Kenji Kodama

Effects of volatile anesthetics on acetylcholine-induced relaxation in the rabbit mesenteric resistance artery

Background Vascular endothelium plays an important role in the regulation of vascular tone. Volatile anesthetics have been shown to attenuate endothelium‐mediated relaxation in conductance arteries, such as aorta. However, significant differences in volatile anesthetic pharmacology between these large vessels and the small vessels that regulate systemic vascular resistance and blood flow have been documented, yet little is known about volatile anesthetic action on endothelial function in resistance arteries. Furthermore, endothelium‐dependent relaxation mediated by factors other than endothelium‐derived relaxing factor (EDRF) has recently been recognized, and there is no information available regarding volatile anesthetic action on non‐EDRF‐mediated endothelium‐dependent relaxation. Methods Employing isometric tension recording and microelectrode methods, the authors first characterized the endothelium‐dependent relaxing and hyperpolarizing actions of acetylcholine (ACh) in rabbit small mesenteric arteries, and tested the sensitivities of these actions to EDRF pathway inhibitors and Potassium sup + channel blockers. They then examined the effects of the volatile anesthetics isoflurane, enflurane, and sevoflurane on ACh‐induced endothelium‐dependent relaxation that was sensitive to EDRF inhibitors and that which was resistant to the EDRF inhibitors but sensitive to blockers of ACh‐induced hyperpolarization. The effects of the volatile anesthetics on endothelium‐independent sodium nitroprusside (SNP)‐induced relaxation were also studied. Results Acetylcholine concentration‐dependently caused both endothelium‐dependent relaxation and hyperpolarization of vascular smooth muscle. The relaxation elicited by low concentrations of ACh (less or equal to 0.1 micro Meter) was almost completely abolished by the EDRF inhibitors NG ‐nitro L‐arginine (LNNA), oxyhemoglobin (HbO sub 2), and methylene blue (MB). The relaxation elicited by higher concentrations of ACh (greater or equal to 0.3 micro Meter) was only attenuated by the EDRF inhibitors. The remaining relaxation, as well as the ACh‐induced hyperpolarization that was also resistant to EDRF inhibitors, were both specifically blocked by tetraethylammonium (TEA greater or equal to 10 mM). Sodium nitroprusside, a NO donor, produced dose‐dependent relaxation, but not hyperpolarization, in the endothelium‐denuded (E[‐]) strips, and the relaxation was inhibited by MB and HbO2, but not TEA (greater or equal to 10 mM). One MAC isoflurane, enflurane, and sevoflurane inhibited both ACh relaxation that was sensitive to the EDRF inhibitors and the ACh relaxation resistant to the EDRF inhibitors and sensitive to TEA, but not SNP relaxation (in the E[‐] strips). An additional finding was that the anesthetics all significantly inhibited norepinephrine (NE) contractions in the presence and absence of the endothelium or after exposure to the EDRF inhibitors. Conclusions The results confirm that ACh has a hyperpolarizing action in rabbit small mesenteric resistance arteries that is independent of EDRF inhibitors but blocked by the Potassium sup + channel blocker TEA. The ACh relaxation in these resistance arteries thus appears to consist of distinct EDRF‐mediated and hyperpolarization‐mediated components. Isoflurane, enflurane, and sevoflurane inhibited both components of the ACh‐induced relaxation in these small arteries, indicating a more global depression of endothelial function or ACh signaling in endothelial cells, rather than a specific effect on the EDRF pathway. All these anesthetics exerted vasodilating action in the presence of NE, the primary neurotransmitter of the sympathetic nervous system, which plays a major role in maintaining vasomotor tone in vivo. This strongly indicates that the vasodilating action of these anesthetics probably dominates over their inhibitory action on the EDRF pathway and, presumably, contributes to their known hypotensive effects in vivo. Finally, the vasodilating action of these anesthetics is, at least in part, independent from endothelium.

Calcineurin-inhibitor-induced pain syndrome after bone marrow transplantation

Calcineurin-inhibitor-induced pain syndrome (CIPS), a rare complication seen in patients with organ transplants, is associated with the use of calcineurin inhibitors (CIs) such as cyclosporine (CSP) and tacrolimus (FK). Patients with this syndrome usually present with severe leg pain. This case report demonstrates the successful pain control of this pain syndrome in a 42-year-old female patient who had been given CIs (FK and CSP) as an immunosuppressive agent after a bone marrow transplant. Twenty-one days after the transplantation, she complained of severe pain in her bilateral lower extremities; this lasted several weeks, and was resistant to ordinary analgesics such as intramuscular pentazocine, intravenous morphine, and even oral nifedipine, which is generally accepted as an effective analgesic agent for the pain in this syndrome. Due to the presence of allodynia, our patient’s pain had neuropathic pain-like characteristics, unlike the pain in previously reported patients with other organ transplants. Her pain was successfully relieved by the administration of oral amytriptyline, clonazepam, oxycodone, and intravenous lidocaine, all of which ordinarily have an analgesic effect on neuropathic pain. CIPS in patients with hematopoietic stem cell transplants treated with FK may have a mechanism by which neuropathic pain may develop that is different from that in patients with other organ transplants.

Changes in body temperature following deflation of limb pneumatic tourniquet

Abstract Study Objectives : To investigate changes in both core and peripheral skin-surface temperatures during and after application of a unilateral leg pneumatic tourniquet in adult patients. Design : Prospective, observational clinical study. Setting : University hospital. Patients : 21 ASA physical status I and II adult patients scheduled for elective leg orthopedic surgery with lumbar epidural anesthesia. Interventions : Rectal and fingertip skin-surface temperatures were recorded every minute after steady-state lumbar epidural anesthesia was established. Measurements and Main Results : Significant ( p p Conclusions : Limb tourniquets appear to cause thermal perturbations during epidural anesthesia. The progressive increases in core temperature during tourniquet application presumably resulted from constraint of metabolic heat to the core thermal compartment, and the greater increases in the skin-surface temperature during tourniquet application appear to represent vasodilation in response to the core hyperthermia. On the other hand, redistribution of body heat and the efflux of hypothermic venous blood from the tourniqueted area into systemic circulation following tourniquet deflation probably decreased the core temperature, which might switch off the thermoregulatory vasodilation, leading to the decreases in skin-surface temperature. Recognition of these thermal perturbations are useful in diagnosing intraoperative thermal perturbations.

Volatile anaesthetic actions on norepinephrine-induced contraction of small splanchnic resistance arteries

The aim of this study was to investigate volatile anaesthetic action on small splanchnic resistance arteries. Employing isometric tension recording, we studied the effects of clinically relevant concentrations (0.25– 1.25 minimum alveolar concentration (MAC)) of isoflurane, sevoflurane and enflurane on contractions induced by norepinephrine (NE), a sympathetic neurotransmitter, in the rabbit small mesenteric artery. Rhythmic oscillations were observed in contractile responses to NE. Both isoflurane (≥ 0.25 MAC, 0.5% (≈0.11 mM)) and sevoflurane (≥ 0.75 MAC, 2.8% (≈=0.38 mM)) inhibited the NE (10 μM)- induced contraction with concomitant inhibition of average amplitude of the oscillations. Only enflurane (≥ 0.25 MAC, 0.7% (≈0.20 mM)) generated vasoconstriction superimposed on the NE-induced contraction; however, the vasoconstriction was transient and was followed by vasorelaxation. Concurrently, enflurane (≥ 0.25 MAC) strongly inhibited the average amplitude of the oscillations; higher concentrations (≥ 1.0 MAC) of enflurane completely eliminated the oscillations. The frequency of the NE-induced oscillations was less affected by the anaesthetics. The observed vasodilator action of these anaesthetics in small resistance arteries may contribute to their hypotensive effects in vivo. The potent inhibition of the rhythmic oscillations also may play a role in volatile anaesthetic-induced alterations in cardiovascular homeostasis.RésuméCette étude avait pour objectif de rechercher les effets de certains anesthésiques volatils sur les petites artères splanchniques de résistance. En enregistrant la tension isométrique, les auteurs ont étudié les effets de concentrations efficaces en clinique (0,25–1,25 MAC d’isoflurane, de sévoflurane et d’enflurane) sur les contractions induites par le neurotransmetteur sympathique norépinéphrine (NE) sur la petite artère mésentérique du lapin. En réponse à la NE, on a observé des oscillations rythmiques contractiles. L’isoflurane (≥ 0,25 MAC, 0,5% (≈0,11 mM)) et le sévoflurane (≥ 0,75 MAC, 2,8% (≈0,38 mM)) inhibaient la contraction induite par la NE (10μM) avec une inhibition simultanée de l’amplitude moyenne des oscillations. Seul l’enflurane (≥ 0,25 MAC, 0,7% (≈0,20 mM)) a provoqué une vasoconstriction superposée à la contraction induite par la NE; cependant, cette vasoconstriction était transitoire et suivie de vasorelaxation. Simultanément, l’enflurane (≥ 0,25 MAC) a inhibé vigoureusement l’amplitude moyenne des oscillations; les concentrations plus élevées (≥ 1,0 MAC) d’enflurane ont éliminé complètement les oscillations. La fréquence des oscillations induites par la NE a été moins affectée par les anesthésiques. L’activité vasodilatatrice observée avec ces anesthésiques sur les petites artères de résistance peut contribuer à leurs effets hypotensifs in vivo. La puissante inhibition des oscillations rythmiques peut aussi jouer un rôle dans les altérations de l’homéostase cardiovasculaire induites par les anesthésiques.

Possible Electromagnetic Interference with Electronic Medical Equipment by Radio Waves Coming from Outside the Hospital

Electromagnetic interference (EMI) with electronic medical equipment by radio waves from mobile telephone handsets has been reported and is currently receiving wide attention. The possibility of EMI with electronic medical equipment by radio waves coming into the hospital has also been pointed out. But so far, there are no reports measuring the frequency distribution of electric field intensity induced by incoming radio waves. Therefore, we measured electric field intensity induced by radio waves coming into our 11-floor hospital, which was under construction. The maximum intensity observed was about 200 V/m at 2.79 GHz, from airport surveillance radar waves. The maximum intensity induced by radio waves from cellular phone base stations was 1.78 V/m. These data show that various frequencies of radio waves are common in this urban area, and that they induce strong electric field intensity. This strong electric field intensity might cause EMI with electronic medical equipment. Measurement of the electromagnetic environment should be done by each hospital in urban areas to prevent EMI with electronic medical equipment.

Effects of heparin on the vasodilator action of protamine in the rabbit mesenteric artery

1 The effects of protamine on the rabbit isolated small mesenteric artery were investigated both in the presence and in the absence of heparin, by the isometric tension‐recording method. 2 The dissociation constant for the binding of heparin to protamine has never been previously reported, so in order to minimize the effects of protamine, known to have a vasodilator action, and to examine only the effects of a heparin‐protamine complex, the experiments with heparin were performed in the presence of high concentrations of heparin (21–700 u ml−1), concentrations at which heparin itself does not affect the vascular tone. 3 Protamine (15–500 μg ml−1), in the absence of heparin, was found to inhibit (P < 0.05) noradrenaline (1 μm)‐induced contractions both in endothelium‐intact and in endothelium‐denuded tissues. 4 Such vasodilator action of protamine in either endothelium‐intact or ‐denuded tissues continued, even in the presence of excess heparin at a heparin/protamine (H/P) ratio of 1.4 uμg−1, but was almost completely blocked in the presence of a much greater excess of heparin (H/P ratio ≥ 4.7 u μg−1): heparin was present both before and during the application of protamine. 5 The vasodilator action of protamine in the absence of heparin was prolonged both in the endothelium‐intact and ‐denuded tissues after protamine had been washed out from the bath with Krebs solution. Although this washing out with a Krebs solution containing excess heparin (4.7 u ml−1) readily reversed such prolonged vasodilator action of protamine both in the endothelium‐denuded strips and in the endothelium‐intact strips which had been pretreated with inhibitors of the endothelium‐derived relaxing factor (EDRF) pathway, it did not affect the prolonged vasodilator action of protamine in the endothelium‐intact strips which received no pharmacological intervention. 6 These results suggest that: (1) only protamine, not a heparin‐protamine complex, exerts vasodilator action in vitro; (2) the vasodilator action of protamine presumably has an EDRF‐mediated component; and (3) protamine probably exerts its direct vasodilator action without entering the smooth muscle cell.

Heparin prevents the vasodilating actions of protamine on human small mesenteric arteries

Despite the wide clinical use of protamine, the precise mechanisms of its hypotensive effects during reversal of heparin anticoagulation have not been elucidated fully. We, therefore, investigated the effects of protamine on isolated human small mesenteric arteries, both in the absence and presence of heparin, employing the isometric tension recording method. Protamine exerted vasodilating actions in the absence of heparin: 1) protamine (> or = 50 or 150 micrograms/mL) inhibited (P < 0.05) both norepinephrine (1 microM)- and high K+ (40 mM)-induced contractions in the presence of extracellular Ca2+ both in endothelium-intact and -denuded tissues; and 2) protamine inhibited (P < 0.05) norepinephrine (1 microM)-induced, but not caffeine (10 mM)-induced, contractions in the absence of extracellular Ca2+. Such vasodilating actions were blocked almost completely in the presence of heparin. We conclude that only protamine, but not a heparin-protamine complex, has a vasodilating action on the human arteries.

Effects of heparin on the inhibitory action of protamine on endothelium-mediated vasorelaxation

The precise mechamism(s) of inhibitory action of protamine on endothelium‐mediated vasorelaxation has not been fully elucidated. In addition, no information is available regarding the effects of a heparin‐protamine complex on the endothelium‐mediated relaxation.

Protamine relaxes vascular smooth muscle by directly reducing cytosolic free calcium concentrations in small resistance arteries

Protamine has been suggested to relax vascular smooth muscle by reducing the intracellular Ca2+ concentration ([Ca2+]i). However, there has been no direct evidence that protamine reduces the [Ca2+]i of vascular smooth muscle. We therefore studied the effects of protamine on changes in [Ca2+]i and tension induced by norepinephrine (NE) and high K+ in endothelium-denuded strips from rabbit small mesenteric artery, using fura-2-fluorometry and isometric tension recording methods. Both NE (1 μM) and high K+ (40 mM) produced a transient phasic increase, followed by a tonic increase in [Ca2+]i and tension. Protamine concentration (15–500 μg·ml−1)-dependently inhibited (P<0.05) the phasic and tonic components of both NE- and high K+-induced contraction with IC50 values of ≈50 μg·ml−1. Protamine (50 μg·ml−1) inhibited (P<0.05) the phasic and tonic increases in [Ca2+]i caused by both NE and high K+ by ≈40%–60%. We conclude that the direct vasodilator action of protamine is due, at least in part, to reduction of [Ca2+]i in vascular smooth muscle; this reduction in [Ca2+]i may be due to inhibition of both Ca2+ influx and Ca2+ release from intracellular Ca2+ stores.

Electromagnetic Noise Superimposed on the Electric Power Supply to Electronic Medical Equipment

The use of mobile medical electronic equipment driven at low electric power outputs has progressed rapidly in recent years. Voltage change and noise superimposed on the power supply could create obstacles to the operation of medical electronic equipment. We observed the quality of the power supply of medical electronic equipment in a university hospital, and found approximately 5% distortion on voltage. Possible causes of the distortion and factors involved in voltage/current distortion are discussed. Also shown are some points for avoiding power supply problems when using medical electronic equipment.