Xenon does not impair the responsiveness of cardiac muscle bundles to positive inotropic and chronotropic stimulation

BACKGROUND: Most volatile anesthetics exhibit a direct myocardial depressant effect. This side effect often limits their applicability in patients with impaired cardiac function. Xenon is a new gaseous anesthetic that did not show any adverse cardiovascular effects in clinical and experimental studies. The authors tested the hypothesis that xenon does not affect myocardial contractility or the positive inotropic effect of isoproterenol, calcium, and increase in pacing rate in isolated guinea pig ventricular muscle bundles. METHODS: Thin ventricular muscle bundles from guinea pig hearts with a mean diameter of 0.4-0.45 mm were prepared under stereomicroscopic control. Force of contraction and contraction times were studied in muscles superfused with medium equilibrated with either 65% xenon and 35% oxygen (xenon group), 1.2% isoflurane in oxygen (isoflurane group), or 65% nitrogen and 35% oxygen (control group). In addition, the positive inotropic effects of calcium, isoproterenol (10(-10)-3 x 10(-8) M) and increasing frequency (0.5-2 Hz) were studied during xenon and isoflurane exposure. RESULTS: In contrast to isoflurane, xenon did not alter myocardial force of contraction or contraction times. The positive inotropic effect of isoproterenol, calcium, and increasing pacing frequencies did not differ between the muscles exposed to xenon and the control group. Isoflurane elicited the expected negative inotropic effect (30% reduction of force of contraction) but did not impair the response to inotropic stimuli. CONCLUSIONS: Xenon does not alter myocardial contractility and the response to inotropic stimuli such as calcium, isoproterenol, or increase in pacing frequency in isolated guinea pig ventricular muscle bundles.     

Xenon Does Not Impair the Responsiveness of Cardiac Muscle Bundles to Positive Inotropic and Chronotropic Stimulation

Background: Most volatile anesthetics exhibit a direct myocardial depressant effect. This side effect often limits their applicability in patients with impaired cardiac function. Xenon is a new gaseous anesthetic that did not show any adverse cardiovascular effects in clinical and experimental studies. The authors tested the hypothesis that xenon does not affect myocardial contractility or the positive inotropic effect of isoproterenol, calcium, and increase in pacing rate in isolated guinea pig ventricular muscle bundles.

Methods: Thin ventricular muscle bundles from guinea pig hearts with a mean diameter of 0.4-0.45 mm were prepared under stereomicroscopic control. Force of contraction and contraction times were studied in muscles superfused with medium equilibrated with either 65% xenon and 35% oxygen (xenon group), 1.2% isoflurane in oxygen (isoflurane group), or 65% nitrogen and 35% oxygen (control group). In addition, the positive inotropic effects of calcium, isoproterenol (10-10 - 3 x 10-8 m) and increasing frequency (0.5-2 Hz) were studied during xenon and isoflurane exposure.

Results: In contrast to isoflurane, xenon did not alter myocardial force of contraction or contraction times. The positive inotropic effect of isoproterenol, calcium, and increasing pacing frequencies did not differ between the muscles exposed to xenon and the control group. Isoflurane elicited the expected negative inotropic effect (30% reduction of force of contraction) but did not impair the response to inotropic stimuli.     

Multicenter randomized comparison of xenon and isoflurane on left ventricular function in patients undergoing elective surgery

BACKGROUND: Volatile anesthetics are commonly used for general anesthesia. However, these can induce profound cardiovascular alterations. Xenon is a noble gas with potent anesthetic and analgesic properties. However, it is uncertain whether xenon alters myocardial function. The aim of this study was therefore to investigate left ventricular function during anesthesia with xenon compared with isoflurane. METHODS: The authors performed a randomized multicenter trial to compare xenon with isoflurane with respect to cardiovascular stability and adverse effects in patients without cardiac diseases scheduled for elective surgery. Two hundred fifty-nine patients were enrolled in this trial, of which 252 completed the study according to the protocol. Patients were anesthetized with xenon or isoflurane, respectively. Before administration of the study drugs and at four time points, the effects of both anesthetics on left ventricular function were investigated using transesophageal echocardiography. RESULTS: Global hemodynamic parameters were significantly altered using isoflurane (P < 0.05 vs. baseline), whereas xenon only decreased heart rate (P < 0.05 vs. baseline). In contrast to xenon, left ventricular end-systolic wall stress decreased significantly in the isoflurane group (P < 0.05 vs. baseline). Velocity of circumferential fiber shortening was decreased significantly in the xenon group but showed a more pronounced reduction during isoflurane administration (P < 0.05 vs. baseline). The contractile index (difference between expected and actually measured velocity of circumferential fiber shortening) as an independent parameter for left ventricular function was significantly decreased after isoflurane (P < 0.0001) but unchanged using xenon. CONCLUSIONS: Xenon did not reduce contractility, whereas isoflurane decreased the contractile index, indicating that xenon enables favorable cardiovascular stability in patients without cardiac diseases.     

Cardiovascular Effects of Xenon in Isoflurane-anesthetized Dogs with Dilated Cardiomyopathy

Background: Clinical interest in xenon has been rekindled recently by new recycling systems that have decreased its relative cost. The cardiovascular effects of xenon were examined in isoflurane-anesthetized dogs before and after the development of rapid left ventricular (LV) pacing-induced cardiomyopathy.

Methods: Dogs (n = 10) were chronically instrumented to measure aortic and LV pressure, LV subendocardial segment length, and aortic blood flow. Hemodynamics were recorded, and indices of LV systolic and diastolic function and afterload were determined in the conscious state and during 1.5 minimum alveolar concentration isoflurane anesthesia alone and combined with 0.25, 0.42, and 0.55 minimum alveolar concentration xenon in dogs with and without cardiomyopathy.

Results: Administration of xenon to healthy dogs anesthetized with isoflurane decreased heart rate and increased the time constant [small tau, Greek] of isovolumic relaxation but did not alter arterial and LV pressures, preload recruitable stroke work slope, and indices of LV afterload. Chronic rapid LV pacing increased the baseline heart rate and LV end-diastolic pressure, decreased arterial and LV systolic pressures, and produced LV systolic and diastolic dysfunction. Administration of xenon to isoflurane-anesthetized, cardiomyopathic dogs did not alter heart rate, arterial and LV pressures, myocardial contractility, and indices of early LV filling and regional chamber stiffness. More pronounced increases in [small tau, Greek] were accompanied by increases in total arterial resistance during administration of xenon to isoflurane-anesthetized cardiomyopathic compared with healthy dogs.     

Establishment of a porcine right ventricular infarction model for cardioprotective actions of xenon and isoflurane

Background: Right ventricular (RV) function is an important determinant of post‐operative outcome. Consequences of RV infarction might be limited by pre‐conditioning with volatile anesthetic drugs. Therefore, we used a porcine model of RV ischemia and reperfusion (IR) injury to study the influence of isoflurane and xenon on the extent and degree of myocardial injury. Methods: IR injury was induced by a 90‐min ligation of the distal right coronary artery and 120‐min reperfusion in thiopental anesthetized pigs. A control group (n=12) was compared with two groups, which received either 0.55 minimum alveolar concentration (MAC) isoflurane (n=10) or xenon (n=12) starting 60 min before ischemia. Myocardial injury was described by three criteria: the infarct size related to area at risk (IS/AAR), the infiltration of neutrophils as determined by myeloperoxidase (MPO) activity, and the plasma levels of tumor necrosis factor α (TNFα), interlukin 6 (IL‐6), myoglobin and troponin‐T (TnT). Results: IS/AAR was reduced from 58.3±6.2% in the control group to 41.8±7.8% after isoflurane and 42.7±8.5% after xenon pre‐treatment, which equals an absolute reduction of 16.5% [95% confidence interval (CI): 10.9–22.1] and 15.5% (95% CI: 10.1–20.9). The maximum increase of TnT could be observed within the xenon group. Both treatment groups were characterized by lower MPO activity, in the infarct and periinfarct region and lower plasma concentrations of TNFα and IL‐6. Conclusions: It could be demonstrated for the first time in a model of RV infarction that the continuous application of isoflurane or xenon before, during and after ischemia reduced the extent (size) and severity (inflammation) of myocardial injury.     

Xenon administration during early reperfusion reduces infarct size after regional ischemia in the rabbit heart in vivo

The noble gas xenon can be used as an anesthetic gas with many of the properties of the ideal anesthetic. Other volatile anesthetics protect myocardial tissue against reperfusion injury. We investigated the effects of xenon on reperfusion injury after regional myocardial ischemia in the rabbit. Chloralose-anesthetized rabbits were instrumented for measurement of aortic pressure, left ventricular pressure, and cardiac output. Twenty-eight rabbits were subjected to 30 min of occlusion of a major coronary artery followed by 120 min of reperfusion. During the first 15 min of reperfusion, 14 rabbits inhaled 70% xenon/30% oxygen (Xenon), and 14 rabbits inhaled air containing 30% oxygen (Control). Infarct size was determined at the end of the reperfusion period by using triphenyltetrazolium chloride staining. Xenon reduced infarct size from 51%+/-3% of the area at risk in controls to 39%+/-5% (P<0.05). Infarct size in relation to the area at risk size was smaller in the xenon-treated animals, indicated by a reduced slope of the regression line relating infarct size to the area at risk size (Control: 0.70+/-0.08, r = 0.93; Xenon: 0.19+/-0.09, r = 0.49, P<0.001). In conclusion, inhaled xenon during early reperfusion reduced infarct size after regional ischemia in the rabbit heart in vivo.     

N-acetylcysteine Improves Cardiac Contractility and Ameliorates Myocardial Injury in a Rat Model of Lung Ischemia and Reperfusion Injury

ObjectivesLung ischemia and reperfusion (I/R) injury is the major complication subsequent to cardiopulmonary bypass surgery and lung transplantation. Lung I/R injury frequently induces cardiac dysfunction leading to significant mortality. So far, the literature on therapeutic interventions in cardiac dysfunction and myocardial injury is still scarce. In this study, we examined the efficacy of N-acetylcysteine (NAC) administration against lung I/R injury–induced cardiac dysfunction.MethodsLung ischemia was established by occluding the left lung hilum for 60 minutes, followed by 2 hours of reperfusion. Studies were performed in 3 groups: sham-operated (same surgical procedure except vessel occlusion; N = 8), lung I/R injury (N = 12), and NAC-administered group (N = 12). The cardiac function was assessed using simultaneous left ventricular (LV) pressure and volume measured via a high-fidelity pressure-volume catheter. Myocardial injury was assessed based on serum creatine kinase muscle brain fraction (CK-MB) and troponin I (cTnI) level, and lung injury based on the degree of protein concentration in lung lavage. We also examined the degrees of myocardial lipid peroxidation and hydroxyl radical production with and without NAC.ResultsDuring lung ischemia, LV stiffness increased with relative intact contractility. After 2 hours of reperfusion, LV contractility decreased with dilated and stiffened ventricle, along with apparent myocardial and lung injury. NAC administration effectively attenuated heart and lung injury, and ameliorated impaired LV contractility and stiffening resulting from lung I/R injury.ConclusionsNAC administration reduced lung I/R-induced increases in myocardial hydroxyl radical production and lipid peroxidation, and ameliorated LV contractility and stiffening.     

Multicenter Randomized Comparison of Xenon and Isoflurane on Left Ventricular Function in Patients Undergoing Elective Surgery

Background: Volatile anesthetics are commonly used for general anesthesia. However, these can induce profound cardiovascular alterations. Xenon is a noble gas with potent anesthetic and analgesic properties. However, it is uncertain whether xenon alters myocardial function. The aim of this study was therefore to investigate left ventricular function during anesthesia with xenon compared with isoflurane.

Methods: The authors performed a randomized multicenter trial to compare xenon with isoflurane with respect to cardiovascular stability and adverse effects in patients without cardiac diseases scheduled for elective surgery. Two hundred fifty-nine patients were enrolled in this trial, of which 252 completed the study according to the protocol. Patients were anesthetized with xenon or isoflurane, respectively. Before administration of the study drugs and at four time points, the effects of both anesthetics on left ventricular function were investigated using transesophageal echocardiography.

Results: Global hemodynamic parameters were significantly altered using isoflurane (P < 0.05 vs. baseline), whereas xenon only decreased heart rate (P < 0.05 vs. baseline). In contrast to xenon, left ventricular end-systolic wall stress decreased significantly in the isoflurane group (P < 0.05 vs. baseline). Velocity of circumferential fiber shortening was decreased significantly in the xenon group but showed a more pronounced reduction during isoflurane administration (P < 0.05 vs. baseline). The contractile index (difference between expected and actually measured velocity of circumferential fiber shortening) as an independent parameter for left ventricular function was significantly decreased after isoflurane (P < 0.0001) but unchanged using xenon.     

Myocardial effects of halothane and isoflurane in senescent rats

BACKGROUND: Aging is associated with marked alterations in myocardial contraction and relaxation, whereas halogenated anesthetics depress myocardial contractility. However, their effects on aging myocardium are unknown. METHODS: Mechanical variables of left ventricular papillary muscles from adult and senescent rats (29 degrees C; pH 7.40; Ca2+ 1.0 or 0.5 mM; stimulation frequency, 12 pulses/min) were studied. The expression of genes coding for the alpha and beta-myosin heavy chain (MHC) and Ca2+ -ATPase of the sarcoplasmic reticulum (SR) were studied. The effects of halothane and isoflurane were studied. The inotropic effects were compared under low and high loads, using the maximum unloaded shortening velocity (Vmax) and maximum isometric active force (AF). The lusitropic effects were compared in isotonic and isometric conditions. RESULTS: Senescent rats had a decrease in contraction and relaxation velocities, associated with a reexpression of beta-MHC mRNAs and a decrease in SR Ca2+ -ATPase mRNAs. Halothane induced a lower negative inotropic effect in senescent rats (1.5 vol%, AF: 53 +/- 14% vs. 39 +/- 12% of baseline values; P < 0.01) whereas isoflurane induced a similar negative inotropic effect (1.5 vol%, AF: 81 +/- 7% vs. 87 +/- 7% of baseline values; NS). Halothane induced a negative lusitropic effect in isotonic conditions in adult, but not in senescent, rats. CONCLUSIONS: The inotropic and lusitropic effects of halothane were less important in senescent than in adult rats, whereas the effects of isoflurane were similar. These differences are probably related to differences in SR function and in the effects of halogenated anesthetics on the SR.     

The effects of acute normovolemic hemodilution on left ventricular systolic and diastolic function in the absence or presence of beta-adrenergic blockade in dogs

Acute normovolemic hemodilution (ANH) increases cardiac output because of a reduction in blood viscosity and enhancement of left ventricular (LV) contractility. The status of LV function, especially LV diastolic function during ANH, remains controversial. We therefore examined LV systolic and diastolic function during ANH. Sixteen dogs were anesthetized with isoflurane in the absence (Group 1) and presence (Group 2) of beta-adrenergic blockade (propranolol 1 mg/kg). LV contractility was quantified by the slope (M(w)) of the stroke work and end-diastolic volume relation. Diastolic function was evaluated with the time constant of LV relaxation (T), chamber stiffness constant (K(c)), peak LV diastolic filling rate during early filling (peak E) and atrial contraction (peak A), and ratio of peak E to peak A (E/A). Normovolemic exchange of blood (50 mL/kg) for 6% hydroxyethyl starch (ANH50) significantly increased M(w) in Group 1 but not in Group 2. In both groups, ANH50 significantly decreased T. ANH50 significantly increased peak E in both groups and peak A in Group 1, and it did not change the E/A ratio or K(c) in either group. ANH causes positive inotropic effects and enhances diastolic function without beta-blockade. Even after beta-adrenergic blockade, ANH improves diastolic function through the reduction of LV ejection impedance. IMPLICATIONS: Acute normovolemic hemodilution enhances LV (left ventricular) diastolic function by alterations in the LV loading condition produced by hemodilution, which mainly contributes to a compensatory increase in cardiac output.     

Myocardial Effects of Halothane and Isoflurane in Senescent Rats

Background: Aging is associated with marked alterations in myocardial contraction and relaxation, whereas halogenated anesthetics depress myocardial contractility. However, their effects on aging myocardium are unknown.

Methods: Mechanical variables of left ventricular papillary muscles from adult and senescent rats (29[degrees]C; pH 7.40; Ca2+ 1.0 or 0.5 mm; stimulation frequency, 12 pulses/min) were studied. The expression of genes coding for the [alpha]- and [beta]-myosin heavy chain (MHC) and Ca2+-ATPase of the sarcoplasmic reticulum (SR) were studied. The effects of halothane and isoflurane were studied. The inotropic effects were compared under low and high loads, using the maximum unloaded shortening velocity (Vmax) and maximum isometric active force (AF). The lusitropic effects were compared in isotonic and isometric conditions.

Results: Senescent rats had a decrease in contraction and relaxation velocities, associated with a reexpression of [beta]-MHC mRNAs and a decrease in SR Ca2+-ATPase mRNAs. Halothane induced a lower negative inotropic effect in senescent rats (1.5 vol%, AF: 53 +/- 14%vs. 39 +/- 12% of baseline values;P < 0.01) whereas isoflurane induced a similar negative inotropic effect (1.5 vol%, AF: 81 +/- 7%vs. 87 +/- 7% of baseline values; NS). Halothane induced a negative lusitropic effect in isotonic conditions in adult, but not in senescent, rats.     

Sevoflurane before or after Ischemia Improves Contractile and Metabolic Function while Reducing Myoplasmic Ca2+ Loading in Intact Hearts

Background: Ca2+ loading occurs during myocardial reperfusion injury. Volatile anesthetics can reduce reperfusion injury. The authors tested whether sevoflurane administered before index ischemia in isolated hearts reduces myoplasmic diastolic and systolic [Ca2+] and improves function more so than when sevoflurane is administered on reperfusion.

Methods: Four groups of guinea pig hearts were perfused with crystalloid solution (55 mmHg, 37[degrees]C): (1) no treatment before 30 min global ischemia and 60 min reperfusion (CON); (2) 3.5 vol% sevoflurane administered for 10 min before ischemia (SBI); (3) 3.5 vol% sevoflurane administered for 10 min after ischemia (SAI); and (4) 3.5 vol% sevoflurane administered for 10 min before and after ischemia (SBAI). Phasic myoplasmic diastolic and systolic [Ca2+] were measured in the left ventricular free wall with the fluorescence probe indo-1.

Results: Ischemia increased diastolic [Ca2+] and diastolic left ventricular pressure (LVP). In CON hearts, initial reperfusion greatly increased diastolic [Ca2+] and systolic [Ca2+] and reduced contractility (systolic-diastolic LVP, dLVP/dtmax), relaxation (diastolic LVP, dLVP/dtmin), myocardial oxygen consumption (Mvo2), and cardiac efficiency. SBI, SAI, and SBAI each reduced ventricular fibrillation, attenuated increases in systolic and systolic-diastolic [Ca2+], improved contractile and relaxation indices, and increased coronary flow, percent oxygen extraction, Mvo2, and cardiac efficiency during 60 min reperfusion compared with CON. SBI was more protective than SAI, and SBAI was generally more protective than SAI.     

Myocardial Effects of Halothane and Isoflurane in Hamsters with Hypertrophic Cardiomyopathy

Background: The effects of halothane and isoflurane on myocardial contraction and relaxation in diseased myocardium are not completely understood.

Methods: The effects of equianesthetic concentrations of halothane and isoflurane on inotropy and lusitropy in left ventricular papillary muscles of healthy hamsters and those with genetically induced cardiomyopathy (strain BIO 14.6) were investigated in vitro (29 [degree sign] Celsius; pH 7.40; Ca2+ 2.5 mM; stimulation frequency, 3/min) in isotonic and isometric conditions.

Results: Halothane induced a negative inotropic effect that was greater in cardiomyopathic than in healthy hamsters (1.5 vol%, active isometric force (AF): 19 +/- 8% vs. 28 +/- 11% of control values; P <0.05). Isoflurane induced a negative inotropic effect that was greater in cardiomyopathic than in healthy hamsters (2.0 vol%, AF: 64 +/- 13% vs. 75 +/- 11% of control values; P < 0.01). However, the negative inotropic effects of halothane and isoflurane were not different for cardiomyopathic or healthy hamsters when their concentrations were corrected for minimum alveolar concentration (MAC) values in each strain. Halothane induced a negative lusitropic effect under low load, which was more important in cardiomyopathic hamsters, suggesting a greater impairment in calcium uptake by the sarcoplasmic reticulum. In contrast, isoflurane induced a moderate positive lusitropic effect under low load in healthy but not in cardiomyopathic hamsters. Halothane and isoflurane induced no significant lusitropic effect under high load.     

Nitrous oxide does not depress left ventricular contractility in ischemic rat heart

The direct effects of nitrous oxide on left ventricular contractility and myocardial oxygen consumption (MVO₂) in the ischemic isolated rat heart were studied. The rat heart was isolated and perfused by a Langendorf technique. The aortic stump was cannulated and the heart was perfused with Kumpeis solution bubbled with 95% O₂ and 5% CO₂ (control phase). A latex balloon was inserted into the left ventricle (LV) to measure LV pressures and dP/dt. Coronary flow was measured and MVO₂ was calculated. After the control phase, perfusion pressure was decreased to induce global ischemia (ischemic phase). There were four groups of eight hearts each: control, nitrogen, nitrous oxide, and halothane groups. After 15 min of ischemic phase, the perfusion pressure was increased and the gas mixture was changed to the standard gas mixture (reperfusion phase). Nitrous oxide did not further depress myocardial contractility compared with nitrogen in the ischemic phase, and did not alter MVO₂ in the ischemic phase compared with nitrogen. Halothane significantly depressed myocardial contractility and decreased MVO₂ in the ischemic phase compared with the control.     

Sevoflurane and isoflurane do not enhance the pre- and postischemic eicosanoid production in guinea pig hearts

Eicosanoids and volatile anesthetics can influence cardiac reperfusion injury. Accordingly, we analyzed the effects of sevoflurane and isoflurane applied in clinically relevant concentrations on the myocardial production of prostacyclin and thromboxane A2 (TxA2) and on heart function. Isolated guinea pig hearts, perfused with crystalloid buffer, performed pressure-volume work. Between two working phases, hearts were subjected to 15 min of global ischemia followed by reperfusion. The hearts received no anesthetic, 1 minimum alveolar anesthetic concentration (MAC) isoflurane (1.2 vol%), or 0.5 and 1 MAC sevoflurane (1 vol% and 2 vol%), either only preischemically or pre- and postischemically. In additional groups, cyclooxygenase function was examined by an infusion of 1 microM arachidonic acid (AA) in the absence and presence of sevoflurane. The variables measured included the myocardial production of prostacyclin, TxA2 and lactate, consumption of pyruvate, coronary perfusion pressure, and the tissue level of isoprostane 8-iso-PGF2alpha. External heart work, determined pre- and postischemically, served to assess recovery of heart function. Volatile anesthetics had no impact on postischemic recovery of myocardial function (50%-60% recovery), perfusion pressure, lactate production, or isoprostane content. Release of prostacyclin and TxA2 was increased in the early reperfusion phase 5-8- and 2-4-fold, respectively, indicating enhanced AA liberation. Isoflurane and sevoflurane did not augment the eicosanoid release. Only 2 vol% sevoflurane applied during reperfusion prevented the increased eicosanoid formation in this phase. Infusion of AA increased prostacyclin production approximately 200-fold under all conditions, decreased pyruvate consumption irreversibly, and markedly attenuated postischemic heart work (25% recovery). None of these effects were mitigated by 2 vol% sevoflurane. In conclusion, only sevoflurane at 2 vol% attenuated the increased liberation of AA during reperfusion. Decreased eicosanoid formation had no effect on myocardial recovery in our experimental setting while excess AA was deleterious. Because eicosanoids influence intravascular platelet and leukocyte adhesion and activation, sevoflurane may have effects in reperfused tissues beyond those of isoflurane. IMPLICATIONS: In an isolated guinea pig heart model, myocardial eicosanoid release was not increased by isoflurane or sevoflurane, either before or after ischemia. Sevoflurane (2 vol%) but not isoflurane attenuated the increased release of eicosanoids during reperfusion.     

Effects of the anesthetic gases xenon, halothane, and isoflurane on calcium and potassium currents in human atrial cardiomyocytes

BACKGROUND: Negative inotropic and proarrhythmic side effects on the heart are well known for the volatile anesthetics halothane and isoflurane but not for the noble gas xenon. We investigated the effects of halothane, isoflurane, and xenon on calcium and potassium currents in human atrial myocytes to elucidate the cellular and molecular basis of their cardiac actions. METHODS: Atrial myocytes were prepared from the right auricles obtained from patients undergoing heart surgery. Ion currents were measured with the whole cell patch clamp technique during superfusion of the cells with solutions that contained halothane, isoflurane, or xenon at concentrations corresponding to their respective minimum alveolar concentration (MAC); gas concentrations were determined with the head space-gas chromatography/mass spectrometry/selected ion monitoring method. RESULTS: L-type calcium currents were significantly depressed by 31.9 +/- 4.1%, from -1.8 +/- 0.3 to -1.2 +/- 0.4 picoampere (pA)/picofarad (pF) (n = 4; P < 0.05) at 1 MAC halothane and by 21.7 +/- 9.2%, from -1.6 +/- 0.7 to -1.2 +/- 0.6 pA/pF (n = 7; P < 0.05) at 1 MAC isoflurane, but not affected by 70% xenon (1 MAC). Inwardly rectifying potassium currents were not influenced by any anesthetic. Halothane (1 MAC) significantly inhibited the transient as well as the sustained part of voltage-gated potassium outward currents, by 19.4 +/- 6.7%, from 6.7 +/- 2.1 to 5.4 +/- 1.6 pA/pF (n = 8; P < 0.05), and by 8.6 +/- 4.8%, from 5.5 +/- 1.7 to 5.0 +/- 1.5 pA/pF (n = 8; P < 0.05), respectively. Transient K+ outward currents were even more inhibited, by 25.8 +/- 4.8%, from 9.8 +/- 3.1 to 7.3 +/- 2.1 pA/pF (n = 5; P < 0.05) at 1 MAC isoflurane, whereas xenon evoked only a slight (albeit significant) inhibition, by 6.1 +/- 3.7%, from 8.2 +/- 6.0 to 7.7 +/- 5.8 pA/pF (n = 10; P < 0.05). Isoflurane and xenon did not affect sustained potassium currents. All effects of the anesthetics were fully reversible after washout. CONCLUSIONS: Halothane and isoflurane exhibited considerable inhibitory effects on voltage-gated cardiac Ca2+ and K+ currents important for the duration of action potentials and the repolarization. Xenon, in contrast, did not affect Ca2+ currents and only slightly inhibited transient K+ outward currents, in line with the almost absent cardiac side effects of the noble gas.     

Effects of xenon anaesthesia on the circulatory response to hypoventilation

Background. Circulatory response to hypoventilation is aimedat eliminating carbon dioxide and maintaining oxygen delivery(DO₂) by increasing cardiac output (CO). The hypothesis thatthis increase is more pronounced with xenon than with isofluraneanaesthesia was tested in pigs. Methods. Twenty pigs received anaesthesia with xenon 0.55 MAC/remifentanil0.5 µg kg^–1 min^–1 (group X, n=10) or isoflurane0.55 MAC/remifentanil 0.5 µg kg^–1min^–1 (groupI, n=10). CO, heart rate (HR), mean arterial pressure (MAP)and left ventricular fractional area change (FAC) were measuredat baseline, after 5 and 15 min of hypoventilation and after5, 15 and 30 min of restored ventilation. Results. CO increased by 10–20% with both anaesthetics,with an equivalent rise in HR, maintaining DO₂ in spite of a20% reduction in arterial oxygen content. Decreased left ventricular(LV) afterload during hypoventilation increased FAC, and thiswas more marked with xenon (0.60–0.66, P<0.05 comparedwith baseline and isoflurane). This difference is attributedto negative inotropic effects of isoflurane. Increased pulmonaryvascular resistance during hypoventilation was found with bothanaesthetics. Conclusion. The cardiovascular effects observed in this modelof moderate hypoventilation were sufficient to maintain DO₂.Although the haemodynamic response appeared more pronouncedwith xenon, differences were not clinically relevant. An increasein FAC with xenon is attributed to its lack of negative inotropiceffects.     

Mepacrine, a phospholipase inhibitor. A potential tool for modifying myocardial reperfusion injury

Cardioprotective effects of phospholipase inhibitor, mepacrine, on ischemic reperfused myocardium were investigated in the isolated in situ pig heart preparation, which was subjected to 120 minutes of regional ischemia, with the final 60 minutes having superimposed global cardioplegic arrest followed by 60 minutes of reperfusion. Mepacrine (0.05 mmol/L) was administered before ischemia into the perfusion circuit in 15 of 29 experiments. Significant depletion of myocardial phospholipids occurred in nontreated animals during 60 minutes of reperfusion. Mepacrine prevented the reperfusion-induced phospholipid degradation. Further, the level of high-energy phosphate compounds was higher during ischemia and reperfusion in the mepacrine-treated hearts. Left ventricular developed pressure, maximum rate of rise of left ventricular pressure, and left ventricular end-diastolic pressure were measured under isovolumic conditions to assess cardiac contractility and compliance. During incubation with mepacrine, before ischemia, left ventricular developed pressure and maximum rate of rise of left ventricular pressure decreased to 45% and 51% of baseline values, respectively. This initial decline was improved to 65% and 70% in mepacrine-treated animals during the early period of regional ischemia. In the nontreated control heart, a progressive decline in contractility was observed with ischemia such that no significant difference was apparent in the two groups. Reperfusion resulted in a further deterioration of global cardiac performance in both mepacrine-treated and control animals. Although pretreatment with mepacrine did not improve contractility, myocardial oxygen consumption, coronary flow, and cardiac compliance significantly improved. These results suggest that myocardial injury may develop during reperfusion after temporary ischemia. Mepacrine inhibits such injury by acting as a phospholipase inhibitor, but it also behaves as a negative inotropic agent in ischemic reperfused myocardium.     

The Comparison of Mitogen-Activated Protein Kinases That Become Activated Within the Left Ventricular and Right Atrial Tissues Following Heart Transplantation in Canine Model

The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in ischemia/reperfusion injury. Some reports have documented MAPKs activation of the myocardium in human models, using right atrial (RA) tissue for samples. This study compared the activation of MAPKs in left ventricle (LV) and RA tissues in canine heart transplantation. Four dogs were used as baseline data at two points, before and 20 min after warm ischemia (baseline model), and eight dogs (four pairs of donor and recipient) were used at other points: 4 h after cold ischemia, and at 10, 60, and 180 min after reperfusion (transplantation model). In the transplantation model, donor hearts were left in situ for 20 min after cardiac arrest, and were immersed in Celsior solution for 4 h after coronary flushing. Orthotopic heart transplantation was then performed. Two groups were created: the LV and RA groups (n = 4 in each group). Heart tissue was harvested from the left ventricular wall in the LV group and from the right atrial appendage in the RA group. The activation of MAPKs, including p38 MAPK, c-Jun N-terminal protein kinase (JNK), and extracellular signal-regulated protein kinase (ERK), was evaluated at each point. The activation patterns of p38 MAPK and ERK were similar in the RA and LV groups, but JNK activation was different in the two groups, after ischemia and reperfusion. Thus, RA tissue may be deliberately used as a substitute for LV tissue when investigating the activation of MAPKs in a human model.     

Cardioprotective effect of ischemic preconditioning on global myocardial ischemia in a sheep right heart bypass model

OBJECTIVES: Ischemic preconditioning has been used to induce the myocardium to adapt to ischemic stress preceded by short periods of ischemia and reperfusion. We used a sheep right heart bypass model with a conductance catheter to assess the cardioprotective effect of ischemic preconditioning on 30-minute normothermic global myocardial ischemia. METHODS: Ischemic preconditioning was conducted in 6 sheep in 35-minute aortic cross-clampings interspersed with 5 minutes of reperfusion during cardiopulmonary bypass, with 6 sheep as time-matched controls. Global myocardial ischemia was subsequently achieved in 30-minute aortic cross-clamping with left ventricular unloading during normothermic cardiopulmonary bypass. Weaning from cardiopulmonary bypass was conducted 40 minutes after reperfusion. Before ischemia and 40, 70, and 100 minutes after reperfusion, left ventricular pressure-volume loops were measured using a conductance catheter during right heart bypass preparation. Left ventricular contractility, diastolic function, and mechanical efficiency were then evaluated. Right heart bypass was instituted to control the preload and to decompress the right ventricle completely, thereby eliminating parallel conductance variation. RESULTS: No differences in the studied parameters were seen between ischemic-preconditioning and control groups before ischemia. Left ventricular contractility, diastolic function, and mechanical efficiency in the ischemic-preconditioning group were significantly superior to those in the control group after reperfusion. CONCLUSIONS: Ischemic preconditioning attenuates postischemic myocardial dysfunction in a sheep model using 30-minute unloaded normothermic global myocardial ischemia. Ischemic preconditioning would thus be clinically significant when the ischemic damage is severe.