Mechanism of Preconditioning by Isoflurane in Rabbits: A Direct Role for Reactive Oxygen Species

Background Reactive oxygen species (ROS) contribute to myocardial protection during ischemic preconditioning, but the role of the ROS in protection against ischemic injury produced by volatile anesthetics has only recently been explored. We tested the hypothesis that ROS mediate isoflurane-induced preconditioning in vivo. Methods Pentobarbital-anesthetized rabbits were instrumented for measurement of hemodynamics and were subjected to a 30 min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive vehicle (0.9% saline), or the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2-mercaptopropionyl glycine (2-MPG; 1 mg. kg(-1).min(-1)), in the presence or absence of 1.0 minimum alveolar concentration (MAC) isoflurane. Isoflurane was administered for 30 min and then discontinued 15 min before coronary artery occlusion. A fluorescent probe for superoxide anion production (dihydroethidium, 2 mg) was administered in the absence of the volatile anesthetic or 5 min before exposure to isoflurane in 2 additional groups (n = 8). Myocardial infarct size and superoxide anion production were assessed using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively. Results Isoflurane (P < 0.05) decreased infarct size to 24 +/- 4% (mean +/- SEM; n = 10) of the left ventricular area at risk compared with control experiments (43 +/- 3%; n = 8). NAC (43 +/- 3%; n = 7) and 2-MPG (42 +/- 5%; n = 8) abolished this beneficial effect, but had no effect on myocardial infarct size (47 +/- 3%; n = 8 and 46 +/- 3; n = 7, respectively) when administered alone. Isoflurane increased superoxide anion production as compared with control experiments (28 +/- 12 -6 +/- 9 fluorescence units; P < 0.05). Conclusions The results indicate that ROS produced following administration of isoflurane contribute to protection against myocardial infarction in vivo.

Download Full-text

Mitochondrial Adenosine Triphosphate–regulated Potassium Channel Opening Acts as a Trigger for Isoflurane-induced Preconditioning by Generating Reactive Oxygen Species

Anesthesiology ◽

10.1097/00000542-200304000-00021 ◽

2003 ◽

Vol 98 (4) ◽

pp. 935-943 ◽

Cited By ~ 78

Author(s):

Katsuya Tanaka ◽

Dorothee Weihrauch ◽

Lynda M. Ludwig ◽

Judy R. Kersten ◽

Paul S. Pagel ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Infarct Size ◽

Adenosine Triphosphate ◽

Superoxide Anion ◽

Reactive Oxygen ◽

Oxygen Species ◽

Superoxide Anion Production ◽

Channel Opening ◽

Anion Production

Background Whether the opening of mitochondrial adenosine triphosphate-regulated potassium (K(ATP)) channels is a trigger or an end effector of anesthetic-induced preconditioning is unknown. We tested the hypothesis that the opening of mitochondrial K(ATP) channels triggers isoflurane-induced preconditioning by generating reactive oxygen species (ROS) in vivo. Methods Pentobarbital-anesthetized rabbits were subjected to a 30-min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive a vehicle (0.9% saline) or the selective mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD) alone 10 min before or immediately after a 30-min exposure to 1.0 minimum alveolar concentration (MAC) isoflurane. In another series of experiments, the fluorescent probe dihydroethidium was used to assess superoxide anion production during administration of 5-HD or the ROS scavengers N-acetylcysteine or N-2-mercaptopropionyl glycine (2-MPG) in the presence or absence of 1.0 MAC isoflurane. Myocardial infarct size and superoxide anion production were measured using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively. Results Isoflurane (P < 0.05) decreased infarct size to 19 +/- 3% (mean +/- SEM) of the left ventricular area at risk as compared to the control (38 +/- 4%). 5-HD administered before but not after isoflurane abolished this beneficial effect (37 +/- 4% as compared to 24 +/- 3%). 5-HD alone had no effect on infarct size (42 +/- 3%). Isoflurane increased fluorescence intensity. Pretreatment with N-acetylcysteine, 2-MPG, or 5-HD before isoflurane abolished increases in fluorescence, but administration of 5-HD after isoflurane only partially attenuated increases in fluorescence produced by the volatile anesthetic agent. Conclusions The results indicate that mitochondrial K(ATP) channel opening acts as a trigger for isoflurane-induced preconditioning by generating ROS in vivo.

Download Full-text

N -Acetylcysteine Restores Isoflurane-induced Preconditioning against Myocardial Infarction during Hyperglycemia

Anesthesiology ◽

10.1097/00000542-200306000-00013 ◽

2003 ◽

Vol 98 (6) ◽

pp. 1384-1390 ◽

Cited By ~ 23

Author(s):

Franz Kehl ◽

John G. Krolikowski ◽

Dorothee Weihrauch ◽

Paul S. Pagel ◽

David C. Warltier ◽

...

Keyword(s):

Myocardial Infarction ◽

Reactive Oxygen Species ◽

Infarct Size ◽

Myocardial Infarct ◽

Reactive Oxygen ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Myocardial Infarct Size ◽

Oxygen Species ◽

Blood Glucose Concentrations

Background Hyperglycemia generates reactive oxygen species and prevents isoflurane-induced preconditioning. The authors tested the hypothesis that scavenging reactive oxygen species with N-acetylcysteine will restore protection against myocardial infarction produced by isoflurane in vivo. Methods Barbiturate-anesthetized dogs (n = 45) were instrumented for measurement of systemic hemodynamics. Myocardial infarct size and coronary collateral blood flow were measured with triphenyltetrazolium staining and radioactive microspheres, respectively. All dogs were subjected to a 60-min left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Dogs were randomly assigned to receive an infusion of 0.9% saline or 15% dextrose in water to increase blood glucose concentrations to 600 mg/dl (hyperglycemia) in the absence or presence of isoflurane (1.0 minimum alveolar concentration) with or without pretreatment with N-acetylcysteine (150 mg/kg i.v.) in six experimental groups. Isoflurane was discontinued, and blood glucose concentrations were allowed to return to baseline values before left anterior descending coronary artery occlusion. Results Myocardial infarct size was 27 +/- 2% (n = 8) of the left ventricular area at risk in control experiments. Isoflurane significantly (P < 0.05) decreased infarct size (13 +/- 2%; n = 7). Hyperglycemia alone did not alter infarct size (29 +/- 3%; n = 7) but abolished the protective effect of isoflurane (25 +/- 2%; n = 8). N-Acetylcysteine alone did not affect infarct size (28 +/- 2%; n = 8) but restored isoflurane-induced cardioprotection during hyperglycemia (10 +/- 1%; n = 7). Conclusions Acute hyperglycemia abolishes reductions in myocardial infarct size produced by isoflurane, but N-acetylcysteine restores these beneficial effects. The results suggest that excessive quantities of reactive oxygen species generated during hyperglycemia impair isoflurane-induced preconditioning in dogs.

Download Full-text

Role of the β1-Adrenergic Pathway in Anesthetic and Ischemic Preconditioning against Myocardial Infarction in the Rabbit Heart In Vivo

Anesthesiology ◽

10.1097/00000542-200609000-00014 ◽

2006 ◽

Vol 105 (3) ◽

pp. 503-510 ◽

Cited By ~ 55

Author(s):

Markus Lange ◽

Thorsten M. Smul ◽

Christoph A. Blomeyer ◽

Andreas Redel ◽

Karl-Norbert Klotz ◽

...

Keyword(s):

Signal Transduction ◽

Coronary Artery ◽

Infarct Size ◽

Ischemic Preconditioning ◽

Myocardial Infarct ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Myocardial Infarct Size ◽

Area At Risk

Background Anesthetic and ischemic preconditioning share similar signal transduction pathways. The authors tested the hypothesis that the beta1-adrenergic signal transduction pathway mediates anesthetic and ischemic preconditioning in vivo. Methods Pentobarbital-anesthetized (30 mg/kg) rabbits (n = 96) were instrumented for measurement of systemic hemodynamics and subjected to 30 min of coronary artery occlusion and 3 h of reperfusion. Sixty minutes before occlusion, vehicle (control), 1.0 minimum alveolar concentration desflurane, or sevoflurane, and esmolol (30.0 mg x kg(-1) x h(-1)) were administered for 30 min, respectively. Administration of a single 5-min cycle of ischemic preconditioning was instituted 35 min before coronary artery occlusion. In separate groups, the selective blocker esmolol or the protein kinase A inhibitor H-89 (250 microg/kg) was given alone and in combination with desflurane, sevoflurane, and ischemic preconditioning. Results Baseline hemodynamics and area at risk were not significantly different between groups. Myocardial infarct size (triphenyltetrazolium staining) as a percentage of area at risk was 61 +/- 4% in control. Desflurane, sevoflurane, and ischemic preconditioning reduced infarct size to 34 +/- 2, 36 +/- 5, and 23 +/- 3%, respectively. Esmolol did not alter myocardial infarct size (65 +/- 5%) but abolished the protective effects of desflurane and sevoflurane (57 +/- 4 and 52 +/- 4%, respectively) and attenuated ischemic preconditioning (40 +/- 4%). H-89 did not alter infarct size (60 +/- 4%) but abolished preconditioning by desflurane (57 +/- 5%) and sevoflurane (61 +/- 1%). Ischemic preconditioning (24 +/- 7%) was not affected by H-89. Conclusions The results demonstrate that anesthetic preconditioning is mediated by the beta1-adrenergic pathway, whereas this pathway is not essential for ischemic preconditioning. These results indicate important differences in the mechanisms of anesthetic and ischemic preconditioning.

Download Full-text

Blockade of CD18-Dependent Neutrophil Adhesion Limits Myocardial Infarct Size Following Coronary Artery Occlusion in Cynomolgus Monkeys

Vascular Endothelium ◽

10.1007/978-1-4615-3736-6_65 ◽

1991 ◽

pp. 298-298

Author(s):

Raymond J. Winquist ◽

P. Frei ◽

M. McFarland ◽

P. Harrison ◽

G. Letts ◽

...

Keyword(s):

Coronary Artery ◽

Infarct Size ◽

Myocardial Infarct ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Neutrophil Adhesion ◽

Myocardial Infarct Size ◽

Cynomolgus Monkeys

Download Full-text

Isoflurane-induced preconditioning is attenuated by diabetes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01130.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. H2018-H2023 ◽

Cited By ~ 71

Author(s):

Katsuya Tanaka ◽

Franz Kehl ◽

Weidong Gu ◽

John G. Krolikowski ◽

Paul S. Pagel ◽

...

Keyword(s):

Blood Glucose ◽

Infarct Size ◽

Myocardial Infarct ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Left Ventricular ◽

Myocardial Infarct Size ◽

Protective Effects ◽

Area At Risk ◽

End Tidal

Volatile anesthetics stimulate, but hyperglycemia attenuates, the activity of mitochondrial ATP-regulated K+ channels. We tested the hypothesis that diabetes mellitus interferes with isoflurane-induced preconditioning. Acutely instrumented, barbiturate-anesthetized dogs were randomly assigned to receive 0, 0.32, or 0.64% end-tidal concentrations of isoflurane in the absence or presence of diabetes (3 wk after administration of alloxan and streptozotocin) in six experimental groups. All dogs were subjected to a 60-min left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Myocardial infarct size (triphenyltetrazolium staining) was 29 ± 3% ( n = 8) of the left ventricular area at risk in control experiments. Isoflurane reduced infarct size (15 ± 2 and 13 ± 1% during 0.32 and 0.64% concentrations; n = 8 and 7 dogs, respectively). Diabetes alone did not alter infarct size (30 ± 3%; n = 8) but blocked the protective effects of 0.32% (27 ± 2%; n = 7) and not 0.64% isoflurane (18 ± 3%; n = 7). Infarct size was directly related to blood glucose concentrations in diabetic dogs, but this relationship was abolished by higher concentrations of isoflurane. The results indicate that blood glucose and end-tidal isoflurane concentrations are important determinants of infarct size during anesthetic-induced preconditioning.

Download Full-text

Myocardial temperature in acute myocardial infarction: protection with mild regional hypothermia

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.1.h220 ◽

1997 ◽

Vol 273 (1) ◽

pp. H220-H227 ◽

Cited By ~ 21

Author(s):

S. L. Hale ◽

R. A. Kloner

Keyword(s):

Infarct Size ◽

Myocardial Infarct ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Control Group ◽

Myocardial Infarct Size ◽

Local Cooling ◽

Risk Zone ◽

Myocardial Temperature

This study tests the hypothesis that a 2-4 degrees C reduction in myocardial temperature, obtained by using topical regional hypothermia (TRH), reduces infarct size. Anesthetized rabbits received coronary artery occlusion and reperfusion. We cooled hearts in the TRH group by applying an ice bag directly over the risk zone; the control group received no intervention. Risk zone myocardial temperature (MT) in the TRH group was reduced at occlusion by 2 degrees C from baseline and after 5 min of occlusion by 3.6 degrees C. In the control group, MT in the risk region remained within 0.3 degree C of baseline. The ischemic area was similar in both groups, yet infarct size in the TRH group was reduced by an average of 65% compared with the control group. Infarct size closely correlated with MT in the risk region at the time of occlusion. In a second protocol in which all hearts were paced, infarct size was 21% of the risk region in TRH hearts compared with 44% in controls. These results strongly support the important role of MT in the progression of necrosis and demonstrate that the application of local cooling to the risk region profoundly reduces myocardial infarct size.

Download Full-text

Morphine Enhances Pharmacological Preconditioning by Isoflurane

Anesthesiology ◽

10.1097/00000542-200303000-00019 ◽

2003 ◽

Vol 98 (3) ◽

pp. 705-711 ◽

Cited By ~ 80

Author(s):

Lynda M. Ludwig ◽

Hemal H. Patel ◽

Garrett J. Gross ◽

Judy R. Kersten ◽

Paul S. Pagel ◽

...

Keyword(s):

Myocardial Infarction ◽

Potassium Channels ◽

Infarct Size ◽

Adenosine Triphosphate ◽

Opioid Receptors ◽

Myocardial Infarct ◽

Coronary Artery Occlusion ◽

Myocardial Infarct Size ◽

Area At Risk

Background Adenosine triphosphate-regulated potassium channels mediate protection against myocardial infarction produced by volatile anesthetics and opioids. We tested the hypothesis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors. Methods Barbiturate-anesthetized rats (n = 131) were instrumented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size was determined using triphenyltetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats received 5-hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or absence of isoflurane, morphine, and morphine plus isoflurane. Results Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) reduced infarct size (41 +/- 3%; n = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further decreased infarct size to 26 +/- 3% (n = 11). 5-HD and naloxone alone did not affect infarct size, but abolished cardioprotection produced by isoflurane, morphine, and morphine plus isoflurane. Conclusions Combined administration of isoflurane and morphine enhances the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors in vivo.

Download Full-text

KATP channels are common mediators of ischemic and calcium preconditioning in rabbits

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.274.4.h1106 ◽

1998 ◽

Vol 274 (4) ◽

pp. H1106-H1112 ◽

Cited By ~ 10

Author(s):

Ichiro Kouchi ◽

Tomoyuki Murakami ◽

Ryuzo Nawada ◽

Masaharu Akao ◽

Shigetake Sasayama

Keyword(s):

Infarct Size ◽

Channel Blocker ◽

Myocardial Infarct ◽

Katp Channels ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Myocardial Infarct Size ◽

Area At Risk ◽

Channel Activation ◽

Calcium Infusion

Calcium preconditioning (CPC), like ischemic preconditioning (IPC), reduces myocardial infarct size in dogs and rats. ATP-sensitive potassium (KATP) channels induce cardioprotection of IPC in these animals. To determine whether KATP channels mediate both IPC and CPC, pentobarbital sodium-anesthetized rabbits received 30 min of coronary artery occlusion followed by 180 min of reperfusion. IPC was elicited by 5 min of occlusion and 10 min of reperfusion, and CPC was elicited by two cycles of 5 min of calcium infusion with an interval period of 15 min. Infarct size expressed as a percentage of the area at risk was 38 ± 3% (mean ± SE) in controls. IPC, CPC, and pretreatment with a KATP channel opener, cromakalim, all reduced infarct size to 13 ± 2, 17 ± 2, and 12 ± 3%, respectively ( P < 0.01 vs. controls). Glibenclamide, a KATP channel blocker administered 45 min (but not 20 min) before sustained ischemia, attenuated the effects of IPC and CPC (31 ± 4 and 41 ± 6%, respectively). Thus KATP channel activation appears to contribute to these two types of cardioprotection in rabbits.

Download Full-text