Noriaki Kanaya

Differential Effects of Propofol and Sevoflurane on Heart Rate Variability

Background Propofol is reported to reduce both sympathetic and parasympathetic tone; however, it is not clear whether the changes in heart rate variability are associated with depth of anesthesia. The purposes of the present study were (1) to evaluate the changes in heart rate variability at different depths of hypnosis and (2) to compare the effects of propofol on heart rate variability with that of sevoflurane. Methods Thirty patients were randomly allocated into the propofol or sevoflurane for induction of anesthesia. The depth of hypnosis was monitored by the Bispectral Index (BIS). Spectral analysis of heart rate variability using a maximum-entropy method resulted in a characteristic power spectrum with two main regions, a high frequency (HF) and a low frequency (LF). Hemodynamics, entropy, LF, HF, and LF/HF were monitored when the patients were awake and after induction of anesthesia. Results Both propofol and sevoflurane decreased blood pressure in a BIS-dependent manner, whereas heart rate showed no significant changes during the study period. In the propofol group, entropy and HF decreased with a reduction in the BIS value. Although LF decreased after induction of anesthesia, propofol caused no further decrease in LF in spite of a reduction in the BIS value. In the sevoflurane group, LF decreased with a reduction in the BIS value. Entropy and HF decreased after induction of anesthesia (BIS at 80); however, no further decreases were observed in spite of a reduction in the BIS value. Conclusions Induction of anesthesia with propofol decreased blood pressure, entropy, and HF in a BIS-dependent manner, indicating that propofol reduces cardiac parasympathetic tone depending on the depth of hypnosis. Conversely, sevoflurane did not show the BIS-dependent decreases in heart rate, blood pressure, HF, and entropy, indicating that sevoflurane has little or no effect on cardiac parasympathetic tone.

Propofol and Ketamine Only Inhibit Intracellular Ca2+Transients and Contraction in Rat Ventricular Myocytes at Supraclinical Concentrations

Background The cellular mechanisms that mediate the cardiodepressant effects of intravenous anesthetic agents remain undefined. The objective of this study was to elucidate the direct effects of propofol and ketamine on cardiac excitation‐contraction coupling by simultaneously measuring intracellular calcium concentration ([Ca2+]i) and shortening in individual, field‐stimulated ventricular myocytes. Methods Freshly isolated rat ventricular myocytes were loaded with the Ca2+ indicator, fura‐2, and placed on the stage of an inverted fluorescence microscope in a temperature‐regulated bath. [Ca2+]i and myocyte shortening (video edge detection) were monitored simultaneously in individual cells that were field‐stimulated at 0.3 Hz. Results Baseline [Ca2+]i (mean +/‐ SEM) was 80 +/‐ 12 nM, and resting cell length was 112 +/‐ 2 micro meter. Field stimulation increased [Ca2+]i to 350 +/‐ 23 nM, and the myocytes shortened by 10% of diastolic cell length. Both intravenous anesthetic agents caused dose‐dependent decreases in peak [Ca2+]i and shortening. At 300 micro Meter, propofol prolonged time to peak concentration and time to 50% recovery for [Ca2+]i and shortening. In contrast, changes in time to peak concentration and time to 50% recovery in response to ketamine were observed only at the highest concentrations. Neither agent altered the amount of Ca2+ released from intracellular stores in response to caffeine. Propofol but not ketamine, however, caused a leftward shift in the dose‐response curve to extracellular Ca2+ for shortening, with no concomitant effect on peak [Ca2+]i. Conclusions These results indicate that both intravenous anesthetic agents have a direct negative inotropic effect, which is mediated by a decrease in the availability of [Ca2+]i. Propofol but not ketamine may also alter sarcoplasmic reticulum Ca2+ handling and increase myofilament Ca2+ sensitivity. The effects of propofol and ketamine are primarily apparent at supraclinical concentrations, however.

Propofol increases myofilament Ca2+ sensitivity and intracellular pH via activation of Na+-H+ exchange in rat ventricular myocytes.

Background The objectives were to determine the extent and mechanism of action by which propofol increases myofilament Ca2+ sensitivity and intracellular pH (pHi) in ventricular myocytes. Methods Freshly isolated adult rat ventricular myocytes were used for the study. Cardiac myofibrils were extracted for assessment of myofibrillar actomyosin adenosine triphosphatase (ATPase) activity. Myocyte shortening (video edge detection) and pHi (2′,7′-bis-(2-carboxyethyl)-5(6′)-carboxyfluorescein, 500/440 ratio) were monitored simultaneously in individual cells field-stimulated (0.3 Hz) and superfused with HEPES-buffered solution (pH 7.4, 30°C). Results Propofol (100 &mgr;m) reduced the Ca2+ concentration required for activation of myofibrillar actomyosin ATPase from pCa 5.7 ± 0.01 to 6.6 ± 0.01. Increasing pHi (7.05 ± 0.03 to 7.39 ± 0.04) with NH4Cl increased myocyte shortening by 35 ± 12%. Washout of NH4Cl decreased pHi to 6.82 ± 0.03 and decreased myocyte shortening to 52 ± 10% of control. Propofol caused a dose-dependent increase in pHi but reduced myocyte shortening. The propofol-induced increase in pHi was attenuated, whereas the decrease in myocyte shortening was enhanced after pretreatment with ethylisopropyl amiloride, a Na+–H+ exchange inhibitor, or bisindolylmaleimide I, a protein kinase C inhibitor. Propofol also attenuated the NH4Cl-induced intracellular acidosis, increased the rate of recovery from acidosis, and attenuated the associated decrease in myocyte shortening. Propofol caused a leftward shift in the extracellular Ca2+–shortening relation, and this effect was attenuated by ethylisopropyl amiloride. Conclusions These results suggest that propofol increases the sensitivity of myofibrillar actomyosin ATPase to Ca2+ (i.e., increases myofilament Ca2+sensitivity), at least in part by increasing pHivia protein kinase C–dependent activation of Na+–H+ exchange.

Forehead is as sensitive as finger pulse oximetry during general anesthesia

PurposeTo compare the performance of a forehead probe to a conventional finger pulse oximetry probe in anesthetized patients.MethodsEighteen patients participated in the study. Each probe was connected to a Nellcor N-550 pulse oximeter. Anesthesia was induced and maintained with propofol. After intubation, the patients received air to achieve a steady-state of peripheral arterial oxygen saturation (SpO2). Ventilation was interrupted to induce a hypoxic state. As soon as one of the two SpO2’s decreased to 90%, the patients’ lungs were ventilated with 100% oxygen. To evaluate the performance of the two pulse oximeters, time to the lowest (TL), time of recovery (TR) and lag times to beginning of SpO2 decrease (Lag) were measured.ResultsThere were no significant differences in TL and TR between forehead and finger pulse oximetry under normal perfusion conditions during general anesthesia. When the axillary artery was compressed to mimic reduced peripheral perfusion, SpO2 in the forehead decreased sooner than in the finger during hypoxia. The forehead and finger TLs were similar, however, TR was significantly longer in the finger.ConclusionThe forehead SpO2 sensor can be used as an alternative to the conventional finger sensor during general anesthesia.RésuméObjectifComparer la performance d’un capteur frontal et d’un capteur traditionnel au doigt chez des patients anesthésiés.MéthodeDix-huit patients ont participé à l’étude. Chaque capteur a été relié à un sphygmo-oxymètre Nellcor N550. L’anesthésie a été induite et maintenue avec du propofol. Après l’intubation, les patients ont reçu de l’air pour l’obtention d’un état d’équilibre de la saturation en oxygène du sang artériel périphérique (SpO2). La ventilation a été interrompue pour induire un état hypoxique. Aussitôt qu’une ou l’autre mesure de SpO2 baissait à 90 %, les patients étaient ventilés avec de l’oxygène à 100 %. La performance des deux appareils a été mesurée par le temps nécessaire pour obtenir la plus basse valeur de SpO2 (TB), le temps nécessaire à la récupération (TR) et les intervalles précédant les baisses de SpO2 (Int).RésultatsIl n’y a pas eu de différences significatives de TF et TR entre les résultats notés au front et au doigt dans des conditions normales de perfusion pendant l’anesthésie générale. Quand l’artère axillaire était compressée pour imiter une perfusion périphérique réduite, la SpO2 diminuait plus vite au front qu’au doigt pendant l’hypoxie. Les TF au front et au doigt ont été similaires, mais le TR a été significativement plus long au doigt.ConclusionLe capteur frontal de SpO2 peut remplacer un capteur traditionnel fixé au doigt pendant l’anesthésie générale.

Propofol Increases Phosphorylation of Troponin I and Myosin Light Chain 2 via Protein Kinase C Activation in Cardiomyocytes

Background Troponin I (TnI) and myosin light chain 2 (MLC2) are important myofibrillar proteins involved in the regulation of myofilament calcium (Ca2+) sensitivity and cardiac inotropy. The objectives of this study were to determine the role of protein kinase C (PKC) in mediating propofol-induced changes in actomyosin adenosine triphosphatase activity in cardiac myofibrils and to examine the extent to which propofol alters the phosphorylation of TnI and MLC2 in cardiomyocytes. Methods Freshly isolated adult rat ventricular myocytes were used for the study. Cardiac myofibrils were extracted for assessment of actomyosin adenosine triphosphatase activity and phosphorylation of TnI and MLC2. Western blot analysis for PKC-&agr; was performed on cardiomyocyte subcellular fractions. Simultaneous measurement of intracellular free Ca2+ concentration ([Ca2+]i) and myocyte shortening was assessed using fura-2 and video edge detection, respectively. Results Propofol (30 &mgr;m) reduced the Ca2+ concentration required for activation of actomyosin adenosine triphosphatase activity, and this effect was abolished by bisindolylmaleimide I. In addition, propofol stimulated dose-dependent phosphorylation of TnI and MLC2. PKC activation with phorbol myristic acetate also stimulated an increase in phosphorylation of TnI and MLC2. The actions of propofol and phorbol myristic acetate together on phosphorylation of TnI and MLC2 were not additive. PKC inhibition with bisindolylmaleimide I attenuated phorbol myristic acetate- and propofol-induced phosphorylation of TnI and MLC2. Propofol stimulated translocation of PKC-&agr; from cytosolic to membrane fraction. Propofol caused a shift in the extracellular Ca2+–shortening relationship, and this effect was abolished by bisindolylmaleimide I. Conclusions These results suggest that propofol increases myofilament Ca2+ sensitivity via a PKC-dependent pathway involving the phosphorylation of MLC2.

Role of Endothelium-derived Hyperpolarizing Factor in Phenylephrine-induced Oscillatory Vasomotion in Rat Small Mesenteric Artery

Background In small mesenteric arteries, endothelium-derived hyperpolarizing factor (EDHF) in addition to endothelium-derived relaxing factors (EDRFs) including NO plays an important role in acetylcholine-induced vasodilation. It has been reported that EDRFs play an important role in &agr;1-adrenoceptor agonist-induced oscillatory vasomotion and in limiting vasoconstrictor response to the agonists; however, contribution of EDHF to the &agr;1-agonist-induced oscillation is unknown. Methods Rat small mesenteric arteries were isolated and cannulated at each end with a glass micropipette. The vessels were immersed in a bath (37°C) containing physiologic saline solution. Changes in vessel diameter were measured using an optical density video detection system. Results Denudation of the endothelium and inhibition of NO synthesis caused a leftward shift in the concentration-response relation for phenylephrine in the mesenteric arteries, whereas inhibition of cyclooxygenase by indomethacin had no effect. Blockade of Ca2+-activated K+ (KCa) channels by charybdotoxin and apamin caused a further leftward shift in the concentration-response relation in the vessels pretreated with N&ohgr;-nitro-l-arginine methylester and indomethacin. Phenylephrine at concentrations higher than 10−6 m caused endothelium-dependent oscillatory vasomotion, which was reduced but not abolished after combined inhibition of the cyclooxygenase and NO synthase pathways. However, the KCa channel blockers completely abolished the remaining component of oscillation. Conclusions Endothelially-derived NO is an important modulator of sustained agonist-induced vasoconstriction. NO, as well as endothelially-derived cyclooxygenase products and EDHF, also contribute significantly to phenylephrine-induced oscillatory vasomotion.

The direct effects of diazepam and midazolam on myocardial depression in cultured rat ventricular myocytes.

We examined the direct myocardial depressant effects of diazepam and midazolam and determined whether a benzodiazepine receptor antagonist, flumazenil, or an L-type Ca2+ channel agonist, Bay K 8644, affects the myocardial depression induced by diazepam and midazolam in cultured rat ventricular myocytes. Ventricular myocytes of neonatal rats were obtained by enzymatic digestion with collagenase and cultured for 6-7 days. The myocytes were stabilized in serum-free medium, and the spontaneous beating rate and amplitude were measured by determining displacement with a fiberoptic sensor. Myocytes were exposed to either diazepam or midazolam at concentrations of 0.1, 1, 10, and 100 micro M. The beating rate and amplitude were measured 4 min after diazepam or midazolam administration. In other cells, either diazepam or midazolam was administered at each concentration in the presence of flumazenil or Bay K 8644. Midazolam and diazepam decreased the beating rate and amplitude concentration-dependently. These myocardial depressant effects were prevented by Bay K 8644 and, to a lesser degree, by flumazenil. Thus, the L-type Ca2+ channel is important in the direct myocardial depression caused by diazepam and midazolam. Implications: This study describes the direct effect of midazolam and diazepam on intrinsic myocardial contraction using cultured rat ventricular heart cells. Both of these drugs have a direct myocardial depressant effect at the cellular level, which is mainly mediated by an inhibition of the sarcolemmal L-type Ca2+ channel. (Anesth Analg 1997;85:729-33)

Atropine for the treatment of hiccup after laryngeal mask insertion.

IMPLICATIONS We describe three patients in whom hiccups were treated successfully by atropine. Although further clinical investigation is needed, atropine may be useful in the treatment of hiccups after the laryngeal mask airway insertion.

Cardioprotective effects of propofol in isolated ischemia-reperfused guinea pig hearts: role of KATP channels and GSK-3β

Purpose: Propofol exerts cardioprotective effects, but the involved mechanisms remain obscure. The present study examines the cardioprotective effects of propofol and its role in cardiac function, including its effect on KATP channel opening and the inhibition of GSK-3ß activity in ischemia-reperfused hearts.Methods: Ischemia-reperfusion (I/R) was produced in isolated guinea pig hearts by stopping coronary perfusion for 25 min, followed by reperfusion. The hearts were incubated for ten minutes, with or without propofol (25 or 50 µM), or for five minutes with 500 µM 5-hydroxydecanoate (a mitochondrial KATP channel blocker) or 30 µM HMR1098 (sarcolemmal KATP channel blocker), followed by five minutes with 50 µM propofol before ischemia. Action potentials on the anterior epicardial surface of the ventricle were monitored using a high-resolution charge-coupled device camera system, and at five minutes after reperfusion, GSK-3ß phosphorylation at the serine residue, Ser9, was examined.Results: After 35 min of reperfusion, propofol (25 and 50 µM) blunted the adverse effects of I/R and reduced infarct size (P<0.05). In addition, prior incubation with 5-hydroxydecanoate or HMR1098 had no effect on functional recovery improved by 50 µM propofol. At five minutes after reperfusion, propofol (25 and 50 µM) shortened the duration of the action potential and increased the levels of phospho-GSK-3ß (P<0.05).Conclusions: Propofol enhanced mechanical cardiac recovery and reduced infarct size. The data further suggest that GSK-3ß play an important role in propofol cardioprotective actions during coronary reperfusion, but mitochondrial KATP channels do not.RésuméObjectif: Le propofol exerce des effets cardioprotecteurs, mais les mécanismes sous-jacents demeurent obscurs. Cette étude examine les effets cardioprotecteurs du propofol et son rôle dans la fonction cardiaque, notamment son effet sur l’ouverture du canal KATP et l’inhibition de l’activité du GSK-3β dans des coeurs ischémiques puis reperfusés.Méthode: L’ischémie reperfusion (I/R) a été provoquée dans des coeurs isolés de cobayes en interrompant la per fusion coronarienne pendant 25 min, puis en les reperfusant. Les coeurs ont été incubés pendant dix minutes, avec ou sans propofol (25 ou 50 µM), ou pendant cinq minutes avec 500 µM de 5-hydroxydecanoate (un bloqueur du canal KATP mitochondrial) ou 30 µM de HMR1098 (un bloqueur du canal KATP sarcolemmal), suivi par cinq minutes avec 50 µM de propofol avant l’ischémie. Les potentiels d’action sur la surface épicardique antérieure du ventricule ont été surveillés à l’aide d’un système de caméra à dispositif à transfert de charge et, cinq minutes après la reperfusion, la phosphorylation du GSK-3β au résidu de sérine, Ser9, a été examiné.Résultats: Après 35 min de reperfusion, le propofol (25 et 50 µM) a émoussé les effets négatifs de l’I/R et réduit la taille de l’infarctus (P<0,05). De plus, l’incubation antérieure avec le 5-hydroxydecanoate ou l’HMR1098 n’a pas eu d’effet sur la récupération fonctionnelle améliorée par 50 µM de propofol. Cinq minutes après la reperfusion, le propofol (25 et 50 µM) a abrégé la durée du potentiel d’action et augmenté les niveaux de phospho-GSK-3β (P<0,05).Conclusion: Le propofol a amélioré la récupération cardiaque mécanique et réduit la taille de l’infarctus. Les données suggèrent aussi que le GSK-3β joue un rôle important dans les actions cardioprotectrices du propofol pendant la reperfusion coronarienne, mais pas les canaux KATP mitochondriaux.

Cardioprotective effect and mechanism of action of landiolol on the ischemic reperfused heart.

PurposeThe authors examined the cardioprotective effect of landiolol, an ultra short-acting, highly selective β1-blocker, and its role in cardiac work, antioxidative effect, and sarcoplasmic reticulum (SR) function in hearts subjected to ischemia-reperfusion.MethodsIsolated guinea pig hearts were subjected to ischemia-reperfusion by stopping the perfusion for 45 min and reperfusing. Before the ischemia, hearts were treated with landiolol (20, 100, or 500 µM) for 15 min (LAN group). In another set of experiments, before ischemia, hearts were washed out for 15 min after treatment with landiolol (WO group). In other hearts, the tissue concentration of malondialdehyde was measured after reperfusion. We also examined the phosphorylation of phospholamban at Ser16 and Thr17residues to evaluate the SR function.ResultsAfter 90 min of reperfusion, left ventricular pressure (LVP) was restored significantly in the LAN-500 µM group regardless of heart rate. However, the improvement in recovery in LVP disappeared in the WO group. The tissue malondialdehyde levels were decreased in the LAN group compared with those in the control group. In the control group, the phosphorylation of phospholamban at Ser16 and Thr17 residues was markedly increased after reperfusion. Landiolol at 500 µM suppressed the increase of phosphorylation at Ser16 residues.ConclusionThe present study demonstrated that landiolol had a lipid peroxidation-reducing effect and suppressed the increase in phospholamban phosphorylation at the Ser16 residue in hearts subjected to ischemia-reperfusion. These findings indicate that landiolol may have an anti-ischemic effect, via an antioxidant effect and/or via preserving SR function during the ischemic period.