Application of high-dose propofol during ischemia improves postischemic function of rat hearts: Effects on tissue antioxidant capacity

Centre for Anesthesia and Analgesia, Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
Canadian Journal of Physiology and Pharmacology (Impact Factor: 1.77). 11/2004; 82(10):919-26. DOI: 10.1139/y04-097
Source: PubMed


Previous studies have shown that reactive oxygen species mediated lipid peroxidation in patients undergoing cardiac surgery occurs primarily during cardiopulmonary bypass. We examined whether application of a high concentration of propofol during ischemia could effectively enhance postischemic myocardial functional recovery in the setting of global ischemia and reperfusion in an isolated heart preparation. Hearts were subjected to 40 min of global ischemia followed by 90 min of reperfusion. During ischemia, propofol (12 microg/mL in saline) was perfused through the aorta at 60 microL/min. We found that application of high-concentration propofol during ischemia combined with low-concentration propofol (1.2 microg/mL) administered before ischemia and during reperfusion significantly improved postischemic myocardial functional recovery without depressing cardiac mechanics before ischemia, as is seen when high-concentration propofol was applied prior to ischemia and during reperfusion. The functional enhancement is associated with increased heart tissue antioxidant capacity and reduced lipid peroxidation. We conclude that high-concentration propofol application during ischemia could be a potential therapeutic and anesthetic strategy for patients with preexisting myocardial dysfunction.

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Available from: Zhengyuan Xia
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    • "Propofol (2,6-diisopropylphenol) is a widely used intravenous anesthetic agent that has been found to prevent myocardial ischemia–reperfusion injury in isolated heart models.1-3 Propofol was used to attenuate cardiac injury in a porcine model of cardiopulmonary bypass and in low risk patients undergoing cardiac surgery.4,5 "
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    ABSTRACT: We previously demonstrated that propofol, an intravenous anesthetic with anti-oxidative properties, activated the phosphoinositide 3-kinase (PI3K)/AKT pathway to increase the expression of B cell lymphoma (Bcl)-2 and, therefore the anti-apoptotic potential on cardiomyocytes. Here, we wanted to determine if propofol can also activate the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway, another branch of cardioprotective signaling. The cellular response of nuclear factor kappa B (NFκB) and STAT3 was also evaluated. Cardiac H9c2 cells were treated by propofol alone or in combination with pretreatment by inhibitors for JAK2/STAT3 or PI3K/AKT pathway. STAT3 and AKT phosphorylation, and STAT3 translocation were measured by western blotting and immunofluorescence staining, respectively. Propofol treatment significantly increased STAT3 phosphorylation at both tyrosine 705 and serine 727 residues. Sustained early phosphorylation of STAT3 was observed with 25~75 μM propofol at 10 and 30 min. Nuclear translocation of STAT3 was seen at 4 h after treatment with 50 μM propofol. In cultured H9c2 cells, we further demonstrated that propofol-induced STAT3 phosphorylation was reduced by pretreatment with PI3K/AKT pathway inhibitors wortmannin or API-2. Conversely, pretreatment with JAK2/STAT3 pathway inhibitor AG490 or stattic inhibited propofol-induced AKT phosphorylation. In addition, propofol induced NFκB p65 subunit perinuclear translocation. Inhibition or knockdown of STAT3 was associated with increased levels of the NFκB p65 subunit. Our results suggest that propofol induces an adaptive response by dual activation and crosstalk of cytoprotective PI3K/AKT and JAK2/STAT3 pathways. Rationale to apply propofol clinically as a preemptive cardioprotectant during cardiac surgery is supported by our findings.
    Full-text · Article · Apr 2014
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    • "As mentioned in the former section, isoflurane preconditioning may rely on the release of small quantity of free radicals, which may be scavenged by propofol. Propofol cardioprotection is dose-dependent both in the clinics (Xia et al., 2006) and experiments (Xia et al., 2004). It is likely that in the joint isoflurane-propofol group, the protective effects observed may solely come from propofol cardioprotection via its antioxidant property, providing that the dose of propofol used is high enough. "
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    ABSTRACT: We compare the cardioprotective effects of anesthetic preconditioning by propofol and/or isoflurane in rats with ischemia-reperfusion injury. Male adult Wistar rats were subjected to 60 min of anterior descending coronary artery occlusion followed by 120 min of reperfusion. Before the long ischemia, anesthetics were administered twice for 10 min followed by 5 min washout. Isoflurane was inhaled at 1 MAC (0.016) in I group, whereas propofol was inhaled intravenously at 37.5 mg/(kg(h) in P group. A combination of isoflurane and propofol was administered simultaneously in I+P group. In control (without anesthetic preconditioning, C group), remarkable myocardial infarction and apoptosis accompanied by an increased level of cardiac troponin T were noted 120 min after ischemia-reperfusion. As compared to those of control group, I and P groups had comparable cardioprotection. In addition, I+P group shares with I and P groups the comparable cardioprotective effects in terms of myocardial infarction and cardiac troponin T elevation. A combination of isoflurane and propofol produced no additional cardioprotection.
    Preview · Article · Oct 2009 · Journal of Zhejiang University SCIENCE B
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    • "Propofol, a highly lipid soluble hypnotic agent, has proven antioxidant activity in both in vitro and in vivo studies; this is based on the fact that its chemical structure is similar to that of a natural antioxidant: i.e., vitamin E .It has been demonstrated that propofol acts as a scavenger of oxygen free radicals, decreasing lipid peroxidation and increasing the antioxidant capacity of erythrocytes and other tissues in organs such as liver, kidney, heart and lung,both experimentally and clinically Kuang et al (2008). However, previous literature demonstrated this antioxidant property of propofol,mostly when administered at a clinically achievable large concentration Xia et al (2004). This high dose is a threat to haemodynamic stability. "
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    ABSTRACT: The normal balance between pro-oxidant and antioxidant substances is transiently altered in favor of the former as a result of surgical trauma. Interest has focused lately on the potential of anesthetics to protect against such oxidant mediated cell damage. The intravenous anesthetic, 2,6-diisopropylphenol, propofol, has been shown to have antioxidant properties. Most of the former studies, however, demonstrated that this antioxidant effect of propofol is more pronounced with the use of high dose. The aim of this study was to assess and compare the impact of low-versus high-dose propofol total intravenous anesthesia (TIVA) on the oxidative status through the determination of serum malondialdehyde (MDA), the oxidative stress biomarker; serum total antioxidant status (TAO), and the erythrocyte antioxidant enzymes:superoxide dismutase (E-SOD) and glutathione peroxidase (E-GPx).Material and Methods: This study was conducted on consented 60 patients (ASA I-II), scheduled for major elective abdominal surgical interventions (Time . 2 hours). General Anesthesia was induced using IV sufentanil: (0.20-0.30 µg Kg), IV vecuronium: (0.08-0.12 mg Kg) .-1 .-1 and propofol IV. Patients were divided into two groups: Group I (HI): (n=30): received IV Propofol (2-2.5 mg Kg) bolus and an induction dose followed by (200 µg Kg min) for maintenance with . -1 . -1. -1 continuous total intravenous anesthesia technique (TIVA). Group II (LO): (n=30): received IV Propofol (1-2.5 mg Kg) bolus as an induction dose followed by (100 µg Kg min) for maintenance . -1 . -1. -1 with continuous total intravenous anesthesia technique (TIVA) using syringe pump. Venous blood samples were taken at pre-induction, 10, 60 minutes after induction, at the end of surgery and 24 hours after recovery for the determination of serum MDA and TAO, and E-SOD and E-GPx. Results: Alterations of serum MDA and TAO and E-SOD were only observed with low-dose propofol.MDA showed a significant drop at the end of surgery (P<0.01), whereas both serum TAO and E-SOD showed significant elevations 10 min after induction of anesthesia and 24 h after surgery (P<0.01). E-GPx, on the other hand, showed significant elevations with both high-dose (1 hour after induction of anesthesia and at the end of surgery, P<0.01), and low-dose propofol (only 1 hour after induction of anesthesia, P<0.01).Marked hemodynamic changes occurred with high dose propofol infusion. Conclusions: Our results revealed that low-dose propofol is superior to high-dose propofol in reducing oxidative stress and enhancing antioxidant defense mechanisms. These results might be attributed to the marked hemodynamic changes occurred with high dose propofol infusion. Further studies, with maintained hemodynamic stabilities, are required to explore the antioxidant potential of high-dose propofol.
    Preview · Article · · Australian Journal of Basic and Applied Sciences
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