Dirk Ebel

Isoflurane Preconditions Myocardium against Infarction via Release of Free Radicals

Background Isoflurane exerts cardioprotective effects that mimic the ischemic preconditioning phenomenon. Generation of free radicals is implicated in ischemic preconditioning. The authors investigated whether isoflurane-induced preconditioning may involve release of free radicals. Methods Sixty-one &agr;-chloralose–anesthetized rabbits were instrumented for measurement of left ventricular (LV) pressure (tip-manometer), cardiac output (ultrasonic flowprobe), and myocardial infarct size (triphenyltetrazolium staining). All rabbits were subjected to 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Rabbits of all six groups underwent a treatment period consisting of either no intervention for 35 min (control group, n = 11) or 15 min of isoflurane inhalation (1 minimum alveolar concentration end-tidal concentration) followed by a 10-min washout period (isoflurane group, n = 12). Four additional groups received the radical scavenger N-(2-mercaptoproprionyl)glycine (MPG; 1 mg · kg−1 · min−1) or Mn(III)tetrakis(4-benzoic acid)porphyrine chloride (MnTBAP; 100 &mgr;g · kg−1 · min−1) during the treatment period with (isoflurane + MPG; n = 11; isoflurane + MnTBAP, n = 9) or without isoflurane inhalation (MPG, n = 11; MnTBAP, n = 7). Results Hemodynamic baseline values were not significantly different between groups (LV pressure, 97 ± 17 mmHg [mean ± SD]; cardiac output, 228 ± 61 ml/min). During coronary artery occlusion, LV pressure was reduced to 91 ± 17% of baseline and cardiac output to 94 ± 21%. After 2 h of reperfusion, recovery of LV pressure and cardiac output was not significantly different between groups (LV pressure, 83 ± 20%; cardiac output, 86 ± 23% of baseline). Infarct size was reduced from 49 ± 17% of the area at risk in controls to 29 ± 19% in the isoflurane group (P = 0.04). MPG and MnTBAP themselves had no effect on infarct size (MPG, 50 ± 14%; MnTBAP, 56 ± 15%), but both abolished the preconditioning effect of isoflurane (isoflurane + MPG, 50 ± 24%, P = 0.02; isoflurane + MnTBAP, 55 ± 10%, P = 0.001). Conclusion Isoflurane-induced preconditioning depends on the release of free radicals.

Impact of preconditioning protocol on anesthetic-induced cardioprotection in patients having coronary artery bypass surgery

OBJECTIVE Anesthetic preconditioning may contribute to the cardioprotective effects of sevoflurane in patients having coronary artery bypass surgery. We investigated whether 2 different sevoflurane administration protocols can induce preconditioning in patients having coronary artery bypass. METHODS Thirty patients were randomly allocated to 1 of 3 groups. All patients received a total intravenous anesthesia with sufentanil (0.3 microg(-1) x kg x h(-1)) and propofol as target controlled infusion (2.5 microg/mL). The control group had no further intervention; 10 minutes prior to establishing the extracorporeal circulation, patients of the sevoflurane-I group received 1 minimum alveolar concentration of sevoflurane for 5 minutes. Patients of the sevoflurane-II group received (2 times) 5 minutes of sevoflurane, interspersed by 5-minute washout 10 minutes prior to extracorporeal circulation. Troponin I was measured as marker of cardiac cellular damage. RESULTS Peak levels of troponin I release were observed at 4 hours after cardiopulmonary bypass and were not affected by 1 cycle of sevoflurane administration (controls: 14 +/- 3 ng/mL vs sevoflurane-I group, 14 +/- 3 ng/mL). Two periods of sevoflurane preconditioning significantly reduced cellular damage compared with controls (peak troponin I level sevoflurane-II group, 7 +/- 2 ng/mL). CONCLUSION These data show that sevoflurane-induced preconditioning is reproducible in patients having coronary artery bypass but depends on the preconditioning protocol used.

Sevoflurane confers additional cardioprotection after ischemic late preconditioning in rabbits

BACKGROUND: Sevoflurane exerts cardioprotective effects that mimic the early ischemic preconditioning phenomenon (EPC) by activating adenosine triphosphate-sensitive potassium (KATP) channels. Ischemic late preconditioning (LPC) is an important cardioprotective mechanism in patients with coronary artery disease. The authors investigated whether the combination of LPC and sevoflurane-induced preconditioning results in enhanced cardioprotection and whether opening of KATP channels plays a role in this new setting. METHODS: Seventy-three rabbits were instrumented with a coronary artery occluder. After recovery for 10 days, they were subjected to 30 min of coronary artery occlusion and 120 min of reperfusion (I/R). Controls (n = 14) were not preconditioned. LPC was induced in conscious animals by a 5-min period of coronary artery occlusion 24 h before I/R (LPC, n = 15). Additional EPC was induced by a 5-min period of myocardial ischemia 10 min before I/R (LPC+EPC, n = 9). Animals of the sevoflurane (SEVO) groups inhaled 1 minimum alveolar concentration of sevoflurane for 5 min at 10 min before I/R with (LPC+SEVO, n = 10) or without (SEVO, n = 15) additional LPC. The KATP channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg) was given intravenously 10 min before sevoflurane administration (LPC+SEVO+5-HD, n = 10). RESULTS: Infarct size of the area at risk (triphenyltetrazolium staining) was reduced from 45 +/- 16% (mean+/-SD, control) to 27 +/- 11% by LPC (P < 0.001) and to 27 +/- 17% by sevoflurane (P = 0.001). Additional sevoflurane administration after LPC led to a further infarct size reduction to 14 +/- 8% (LPC+SEVO, P = 0.003 vs. LPC; P = 0.032 vs. SEVO), similar to the combination of LPC and EPC (12 +/- 8%; P = 0.55 vs. LPC+SEVO). Cardioprotection induced by LPC+SEVO was abolished by 5-HD (LPC+SEVO+5-HD, 41 +/- 19%, P = 0.001 vs. LPC+SEVO). CONCLUSIONS: Sevoflurane administration confers additional cardioprotection after LPC by opening of KATP channels.

Effect of acidotic blood reperfusion on reperfusion injury after coronary artery occlusion in the dog heart.

A prolongation of the intracellular acidosis after myocardial ischemia can protect the myocardium against reperfusion injury. In isolated hearts, this was achieved by prolongation of the extracellular acidosis. The aim of this study was to investigate whether regional reperfusion with acidotic blood after coronary artery occlusion can reduce infarct size and improve myocardial function in vivo. Anesthetized open-chest dogs were instrumented for measurement of regional myocardial function, assessed by sonomicrometry as systolic wall thickening (sWT). Infarct size was determined by triphenyltetrazolium staining after 3 h of reperfusion. The left anterior descending coronary artery (LAD) was perfused through a bypass from the left carotid artery. The animals underwent 1 h of LAD occlusion and subsequent bypass-reperfusion with normal blood (control, n = 6) or blood equilibrated to pH = 6.8 by using 0.1 mM HCl during the first 30 min of reperfusion (HCl, n = 5). Regional collateral blood flow (RCBF) at 30-min occlusion was measured by using colored microspheres. There was no difference in recovery of sWT in the LAD-perfused area between the two groups at the end of the experiments [-2.8+/-1.2% (HCl) vs. -4.4+/-2.5% (control); mean +/- SEM; p = NS]. RCBF was comparable in both groups. Infarct size (percentage of area at risk) was reduced in the treatment group (12.8+/-2.8%) compared with the control group (26.2+/-4.8%; p < 0.05). These results indicate that reperfusion injury after coronary artery occlusion can be reduced by a prolonged local extracellular acidosis in vivo.

The direct myocardial effects of xenon in the dog heart in vivo

Xenon has minimal hemodynamic side effects, but no data are available on its direct myocardial effects in vivo. We examined myocardial function during the global and regional administration of xenon in the dog heart. Anesthetized (midazolam/piritramide) dogs (n = 8) were instrumented for measurement of left ventricular pressure, cardiac output, and blood flow in the left anterior descending coronary artery (LAD) and circumflex coronary artery. Regional myocardial function was assessed by sonomicrometry in the antero-apical and the postero-basal wall. Hemodynamics were recorded during baseline conditions and during inhalation of 50% or 70% xenon, respectively. Subsequently, a bypass containing a membrane oxygenator was installed from the carotid artery to the LAD, allowing xenon administration only to the LAD-dependent myocardium. No changes in myocardial function were observed during inhalation of xenon. The regional administration of 50% xenon had no significant effect on regional myocardial function (systolic wall thickening and mean velocity of systolic wall thickening). Seventy percent xenon reduced systolic wall thickening by 7.2% ± 4.0% and mean velocity of systolic wall thickening by 8.2% ± 4.0% in the LAD-perfused area (P < 0.05). There were no changes of global hemodynamics, coronary blood flow, and regional myocardial function in the circumflex coronary artery-dependent myocardium. Xenon produces a small but consistent direct negative inotropic effect in vivo.

Sevoflurane-induced Preconditioning Impact of Protocol and Aprotinin Administration on Infarct Size and Endothelial Nitric-Oxide Synthase Phosphorylation in the Rat Heart In Vivo

Background:Sevoflurane induces preconditioning (SevoPC). The effect of aprotinin and the involvement of endothelial nitric-oxide synthase (NOS) on SevoPC are unknown. We investigated (1) whether SevoPC is strengthened by multiple preconditioning cycles, (2) whether SevoPC is blocked by aprotinin, and (3) whether endothelial NOS plays a crucial role in SevoPC. Methods:Anesthetized male Wistar rats were randomized to 15 groups (each n = 6) and underwent 25-min regional myocardial ischemia and 2-h reperfusion. Controls were not treated further. Preconditioning groups inhaled 1 minimum alveolar concentration of sevoflurane for 5 min (SEVO-I), twice for 5 min each (SEVO-II), three times for 5 min each (SEVO-III), or six times for 5 min each (SEVO-VI). Aprotinin was administered with and without sevoflurane. Involvement of endothelial NOS was determined with the nonspecific NOS blocker N-nitro-l-arginine-methyl-ester, the specific neuronal NOS blocker 7-nitroindazole, and the specific inducible NOS blocker aminoguanidine. Results:SevoPC reduced infarct size in all protocols (SEVO-I, 42 ± 6%; SEVO-II, 33 ± 4%; SEVO-III, 11 ± 5%; SEVO-VI, 16 ± 4%; all P < 0.001 vs. control, 67 ± 3%) and was least after three and six cycles of sevoflurane (P < 0.001 vs. SEVO-II and -I, respectively). Aprotinin alone had no effect on infarct size but blocked SevoPC. N-nitro-l-arginine-methyl-ester abolished SevoPC (67 ± 4%; P < 0.05 vs. SEVO-III). Aminoguanidine and 7-nitroindazole blocked SevoPC only partially (25 ± 6 and 31 ± 6%, respectively; P < 0.05 vs. SEVO-III and control). SevoPC induced endothelial NOS phosphorylation, which was abrogated by aprotinin. Conclusion:SevoPC is strengthened by multiple preconditioning cycles, and phosphorylation of endothelial NOS is a crucial step in mediating SevoPC. These effects are abolished by aprotinin.

Blockade of anaesthetic-induced preconditioning in the hyperglycaemic myocardium: The regulation of different mitogen-activated protein kinases

Preconditioning by volatile anaesthetics is blocked by hyperglycaemia. The regulation of mitogen-activated protein kinases during this effect has yet not been investigated. For infarct size measurements, anaesthetized rats were subjected to 25 min coronary artery occlusion followed by 120 min reperfusion. Control animals were not further treated. One group was preconditioned by two 5-min periods of desflurane inhalation (desflurane preconditioning, Des-preconditioning, 1MAC), each followed by 10-min washout. Four groups received glucose 50% in order to achieve blood glucose concentrations between 22.2 and 33.3 mM/l. Glucose infusion started 40 min before ischaemia (early hyperglycaemia, EH) and stopped with the onset of artery occlusion with (EH+Des-preconditioning) or without (EH) preconditioning. The other two groups received glucose during ischaemia (late hyperglycaemia, LH), again with (LH+Des-preconditioning) or without (LH) preconditioning. Additional hearts were excised for Western blot of mitogen-activated protein kinases. Infarct size was reduced from 51.7+/-9.0% in controls to 28.8+/-11.8% after Des-preconditioning (P<0.01 vs Con). Hyperglycaemia alone did not affect infarct size (EH, 51.5+/-9.0%, LH, 44.3+/-16.9%), but EH as well as LH blocked Des-preconditioning (49.1+/-12.3%, P<0.01, 48.1+/-17.6%, P<0.05 vs Des-preconditioning). All three mitogen-activated protein kinases showed a similar time course pattern of phosphorylation in the Des-preconditioning, EH and EH+Des-preconditioning group. Despite the lack of cardioprotection, mitogen-activated protein kinases are activated in hyperglycaemic myocardium. Therefore, it can be assumed that the hyperglycaemic induced blockade of Des-preconditioning is situated downstream or in parallel of these mitogen-activated protein kinases or involves different signal transduction pathways.

Role of Tyrosine Kinase in Desflurane-induced Preconditioning

BackgroundShort administration of volatile anesthetics preconditions myocardium and protects the heart against the consequences of subsequent ischemia. Activation of tyrosine kinase is implicated in ischemic preconditioning. The authors investigated whether desflurane-induced preconditioning depends on activation of tyrosine kinase. MethodsSixty-four rabbits were instrumented for measurement of left ventricular pressure, cardiac output, and myocardial infarct size (IS). All rabbits were subjected to 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Rabbits underwent a treatment period consisting of either no intervention for 35 min (control group, n = 12) or 15 min of 1 minimum alveolar concentration desflurane inhalation followed by a 10-min washout period (desflurane group, n = 12). Four additional groups received the tyrosine kinase inhibitor genistein (5 mg/kg) or lavendustin A (1.3 mg/kg) at the beginning of the treatment period with (desflurane–genistein group, n = 11; desflurane–lavendustin A group, n = 12) or without desflurane inhalation (genistein group, n = 9; lavendustin A group, n = 8). ResultsHemodynamic values were similar in all groups during baseline (left ventricular pressure, 87 ± 14 mmHg [mean ± SD]; cardiac output, 198 ± 47 ml/min), during coronary artery occlusion (left ventricular pressure, 78 ± 12 mmHg; cardiac output, 173 ± 39 ml/min), and after 2 h of reperfusion (left ventricular pressure, 59 ± 17; cardiac output, 154 ± 43 ml/min). IS in the control group was 55 ± 10% of the area at risk. The tyrosine inhibitors had no effect on IS (genistein group, 56 ± 13%; lavendustin A group, 49 ± 13%; each P = 1.0 vs. control group). Desflurane preconditioning reduced IS to 40 ± 15% (P = 0.04 vs. control group). Tyrosine kinase inhibitor administration had no effect on IS reduction (desflurane–genistein group, 44 ± 13%; desflurane–lavendustin A group, 44 ± 16%; each P = 1.0 vs. desflurane group). ConclusionDesflurane-induced preconditioning does not depend on tyrosine kinase activation.

Effects of partial liquid ventilation on regional pulmonary blood flow distribution of isolated rabbit lungs

Objective: Partial liquid ventilation with perfluorocarbons may increase alveolar hydrostatic transmural pressure and may result in a redistribution of pulmonary blood flow from dependent to nondependent lung regions. To test this hypothesis under controlled study conditions, we determined intrapulmonary blood flow distributions during gas and perfluorocarbon ventilation in isolated rabbit lungs. Design: Controlled animal study with an ex vivo isolated lung preparation. Setting: Research laboratory for Experimental Anesthesiology at the Heinrich‐Heine‐University of Düsseldorf. Subjects: New Zealand White rabbits. Interventions: The lungs were perfused with autologous blood at constant flow (150 mL/min) and ventilated with 5% CO2 in air (positive end‐expiratory pressure, 2 cm H2O; tidal volume, 10 mL/kg body weight; respiratory rate, 30 breaths/min) without and with perfluorocarbon administered intratracheally (15 mL/kg). Measurements and Main Results: Regional lung perfusion was measured with colored microspheres in apical, central, peripheral, and basal samples before and after bronchial instillation of perfluorocarbons. Compared with gas ventilation, intrapulmonary blood flow during perfluorocarbon ventilation was higher in apical samples (49.4 ± 8.6 mL/min/g vs. 38.3 ± 6.8 mL/min/g dry weight; p = .03) and lower in basal samples (22.2 ± 5.1 mL/min/g vs. 39.9 ± 8.2 mL/min/g; p = .04). Conclusions: Our findings suggest that during partial liquid ventilation, intrapulmonary blood flow is redistributed toward less‐dependent lung regions.