Nobuyoshi Kusama

Involvement of H2O2 in superoxide-dismutase-induced enhancement of endothelium-dependent relaxation in rabbit mesenteric resistance artery.

The mechanism underlying the enhancement by superoxide dismutase (SOD) of endothelium‐dependent relaxation was investigated in rabbit mesenteric resistance arteries. SOD (200 U ml−1) increased the production of H2O2 in smooth muscle cells (as indicated by the use of an H2O2‐sensitive fluorescent dye). Neither SOD nor catalase (400 U ml−1) modified either the resting membrane potential or the hyperpolarization induced by acetylcholine (ACh, 1 μM) in smooth muscle cells. In arteries constricted with noradrenaline, the endothelium‐dependent relaxation induced by ACh (0.01–1 μM) was enhanced by SOD (200 U ml−1) (P<0.01). This action of SOD was inhibited by L‐NG‐nitroarginine (nitric oxide (NO)‐synthase inhibitor) but not by either charybdotoxin+apamin (Ca2+‐activated‐K+‐channel blockers) or diclofenac (cyclooxygenase inhibitor). Neither ascorbate (50 μM) nor tiron (0.3 mM), superoxide scavengers, had any effect on the ACh‐induced relaxation, but each attenuated the enhancing effect of SOD on the ACh‐induced relaxation. Similarly, catalase (400 U ml−1) inhibited the effect of SOD without changing the ACh‐induced relaxation. In endothelium‐denuded strips constricted with noradrenaline, SOD enhanced the relaxation induced by the NO donor 1‐hydroxy‐2‐oxo‐3‐(N‐methyl‐3‐aminopropyl)‐3‐methyl‐1‐triazene (NOC‐7) (P<0.05). Ascorbate and catalase each attenuated this effect of SOD. H2O2 (1 μM) enhanced the relaxation on the noradrenaline contraction induced by NOC‐7 and that induced by 8‐bromo‐cGMP, a membrane‐permeable analogue of guanosine 3′,5′ cyclic monophosphate (cGMP). SOD had no effect on cGMP production, whether measured in endothelium‐intact strips following an application of ACh (0.1 μM) or in endothelium‐denuded strips following an application of NOC‐7 (0.1 μM). It is suggested that in rabbit mesenteric resistance arteries, SOD increases the ACh‐induced, endothelium‐dependent relaxation by enhancing the action of NO in the smooth muscle via its H2O2‐producing action (rather than via a superoxide‐scavenging action).

Reduced hyperpolarization in endothelial cells of rabbit aortic valve following chronic nitroglycerine administration

This study was undertaken to determine whether long‐term in vivo administration of nitroglycerine (NTG) downregulates the hyperpolarization induced by acetylcholine (ACh) in aortic valve endothelial cells (AVECs) of the rabbit and, if so, whether antioxidant agents can normalize this downregulated hyperpolarization. ACh (0.03–3 μM) induced a hyperpolarization through activations of both apamin‐ and charybdotoxin‐sensitive Ca2+‐activated K+ channels (KCa) in rabbit AVECs. The intermediate‐conductance KCa channel (IKCa) activator 1‐ethyl‐2‐benzimidazolinone (1‐EBIO, 0.3 mM) induced a hyperpolarization of the same magnitude as ACh (3 μM). The ACh‐induced hyperpolarization was significantly weaker, although the ACh‐induced [Ca2+]i increase was unchanged, in NTG‐treated rabbits (versus NTG‐untreated control rabbits). The hyperpolarization induced by 1‐EBIO was also weaker in NTG‐treated rabbits. The reduced ACh‐induced hyperpolarization seen in NTG‐treated rabbits was not modified by in vitro application of the superoxide scavengers Mn‐TBAP, tiron or ascorbate, but it was normalized when ascorbate was coadministered with NTG in vivo. Superoxide production within the endothelial cell (estimated by ethidium fluorescence) was increased in NTG‐treated rabbits and this increased production was normalized by in vivo coadministration of ascorbate with the NTG. It is suggested that long‐term in vivo administration of NTG downregulates the ACh‐induced hyperpolarization in rabbit AVECs, possibly through chronic actions mediated by superoxide.

Nitric oxide inhalation is useful in the management of right ventricular failure caused by myocardial infarction.

ObjectiveTo describe hemodynamic improvement in a patient treated with nitric oxide (NO) inhalation in the management of right ventricular failure caused by myocardial infarction. DesignCase report. SettingAn intensive care unit of a university hospital. PatientA 66-yr-old man with severe right ventricular failure caused by acute myocardial infarction. InterventionsNitric oxide inhalation through a ventilator circuit. Measurements and Main ResultsThe patient complained of chest pain. When myocardial infarction was diagnosed, he underwent percutaneous transluminal coronary angioplasty and percutaneous transluminal coronary recanalization, but they were not effective. We instituted intra-aortic balloon pumping and brought the patient to the intensive care unit (ICU). Even with high-dose inotropic support, his hemodynamics deteriorated gradually. On the patient’s seventh day in the ICU, we started NO inhalation at 5–10 ppm in an attempt to relieve his right heart failure. Immediately after NO inhalation was started, his hemodynamics improved significantly, and we could wean the patient from intra-aortic balloon pumping. NO inhalation was continued for 9 days and was successfully discontinued without circulatory deterioration. He was discharged from our hospital uneventfully. ConclusionNitric oxide inhalation improved hemodynamics in our patient with right ventricular failure after myocardial infarction. Our report suggests that a clinical trial of NO treatment for severe right ventricular failure caused by myocardial infarction is warranted.

Characteristics of attenuated endothelium-dependent relaxation seen in rabbit intrapulmonary vein following chronic nitroglycerine administration.

1 This study was undertaken to determine whether long‐term in vivo administration of nitroglycerine (NTG) downregulates the endothelium‐dependent relaxation induced by acetylcholine (ACh) in the rabbit intrapulmonary vein and, if so, whether the type 1 angiotensin II receptor (AT1R) blocker valsartan normalizes this downregulated relaxation. 2 In strips treated with the cyclooxygenase inhibitor diclofenac, ACh induced a relaxation only when the endothelium was intact. A small part of this ACh‐induced relaxation was inhibited by coapplication of two Ca2+‐activated K+‐channel blockers (charybdotoxin (CTX)+apamin) and the greater part of the response was inhibited by the nitric‐oxide‐synthase inhibitor Nω‐nitro‐L‐arginine (L‐NNA). 3 The endothelium‐dependent relaxation induced by ACh, but not the endothelium‐independent relaxation induced by the nitric oxide donor NOC‐7, was significantly reduced in NTG‐treated rabbits (versus those in NTG‐nontreated control rabbits). The attenuated relaxation was normalized by coapplication of valsartan with the NTG. 4 In the vascular wall, both the amount of localized angiotensin II and the production of superoxide anion were increased by in vivo NTG treatment. These variables were normalized by coapplication of valsartan with the NTG. 5 It is suggested that long‐term in vivo administration of NTG downregulates the ACh‐induced endothelium‐dependent relaxation, mainly through an inhibition of endothelial nitric oxide production in the rabbit intrapulmonary vein. A possible role for AT1R is proposed in the mechanism underlying this effect.

Role of PKC in the attenuation of the cGMP-mediated relaxation of skinned resistance artery smooth muscle seen in glyceryl-trinitrate-tolerant rabbit

We examined whether 10 days’ in vivo treatment with glyceryl trinitrate (GTN) might reduce cGMP‐induced relaxation in the smooth muscle of rabbit mesenteric resistance arteries and, if so, whether protein kinase C (PKC) plays a role in this downregulation. The relaxation responses to GTN and the nitric oxide donor NOC‐7 were significantly reduced in endothelium‐denuded strips from GTN‐treated rabbits. In β‐escin‐skinned smooth muscle, the ability of 8‐bromoguanosine 3′,5′ cyclic monophosphate (8‐Br‐cGMP, a phosphodiesterase‐resistant cGMP analogue) to relax the contraction induced by 0.3 μM Ca2+ was significantly reduced in GTN‐treated rabbits. In β‐escin‐skinned smooth muscle, an inhibitor of conventional and/or novel PKCs, GF109203X (0.6 μM), inhibited the Ca2+‐induced contraction and enhanced the 8‐Br‐cGMP‐induced relaxation. However, since the relaxing ability of 8‐Br‐cGMP was found to be unchanged by GF109203X when contractions were amplitude‐matched (0.2 μM Ca2+ alone vs 0.3 μM Ca2++GF109203X), the increase in the 8‐Br‐cGMP‐response seen with GF109203X was probably due to its inhibitory action on the Ca2+‐induced contraction. Furthermore, although the PKC activator phorbol 12,13‐dibutyrate (PDBu, 0.1 μM) decreased the 8‐Br‐cGMP‐induced relaxation of the Ca2+ (0.3 μM) contraction, this was probably due to its enhancement of the Ca2+‐induced contraction since no such effect of PDBu was seen when the Ca2+‐induced contractions were amplitude‐matched (0.2 μM Ca2++PDBu vs 0.3 μM Ca2+ alone). These results suggest that the relaxing response to cGMP is reduced in the smooth muscle of mesenteric resistance arteries in GTN‐treated rabbits but that conventional and/or novel PKCs do not play a major role in maintaining this downregulation.

Effects of chronic in vivo administration of nitroglycerine on ACh-induced endothelium-dependent relaxation in rabbit cerebral arteries.

In the setting of nitrate tolerance, endothelium‐dependent relaxation is reduced in several types of peripheral vessels. However, it is unknown whether chronic in vivo administration of nitroglycerine modulates such relaxation in cerebral arteries.

Midazolam inhibits the formation of amyloid fibrils and GM1 ganglioside-rich microdomains in presynaptic membranes through the gamma-aminobutyric acid A receptor

Recent studies have suggested that a positive correlation exists between surgical interventions performed under general anesthesia and the risk of developing Alzheimers disease (AD) in the late postoperative period. It has been reported that amyloid β-protein (Αβ) fibrillogenesis, which is closely related to AD, is accelerated by exposure to anesthetics. However, the mechanisms underlying these effects remain uncertain. This study was designed to investigate whether the anesthetic midazolam affects Αβ fibrillogenesis, and if so, whether it acts through GM1 ganglioside (GM1) on the neuronal surface. Midazolam treatment decreased GM1 expression in the detergent-resistant membrane microdomains of neurons, and these effects were regulated by the gamma-aminobutyric acid-A receptor. Midazolam inhibited Αβ fibril formation from soluble Αβ on the neuronal surface. In addition, midazolam suppressed GM1-induced fibril formation in a cell-free system. Moreover, midazolam inhibited the formation of Αβ assemblies in synaptosomes isolated from aged mouse brains. These finding suggested that midazolam has direct and indirect inhibitory effects on Αβ fibrillogenesis.

Effect of maternal low-dose glucose during Cesarean sectionon neonatal hypoglycemia

Abstract Background: Although rapid infusion of glucose during Cesarean section is associated with maternal and fetal hyperglycemia and subsequent neonatal reflex hypoglycemia, the optimal amount of glucose to

Administration of low dose of glucose suppresses catabolism under general anaesthesia maintained with remifentanil

Abstract Background: The aim of this prospective randomized controlled study was to examine the optimal rate of glucose administration for preventing catabolism under general anaesthesia maintained with