Reactive oxygen or nitrogen species play an integral role in both myocardial injury and repair. This dichotomy is differentiated at the level of species type, amount and duration of free radical generated. Homeostatic mechanisms designed to prevent free radical generation in the first instance, scavenge, or enzymatically convert them to less toxic forms and water, playing crucial roles in the maintenance of cellular structure and function. The outcome between functional recovery and dysfunction is dependent upon the inherent ability of these homeostatic antioxidant defences to withstand acute free radical generation, in the order of seconds to minutes. Alternatively, pre-existent antioxidant capacity (from intracellular and extracellular sources) may regulate the degree of free radical generation. This converts reactive oxygen and nitrogen species to the role of second messenger involved in cell signalling. The adaptive capacity of the cell is altered by the balance between death or survival signal converging at the level of the mitochondria, with distinct pathophysiological consequences that extends the period of injury from hours to days and weeks. Hyperglycaemia, hyperlipidaemia and insulin resistance enhance oxidative stress in the diabetic myocardium that cannot adapt to ischaemia-reperfusion. Altered glucose flux, mitochondrial derangements and nitric oxide synthase uncoupling in the presence of decreased antioxidant defence and impaired prosurvival cell signalling may render the diabetic myocardium more vulnerable to injury, remodelling and heart failure.
Propofol is a widely used intravenous anesthetic agent with antioxidant properties secondary to its phenol based chemical structure. Treatment with propofol has been found to attenuate oxidative stress and prevent ischemia/reperfusion injury in rat heart. Here, we report that propofol protects cardiac H9c2 cells from hydrogen peroxide (H 2 O 2 )-induced injury by triggering the activation of Akt and a parallel up-regulation of Bcl-2. We show that pretreatment with propofol significantly protects against H 2 O 2 -induced injury. We further demonstrate that propofol activates the PI3K-Akt signaling pathway. The protective effect of propofol on H 2 O 2 -induced injury is reversed by PI3K inhibitor wortmannin, which effectively suppresses propofol-induced activation of Akt, upregulation of Bcl-2, and protection from apoptosis. Collectively, our results reveal a new mechanism by which propofol inhibits H 2 O 2 -induced injury in cardiac H9c2 cells, supporting a potential application of propofol as a preemptive cardioprotectant in clinical settings such as that during coronary bypass surgery.
We investigated if increasing propofol's dosage to augment its antioxidant capacity during cardiopulmonary bypass (CPB) could confer cardiac protection. Fifty-four coronary artery bypass graft surgery patients were randomly assigned to small-dose propofol (Group P; n = 18), large-dose propofol (Group HiP; n = 18), or isoflurane Group (Group I; n = 18). After the induction, anesthesia was maintained with an inspired concentration of isoflurane 1%-3.5% (Group I) or a continuous infusion of propofol 60 microg x kg(-1) x min(-1) (Group P) throughout the surgery. In Group HiP, this dose of propofol was increased to 120 microg x kg(-1) x min(-1) for 10 min before the onset of CPB until 15 min after aortic unclamping and then decreased to 60 microg x kg(-1) x min(-1) until the end of surgery. The duration of aortic cross-clamping was 83 +/- 24, 88 +/- 22, and 81 +/- 20 min in Group P, Group HiP, and Group I, respectively (P > 0.1). Plasma malondialdehyde, a marker of oxidative stress, was significantly lower at 8 h after CPB, and Troponin I was lower at 24 h after CPB in Group HiP compared with Group P and Group I (P < 0.05). There was a significant reduction in inotropic requirements for separation from CPB in Group HiP compared with Group I. Postoperative systemic vascular resistance was significantly reduced in Group HiP as compared with Group I. Mean cardiac index was significantly higher at 24 h after CPB in Group HiP compared with Group P and Group I (P < 0.05) (Group I, 2.2 +/- 0.1; Group P, 2.3 +/- 0.2; and Group HiP, 2.8 +/- 0.3 L x min(-1) x m(-2), respectively). The duration of intensive care unit stay was significantly shorter in Group Hi-P compared with Group I. We conclude that administration of a large dose of propofol during CPB attenuates postoperative myocardial cellular damage as compared with isoflurane or small-dose propofol anesthesia.
We examined the effects of propofol (2,6-diisopropylphenol) on functional recovery and 15-F2t-isoprostane generation during ischemia-reperfusion in Langendorff-perfused rat hearts. Before the induction of 40 min of global ischemia, hearts were perfused (10 min) with propofol at 5 (lo-P) or 12 microg/mL (hi-P) in saline or with saline only (control). During ischemia, saline, lo-P, or hi-P was perfused through the aorta at 60 microL/min. During the first 15 min of reperfusion, propofol (5 or 12 microg/mL) was continued, followed by perfusion with 5 microg/mL propofol for 75 min in both propofol-treated groups. After 90 min of reperfusion (Rep-90), heart tissues were harvested for assessment of antioxidant status. In hi-P, we observed increased latency to and greater reduction of ischemic contracture relative to the lo-P or control groups. 15-F2t-Isoprostane concentrations increased during ischemia and were significantly lower in hi-P and lo-P than in control (P < 0.01). At Rep-90, myocardial functional recovery was greater in both propofol-treated groups relative to control, and it correlated positively with tissue antioxidant capacity preservation. Tissue antioxidant capacity was better preserved in hi-P than in lo-P treatment (P < 0.05). We conclude that oxidant injury occurs during ischemia and reperfusion, and propofol provides dose-dependent protection primarily by enhancing tissue antioxidant capacity and reducing lipid peroxidation.
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