Il Woo Shin

Propofol protects the autophagic cell death induced by the ischemia/reperfusion injury in rats

Autophagy has been implicated in cardiac cell death during ischemia/reperfusion (I/R). In this study we investigated how propofol, an antioxidant widely used for anesthesia, affects the autophagic cell death induced by the myocardial I/R injury. The infarction size in the myocardium was dramatically reduced in rats treated with propofol during I/R compared with untreated rats. A large number of autophagic vacuoles were observed in the cardiomyocytes of I/R-injured rats but rarely in I/R-injured rats treated with propofol. While LC3-II formation, an autophagy marker, was up-regulated in the I/R-injured myocardium, it was significantly down-regulated in the myocardial tissues of I/R-injured and propofol-treated rats. Moreover, propofol inhibited the I/R-induced expression of Beclin-1, and it accelerated phosphorylation of mTOR during I/R and Beclin-1/Bcl-2 interaction in cells, which indicates that it facilitates the inhibitory pathway of autophagy. These data suggest that propofol protects the autophagic cell death induced by the myocardial I/R injury.

Propofol limits rat myocardial ischemia and reperfusion injury with an associated reduction in apoptotic cell death in vivo

Propofol, a rapidly acting, short duration, intravenous hypnotic anesthetic induction agent, is often used in clinical situations where myocardial ischemia/ reperfusion (I/R) injury is a threat. The aim of the present study was to evaluate the protective effect of propofol on myocardial I/R injury in rat due to apoptosis. Myocardial I/R injury were induced by occluding the left anterior descending (LAD) coronary artery for 25 min followed by either 2 h or 6 h reperfusion. Apoptosis was evaluated by Western blot analysis (Bcl-2, Bax expression), DNA strand breaks, TUNEL analysis and measuring myocardial caspase-3 activity. Propofol significantly reduced infarct size and improved I/R-induced myocardial contractile dysfunction by improving left ventricular diastolic pressure and positive and negative maximal values of the first derivative (+dp/dt) of left ventricular pressure. Propofol increased Bcl-2/Bax expression ratio and decreased caspase-3 activity in I/R rat hearts, which resulted in reduction of myocardial apoptosis as evidenced by TUNEL analysis and DNA laddering experiments. In an in vitro study, propofol increased H9c2 cell viability against oxidative stress induced by glucose oxidase (GOX) in a dose-dependent manner. These data suggest propofol limits I/R injury with an associated reduction in apoptotic cell death in vivo.

Mitigation of H2O2-induced autophagic cell death by propofol in H9c2 cardiomyocytes

Autophagy, a self-eating process, is responsible for degradation of long-lived proteins and damaged cellular proteins/organelles. Double-membrane autophagosomes, formed during the process, engulf proteins/organelles and fuse with lysosomes to degrade the contents. It is important to maintain cell homeostasis and many physiological processes including cellular responses to oxidative stress. Oxidative stress induced by myocardial infarction is a major factor of heart failures. In this study, we examined how propofol modulates hydrogen peroxide (H2O2)-induced autophagic cell death in H9c2 cardiomyocytes. H2O2 dramatically induced cell death, which was similarly reduced in the presence of either propofol or autophagy inhibitors (e.g., wortmannin), suggesting that propofol has a protective effect in H2O2-induced autophagic cell death. Acidic autophagic vacuoles were elevated in H2O2-treated H9c2 cells, but they were largely decreased in the presence of propofol. Furthermore, many autophagy-related proteins such as LC3-II, ATG proteins, p62, AMPK, and JNK were activated in H2O2-treated H9c2 cells and were significantly deactivated in the presence of propofol. These results show that propofol regulates oxidative stress-induced autophagic cell death in cardiomyocytes. We further suggest that propofol can act as a cardioprotectant in heart diseases.

Lipid emulsion-mediated reversal of toxic-dose aminoamide local anesthetic-induced vasodilation in isolated rat aorta

Background Intravenous lipid emulsion has been used to treat systemic toxicity of local anesthetics. The goals of this in vitro study were to determine the ability of two lipid emulsions (Intralipid® and Lipofundin® MCT/LCT) to reverse toxic dose local anesthetic-induced vasodilation in isolated rat aortas. Methods Isolated endothelium-denuded aortas were suspended for isometric tension recording. Vasodilation was induced by bupivacaine (3 × 10-4 M), ropivacaine (10-3 M), lidocaine (3 × 10-3 M), or mepivacaine (7 × 10-3 M) after precontraction with 60 mM KCl. Intralipid® and Lipofundin® MCT/LCT were then added to generate concentration-response curves. We also assessed vasoconstriction induced by 60 mM KCl, 60 mM KCl with 3 × 10-4 M bupivacaine, and 60 mM KCl with 3 × 10-4 M bupivacaine plus 1.39% lipid emulsion (Intralipid® or Lipofundin® MCT/LCT). Results The two lipid emulsions reversed vasodilation induced by bupivacaine, ropivacaine, and lidocaine but had no effect on vasodilation induced by mepivacaine. Lipofundin® MCT/LCT was more effective than Intralipid® in reversing bupivacaine-induced vasodilation. The magnitude of lipid emulsion-mediated reversal of vasodilation induced by high-dose local anesthetics was as follows (from highest to lowest): 3 × 10-4 M bupivacaine-induced vasodilation, 10-3 M ropivacaine-induced vasodilation, and 3 × 10-3 M lidocaine-induced vasodilation. Conclusions Lipofundin® MCT/LCT-mediated reversal of bupivacaine-induced vasodilation was greater than that of Intralipid®; however, the two lipid emulsions equally reversed vasodilation induced by ropivacaine and lidocaine. The magnitude of lipid emulsion-mediated reversal of vasodilation appears to be correlated with the lipid solubility of the local anesthetic.

Myocardial protective effect by ulinastatin via an anti-inflammatory response after regional ischemia/reperfusion injury in an in vivo rat heart model.

Background Ulinastatin has anti-inflammatory properties and protects organs from ischemia/reperfusion-induced injury. The aim of this study was to investigate whether ulinastatin provides a protective effect on a regional myocardial ischemia/reperfusion injury in an in vivo rat heart model and to determine whether the anti-inflammatory response is related to its myocardial protective effect. Methods Rats were randomized to two groups. One group is received ulinastatin (50,000 U/kg or 100,000 U/kg) diluted in normal saline and the other group is received normal saline, which was administered intraperitoneally 30 min before the ischemic insult. Reperfusion after 30 min of ischemia of the left coronary artery territory was applied. Hemodynamic measurements were recorded serially during 6 h after reperfusion. After the 6 h reperfusion, myocardial infarct size, cardiac enzymes, myeloperoxidase activity, and inflammatory cytokine levels were compared between the ulinastatin treated and untreated groups. Results Ulinastatin improved cardiac function and reduced infarct size after regional ischemia/reperfusion injury. Ulinastatin significantly attenuated tumor necrosis factor-α expression and reduced myeloperoxidase activity. Conclusions Ulinastatin showed a myocardial protective effect after regional ischemia/reperfusion injury in an in vivo rat heart model. This protective effect of ulinastatin might be related in part to ulinastatins ability to inhibit myeloperoxidase activity and decrease expression of tumor necrosis factor-α.

Propofol has delayed myocardial protective effects after a regional ischemia/reperfusion injury in an in vivo rat heart model

Background It is well known that propofol protects myocardium against myocardial ischemia/reperfusion injury in the rat heart model. The aim of this study was to investigate whether propofol provides a protective effect against a regional myocardial ischemia/reperfusion injury in an in vivo rat heart model after 48 h of reperfusion. Methods Rats were subjected to 25 min of left coronary artery occlusion followed by 48 h of reperfusion. The sham group received profopol without ischemic injury. The control group received normal saline with ischemia/reperfusion injury. The propofol group received profopol with ischemia/reperfusion injury. The intralipid group received intralipid with ischemia/reperfusion injury. A microcatheter was advanced into the left ventricle and the hemodynamic function was evaluated. The infarct size was determined by triphenyltetrazolium staining. The serum level of cardiac troponin-I (cTn-I) was determined by ELISA (enzyme-linked immunosorbent assay). Results Propofol demonstrated protective effects on hemodynamic function and infarct size reduction. In the propofol group, the +dP/dtmax (P = 0.002) was significantly improved compared to the control group. The infarct size was 49.8% of the area at risk in the control group, and was reduced markedly by administration of propofol to 32.6% in the propofol group (P = 0.014). The ischemia/reperfusion-induced serum level of cTn-I was reduced by propofol infusion during the peri-ischemic period (P = 0.0001). Conclusions Propofol, which infused at clinically relevant concentration during the peri-ischemic period, has delayed myocardial protective effect after regional myocardial ischemia/reperfusion injury in an in vivo rat heart model after 48 h of reperfusion.

Bupivacaine-induced Vasodilation Is Mediated by Decreased Calcium Sensitization in Isolated Endothelium-denuded Rat Aortas Precontracted with Phenylephrine

Background A toxic dose of bupivacaine produces vasodilation in isolated aortas. The goal of this in vitro study was to investigate the cellular mechanism associated with bupivacaine-induced vasodilation in isolated endotheliumdenuded rat aortas precontracted with phenylephrine. Methods Isolated endothelium-denuded rat aortas were suspended for isometric tension recordings. The effects of nifedipine, verapamil, iberiotoxin, 4-aminopyridine, barium chloride, and glibenclamide on bupivacaine concentration-response curves were assessed in endothelium-denuded aortas precontracted with phenylephrine. The effect of phenylephrine and KCl used for precontraction on bupivacaine-induced concentration-response curves was assessed. The effects of verapamil on phenylephrine concentration-response curves were assessed. The effects of bupivacaine on the intracellular calcium concentration ([Ca2+]i) and tension in aortas precontracted with phenylephrine were measured simultaneously with the acetoxymethyl ester of a fura-2-loaded aortic strip. Results Pretreatment with potassium channel inhibitors had no effect on bupivacaine-induced relaxation in the endothelium-denuded aortas precontracted with phenylephrine, whereas verapamil or nifedipine attenuated bupivacaine-induced relaxation. The magnitude of the bupivacaine-induced relaxation was enhanced in the 100 mM KCl-induced precontracted aortas compared with the phenylephrine-induced precontracted aortas. Verapamil attenuated the phenylephrine-induced contraction. The magnitude of the bupivacaine-induced relaxation was higher than that of the bupivacaine-induced [Ca2+]i decrease in the aortas precontracted with phenylephrine. Conclusions Taken together, these results suggest that toxic-dose bupivacaine-induced vasodilation appears to be mediated by decreased calcium sensitization in endothelium-denuded aortas precontracted with phenylephrine. In addition, potassium channel inhibitors had no effect on bupivacaine-induced relaxation. Toxic-dose bupivacaine- induced vasodilation may be partially associated with the inhibitory effect of voltage-operated calcium channels.

A Patient with Kikuchi's Disease: What Should Pain Clinicians Do?

Kikuchis disease (KD) is an idiopathic and self-limiting necrotizing lymphadenitis that predominantly occurs in young females. It is common in Asia, and the cervical lymph nodes are commonly involved. Generally, KD has symptoms and signs of lymph node tenderness, fever, and leukocytopenia, but there are no reports on treatment for the associated myofacial pain. We herein report a young female patient who visited a pain clinic and received a trigger point injection 2 weeks before the diagnosis of KD. When young female patients with myofascial pain visit a pain clinic, doctors should be concerned about the possibility of KD, which is rare but can cause severe complications.

Lipofundin® MCT/LCT 20% increase left ventricular systolic pressure in an ex vivo rat heart model via increase of intracellular calcium level

Background Lipid emulsions have been used to treat various drug toxicities and for total parenteral nutrition therapy. Their usefulness has also been confirmed in patients with local anesthetic-induced cardiac toxicity. The purpose of this study was to measure the hemodynamic and composition effects of lipid emulsions and to elucidate the mechanism associated with changes in intracellular calcium levels in myocardiocytes. Methods We measured hemodynamic effects using a digital analysis system after Intralipid® and Lipofundin® MCT/LCT were infused into hearts hanging in a Langendorff perfusion system. We measured the effects of the lipid emulsions on intracellular calcium levels in H9c2 cells by confocal microscopy. Results Infusion of Lipofundin® MCT/LCT 20% (1 ml/kg) resulted in a significant increase in left ventricular systolic pressure compared to that after infusing modified Krebs-Henseleit solution (1 ml/kg) (P = 0.003, 95% confidence interval [CI], 2.4–12.5). Lipofundin® MCT/LCT 20% had a more positive inotropic effect than that of Intralipid® 20% (P = 0.009, 95% CI, 1.4–11.6). Both lipid emulsion treatments increased intracellular calcium levels. Lipofundin® MCT/LCT (0.01%) increased intracellular calcium level more than that of 0.01% Intralipid® (P < 0.05, 95% CI, 0.0–1.9). Conclusions These two lipid emulsions had different inotropic effects depending on their triglyceride component. The inotropic effect of lipid emulsions could be related with intracellular calcium level.

Spinal cord stimulation for intractable post-thoracotomy pain syndrome − A case report −

Post-thoracotomy syndrome is a condition characterized by pain that continues for more than 2 months after a thoracotomic procedure. Some patients suffer from devastating chest pain despite receiving multimodal treatment such as analgesics, antidepressants, anticonvulsants and nerve blockers. Spinal cord stimulation has been reported to be a promising relief for the intractable neuropathic pain. A 60-year-old man who had been suffering from post-thoracotomy pain for 20 years showed relief of pain after spinal cord stimulation. Spinal cord stimulation thus seems to be a viable option for patients who do not respond to conventional pain management therapy.