Yuichi Ishibe

Effect of Sevoflurane on Hypoxic Pulmonary Vasoconstriction in the Perfused Rabbit Lung

BackgroundIn vitro studies have shown that isoflurane, enflurane, and halothane Inhibit the hypoxic pulmonary vasoconstriction (HPV) with essentially the same potency. The aim of this study is to compare the effects of Sevoflurane and Isoflurane on HPV in constant-flow perfused rabbit lungs. MethodsConstant-flow perfused lungs from Japanese white rabbits were tested. The lungs were divided into three groups: isoflurane alone (n = 6), Sevoflurane alone (n = 6), and sevoflurane with ibuprofen pretreatment (n = 6). Baseline HPV responses were measured as the pulmonary arterial pressure Increased after changing inspired oxygen concentration from 95% for 15 min to 3% (with 5% CO2) for 5 min without anesthetic administration. Next, three different concentrations of anesthetics were added to the inspired gas for 15 min in random order. The HPV response in the presence of anesthetic was expressed as a percentage of the pressor response in the absence of anesthetics, and dose-response relationships were calculated using the nonlinear least-squares method. ResultsIsoflurane and Sevoflurane both depressed the HPV response in a dose-related manner. The half-inhibition values (ED50) of HPV with isoflurane and Sevoflurane were 0.85 ± 0.22 MAC and 1.00 ± 0.12 MAC (mean ± SD), respectively, and were not statistically different. Ibuprofen pretreatment did not alter ED50 and slope of dose-response curve, although the absolute value of pressor response in the sevoflurane group with ibuprofen pretreatment was greater than that in the sevoflurane alone group at every concentration of sevoflurane. ConclusionsSevoflurane inhibits the HPV response in a dose-related manner, and its potency is similar to that of isoflurane in vitro. Cyclooxygenase products do not mediate the inhibition of HPV by sevoflurane.

The effect of thoracic epidural anesthesia on hypoxic pulmonary vasoconstriction in dogs : an analysis of the pressure-flow curve

The aim of the present study was to examine whether hypoxic pulmonary vasoconstriction (HPV) is preserved during one-lung ventilation combined with thoracic epidural anesthesia (TEA) in dogs. Using a separately ventilated left lower lobe (LLL) in situ, the pressure-flow (P-Q) curve was obtained. The HPV response was assessed by the shift of the P-Q curve, changes in blood flow diversion rate (FDR) and decrease in PaO2 during hypoxic gas ventilation of LLL. In the control group (n = 7), the shift of P-Q curve, changes in FDR, and decrease in PaO2 remained constant during four consecutive hypoxic stimulations. In the TEA group (n = 6), the P-Q curve shifted to the left during hyperoxia, but the magnitude of the shift during hypoxia was unchanged. FDR and decrease in PaO2 were significantly reduced compared with baseline values (P < 0.05 with analysis of variance). TEA reduced heart rate, cardiac output, mean arterial pressure, mean pulmonary arterial pressure, and mixed venous oxygen tension. Our results suggest that TEA did not affect the primary pulmonary vascular tone at baseline or during lobar hypoxia, but enhanced the diversion of blood flow and arterial blood oxygenation during lobar hypoxia. This enhanced HPV response probably reflects hemodynamic changes, such as decreased cardiac output with resultant low mixed venous oxygen tension, due to sympathetic nerve activity blockade by TEA. (Anesth Analg 1996;82:1049-55)

Exhaled nitric oxide level decreases after cardiopulmonary bypass in adult patients

ObjectiveTo measure exhaled nitric oxide (NO) and compare it with lung function after cardiopulmonary bypass (CPB) in adult patients. Pulmonary dysfunction is sometimes observed after CPB. Impaired production of NO may account for this dysfunction. DesignProspective, single-center, observational study. SettingUniversity hospital operating room, intensive care unit. PatientsSixteen adult patients undergoing cardiac surgery with CPB. InterventionsNone except cardiac surgery with CPB. Measurements and Main ResultsExhaled NO was measured continuously by the chemiluminescence method and was expressed as the peak and mean NO concentrations, and the NO output (VNO). These parameters were calculated by averaging four sequential tidal NO values. The data were obtained serially from before CPB to 16 hrs after CPB. Lung function was evaluated by monitoring lung compliance, pulmonary artery pressure, and alveolar–arterial oxygen difference (P(a-a)o2). The cardiac index did not change except for a significant increase at 16 hrs compared with 6 hrs after CPB. Peak NO, mean NO, and VNO decreased from 15.4 ± 2.0 ppb (before CPB) to 8.2 ± 0.8 ppb (6 hrs after CPB), from 5.7 ± 0.7 ppb to 2.8 ± 0.6 ppb, and from 29.2 ± 3.1 nL/min to 15.7 ± 2.2 nL/min, respectively. These changes were associated with the increases in pulmonary artery pressure and alveolar–arterial oxygen difference, and the decrease in lung compliance. VNO recovered to the level measured before CPB 16 hrs after CPB, which was consistent with the physiologic recovery in pulmonary hypertension, lung compliance, and gas exchange. ConclusionMeasurement of exhaled NO as VNO, which was associated with lung dysfunction, may be an indicator of lung injury in adult patients after cardiopulmonary bypass.

Oral administration of geranylgeranylacetone improves survival rate in a rat endotoxin shock model: administration timing and heat shock protein 70 induction.

The present study was performed to determine whether oral pretreatment with geranylgeranylacetone (GGA) inhibits proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated rats and protects rats against death from LPS-induced endotoxin shock, and whether such protection by GGA is related to heat shock protein (HSP) 70 induction in multiple organs of rats. GGA (200 mg/kg) was given orally to rats. LPS (20 mg/kg) was administered intraperitoneally 4, 8, 16, or 24 h after GGA administration. The survival of rats was monitored over 24 h after LPS administration. GGA treatment at 8 or 16 h before LPS dramatically improved the survival rate of LPS-treated rats. Plasma levels of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) and NO 6 h after LPS administration in these GGA-pretreated rats were less than one-half of those in rats treated with LPS alone. A GGA challenge 8 or 16 h before LPS administration enhanced HSP70 expression in rat organs after LPS. Treatment with GGA 8 h before LPS minimized hepatic and renal damage. Furthermore, the protective effect of GGA on mortality in LPS-treated rats was inhibited with quercetin, known as an HSP70 inhibitor. These results suggest that oral administration of GGA at an optimal time before LPS injection induces and enhances HSP70 expression in several organs, inhibits proinflammatory cytokine and NO production, and prevents organ damage, resulting in an improved survival rate.

Mechanisms of protection by melatonin against acetaminophen-induced liver injury in mice

Abstract:  The present study was performed to determine whether melatonin protects mouse liver against severe damage induced by acetaminophen (APAP) administration and where melatonin primarily functions in the metabolic pathway of APAP to protect mouse liver against APAP‐induced injury. Treatment of mice with melatonin (50 or 100 mg/kg, p.o.) 8 or 4 hr before APAP administration (750 mg/kg, p.o.) suppressed the increase in plasma alanine aminotransferase and aspartate aminotransferase activities in a dose‐ and a time‐dependent manner. Melatonin treatment (100 mg/kg, p.o.) 4 hr before APAP administration remarkably inhibited centrilobular hepatic necrosis with inflammatory cell infiltration and increases in hepatic lipid peroxidation and myeloperoxidase activity, an index of tissue neutrophil infiltration, as well as release of nitric oxide and interleukin‐6 into blood circulation at 9 hr after APAP administration. However, melatonin neither affected hepatic reduced glutathione (GSH) content nor spared hepatic GSH consumption by APAP treatment. Moreover, pretreatment with melatonin 4 hr before APAP administration did not influence the induction of hepatic heat shock protein 70 (HSP70) by APAP and melatonin alone did not induce HSP70 in mouse liver. These results indicate that exogenously administered melatonin exhibits a potent hepatoprotective effect against APAP‐induced hepatic damage probably downstream of the activity of cytochrome P450 2E1, which works upstream of GSH conjugation in the pathway of APAP metabolism, via its anti‐nitrosative and anti‐inflammatory activities in addition to its antioxidant activity.

Geranylgeranylacetone ameliorates inflammatory response to lipopolysaccharide (LPS) in murine macrophages: inhibition of LPS binding to the cell surface.

We investigated whether pretreatment with geranylgeranylacetone (GGA), a potent heat shock protein (HSP) inducer, could inhibit proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated murine macrophages. The levels of NO and tumor necrosis factor-α (TNF-α) released from murine macrophage RAW 264 cells were increased dose- and time-dependently following treatment with LPS (1 µg/ml). GGA (80 µM) treatment 2 h before LPS addition significantly suppressed TNF-α and NO productions at 12 h and 24 h after LPS, respectively, indicating that GGA inhibits activation of macrophages. However, replacement by fresh culture medium before LPS treatment abolished the inhibitory effect of GGA on NO production in LPS-treated cells. Furthermore, GGA inhibited both HSP70 and inducible NO synthase expressions induced by LPS treatment despite an HSP inducer. When it was examined whether GGA interacts with LPS and/or affects expression of Toll-like receptor 4 (TLR4) and CD14 on the cell surface, GGA inhibited the binding of LPS to the cell surface, while GGA did not affect TLR4 and CD14 expressions. These results indicate that GGA suppresses the binding of LPS to the cell surface of macrophages, resulting in inhibiting signal transduction downstream of TLR4.

Clonidine premedication effects on inhaled induction with sevoflurane in adults: a prospective, double-blind, randomized study.

Background:  The purpose of this study was to evaluate whether oral clonidine premedication becomes an alternative to N2O in terms of shortening the induction time and attenuation of the adrenergic response to tracheal intubation during inhalation induction with sevoflurane, and to evaluate the quality of anesthetic induction according to the patients satisfaction.

Role of potassium channels in isoflurane- and sevoflurane-induced attenuation of hypoxic pulmonary vasoconstriction in isolated perfused rabbit lungs.

BackgroundAlthough potassium channels are thought to be responsible for the initiation of hypoxic pulmonary vasoconstriction (HPV), their role in the HPV-inhibitory effect of volatile anesthetics is unclear. The current study tested if the HPV-inhibitory effect of isoflurane and sevoflurane can be affected by changing the potassium-channel opening status with specific potassium-channel inhibitors in isolated rabbit lungs. MethodsIsolated rabbit lungs were divided into eight groups (n = 6 each in isoflurane groups and n = 8 in sevoflurane groups): those receiving no inhibitor treatment = control-isoflurane and control-sevoflurane groups; those treated with an adenosine triphosphate-sensitive potassium (KATP)-channel inhibitor, glibenclamide = glibenclamide–isoflurane and glibenclamide-sevoflurane groups; those treated with a high-conductance calcium-activated potassium (KCa)-channel inhibitor, iberiotoxin = iberiotoxin–isoflurane and iberiotoxin–sevoflurane groups; and those treated with a voltage-sensitive potassium (KV)-channel inhibitor, 4-aminopyridine = 4-aminopyridine–isoflurane and 4-aminopyridine–sevoflurane groups. The effect of anesthetic on HPV was tested by exposure of the lungs to isoflurane at a concentration of 0, 0.5, 1, or 2 minimum alveolar concentration, or to sevoflurane at a concentration of 0, 0.5, 1, or 1.62 minimum alveolar concentration. The relation between anesthetic concentrations and the HPV response was analyzed by the Wagner equation. ResultsThe inhibition of KV channels by 4-aminopyridine and KCa channels by iberiotoxin augmented the HPV response. The isoflurane-induced attenuation of HPV was attenuated by voltage-sensitive potassium-channel inhibition with 4-aminopyridine, potentiated by KCa-channel inhibition with iberiotoxin, but not affected by KATP-channel inhibition with glibenclamide. The sevoflurane-induced attenuation of HPV was not affected by any of the potassium-channel inhibitors. ConclusionsIsoflurane may modulate the HPV response partially through KCa and KV channels, but sevoflurane may attenuate the HPV response through other pathways rather than through the currently investigated potassium channels in isolated rabbit lungs.

Effects of hypoxic exercise conditioning on work capacity, lactate, hypoxanthine and hormonal factors in men.

1. Hypoxanthine is a purine degradation product and exercise plasma hypoxanthine can be an index of ATP supply–demand imbalance during exercise. The present study determined the effects of hypoxic exercise conditioning on work capacity, blood lactate, plasma hypoxanthine and various neurohormonal factors.

Isoflurane inhibits endothelium-mediated nitric oxide relaxing pathways in the isolated perfused rabbit lung

PurposeThe role of volatile anaesthetics on nitric oxide (NO)-dependent relaxation is unclear in the pulmonary circulation. We examined the effects of isoflurane on NO-dependent relaxation in isolated perfused rabbit lungs.MethodsEighteen rabbit lungs were perfused in a constant-flow recirculation manner. In study I (n= 12), acetylcholme (ACh, 4 × 10−10 − 10−8 M) or nitroglycenne (NTG, 6 × 10−10−10−8 M) was cumulatively injected into the pulmonary artery in the absence or presence of isoflurane (1, 2 MAC). In study 2 (n=6), ACh was injected as in study I in the presence or absence of Nω-nitro-L-arginine methyl ester (L-NAME, 100 μM), an NO synthesis blocker. In all experiments, indomethacin was administered to prevent formation of vasoactive prostanoid metabolites, and the pulmonary vessels were preconstricted with prostaglandin F2α (PGF2α) infused before ACh or NTG injection. The ACh-or NTG-induced relaxation was expressed as % decrease in PGF2α preconstriction.ResultsIsoflurane at 2 MAC attenuated the dose-dependent relaxation to ACh at doses of 4 × 10−9 M and 4 × 10−8 M from 27.8 ± 4.3% and 38.8 ± 5.3% to 17.0 ± 3.5% and 25.5 ± 4.9%, respectively (P < 0.05). Isoflurane did not change the dose-dependent relaxation to NTG and L-NAME abolished the ACh-induced relaxation.ConclusionIsoflurane inhibited NO-dependent relaxation in the pulmonary circulation at a site distal to the endothelial cell receptor-mediated responses but proximal to guanylate cyclase activation of vascular smooth muscle. Acetylcholine-induced relaxation in isolated perfused rabbit lungs was regulated primarily by NO.RésuméObjectifNous connaissons mal l’influence des anesthésiques volatils sur la relaxation de la circulation pulmonaire dépendante du monoxyde d’azote (NO). Cette étude analyse les effets de l’isoflurane sur la relaxation NO-dépendante de poumons perfusés de lapins.MéthodesDix-huit poumons de lapins ont été perfusés par recirculation à débit constant. Dans l’étude I (n= 12), on a injecté de l’acétylcholine (ACh, 4 × 10−1−10−8 M) ou de la nitroglycénne (NTG, 6 × 10−10−10−8 M) avec ou sans isoflurane (1,2 MAC). Dans l’étude 2, (n=6), l’ACh a été injectée seule comme dans l’étude I ou associée au Nω-nitro-L-arginine méthyl ester (L-NAME, 100 μM), un inhibiteur de la synthèse du NO. Toutes les expériences ont comporté l’administration d’indométhacme pour prévenir la formation de métabolites protanoïdes vasoactifs ainsi que la constriction préalable avec de la prostaglandine F2α (PGF2α) administrée en perfusion avant l’injection de l’ACh et de la NTG. La relaxation induite par ACh ou NTG était exprimée en fonction de la diminution du pourcentage de constriction provoquée par la PGF2α.RésultatsL’isoflurane à 2 MAC atténuait la relaxation à l’ACh proportionnellement aux doses de 4 × 10−9 et 4 × 10−8 M respectivement de 27.8 ± 4,3% et 38,8 ± 5,3% à 17,0 ± 3,5% et 25,5 ± 4,9% (P < 0,05). Lisoflurane ne modifiait la relaxation de la circulation pulmonaire NO-dépendante à la NTG; le L-Name abolissait la relaxation induite par l’ACH.ConclusionLisoflurane inhibe la relaxation NO-dépendante dans la circulation pulmonaire à un site distal à celui des réponses transmises par médiation du récepteur endothélial cellulaire mais proximal à l’activation par le guanylate cyclase du muscle vasculaire lisse. Le NO est le régulateur primaire de la relaxation induite par l’ACh dans le poumon de lapin perfusé.