Same as the control group). Since the use of MPG deprived the recovery of myocardial contraction in the desflurane and sevoflurane groups, they believed that OS was involved in the cardiac arrest mechanism induced by VA preconditioning. Through in vitro experimental studies, the signal transduction mechanism of cardioplegia in human tissues was evaluated. However, further in vivo studies are needed to clearly determine that VA pretreatment as a treatment option has a protective effect on the myocardium of patients with myocardial ischemia.

　　The side effects of gas anesthetics on the heart give traditional anesthetic concentrations. All VAs have clinically relevant myocardial depression. Although the use of VAs can help protect eyesight, it should be considered for patients with obvious heart failure.

　　In addition, using clinically appropriate VA concentrations, myocardial inhibition can cause vasodilation and hemodynamic instability in patients with ischemic heart disease. In addition, some studies have shown that the use of VA can lead to a longer QT interval. This is because the longer the QT interval, the greater the risk of arrhythmia. The QT interval is the depolarization and repolarization part of the depolarization and repolarization cycle of the central ventricle, and represents the electrical activity of the heart on the ECG. Prolonging the QT interval increases the risk of patients with torsade de pointes ventricular tachycardia, which may cause ventricular fibrillation, as reported with the use of VA anesthetics. Nevertheless, patients who use VA are known as safe and known long QT syndrome. In addition, studies have shown that the use of VA can prolong the QT interval, but the incidence of ventricular arrhythmias in 10535 patients receiving sevoflurane coronary artery bypass is lower than that of propofol anesthesia. I will. Other patients undergoing coronary artery bypass grafting have not reported an increase in ventricular arrhythmia after VA preconditioning. In addition, animal studies have shown anti-arrhythmic effects before or after VA treatment. However, depending on the patient's condition, arrhythmia and hemodynamic instability may be induced, such as severe myocardial ischemia before surgery. Care should be taken when using VA pretreatment to protect the heart.

　　No cardioprotective function: Angriloetal recently discovered that VA pretreatment has no cardioprotective function in non-cardiac surgery. This study found a decrease in troponin release in patients undergoing non-cardiac surgery.