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Ko Takakura

Publications and source records attributed to Ko Takakura.

10 recordsLinked to original sources
PubMed2006

Protamine sulfate causes endothelium-independent vasorelaxation via inducible nitric oxide synthase pathway.

PURPOSE: The precise mechanism of systemic hypotension frequently observed with the use of protamine is unclear. Although it has been reported that protamine stimulates the release of nitric oxide (NO) from endothelium NO synthase (eNOS), the association with inducible NOS (iNOS) remains unknown, despite the induction of iNOS by lipopolysaccharides (LPS) and/or inflammatory cytokines during cardiopulmonary bypass (CPB). The purpose of this study was to determine whether protamine stimulates the release of NO from iNOS induced by LPS. METHODS: We performed prospective and controlled functional examinations with isolated endothelium-denuded thoracic aortas from 21 male Wister rats. Aortic strips were mounted in Krebs solution and treated with LPS (1 microg x mL(-1)) for six hours to induce iNOS. Changes in tension caused by L-arginine (a substrate of NOS), protamine or a heparin-protamine complex (heparin: protamine = 1 unit: 10 microg) were measured in strips pre-contracted by phenylephrine. RESULTS: No drug relaxed the strips before LPS-treatment, but each drug relaxed the strips in a dose-dependent manner after LPS-treatment (P < 0.05). Aminoguanidine (an iNOS inhibitor) and methylene blue (a guanylyl cyclase inhibitor) inhibited the relaxations. CONCLUSION: These results indicate that protamine and the heparin-protamine complex stimulated the release of NO from iNOS. As iNOS is induced during CPB, protamine or a heparin-protamine complex might cause systemic hypotension, at least in part, by stimulating iNOS.

Animals↗
PubMed2006

The inhibitory effects of local anesthetics on primary sensory nerve and parasympathetic nerve in rabbit eye.

Primary sensory nerves transmit information to both the periphery and central nervous systems, and they mediate neurogenic inflammation by release of neurotransmitters, such as tachykinins, in the periphery. Because the effect of local anesthetics on neurogenic inflammation is a subject of controversy, we investigated the direct effect of local anesthetics on tachykininergic neurotransmission, comparing it with cholinergic neurotransmission in the rabbit iris sphincter muscle. Rabbit iris sphincter muscle is innervated by trigeminal tachykininergic and parasympathetic cholinergic nerves, and the electrical transmural stimulation produces tachykininergic and cholinergic contractions. Cocaine and lidocaine (1-300 microM) attenuated tachykininergic and cholinergic contractions induced by electrical transmural stimulation in concentration- and stimulus frequency-dependent manner. However, the sensitivity to both local anesthetics was slightly, but significantly, higher in tachykininergic than in cholinergic responses. Exogenous neurokinin A and carbachol produced contractions that were not inhibited by 100 microM of cocaine and lidocaine. These results show that local anesthetics have a direct inhibitory effect on tachykininergic neurotransmission of the trigeminal sensory nerve, and the effect on this nerve is more potent than on the parasympathetic nerve and suggests that local anesthetics may have antineurogenic inflammatory effects via the inhibitory effects on the peripheral transmission of primary sensory nerve.

Anesthetics, Local↗
PubMed2005

Reversed-phase liquid chromatographic retention and membrane activity relationships of local anesthetics.

The chromatographic retention and membrane activity relationships of local anesthetics were studied to address the possible mechanisms for structure specificity and inflammation-associated decrease of their effects. Five representative drugs (3 mM for each) were reacted with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine liposomes in 25 mM potassium phosphate buffer (pH 5.9-7.9, containing 100 mM NaCl and 0.1 mM EDTA) for 10 min at 37 degrees C and the membrane fluidity changes were analyzed by measuring fluorescence polarization with 1,6-diphenyl-1,3,5-hexatriene. Their capacity factors were determined on octadecyl-, octyl- and phenyl-bonded silica columns with a mobile phase consisting of 25 mM potassium phosphate buffer (pH 5.9-7.9, containing 100 mM NaCl and 0.1 mM EDTA)-methanol (30:70, v/v) at a flow rate of 1.0 ml/min and at a column temperature of 37 degrees C and diode-array detection. Mepivacaine, prilocaine, lidocaine, ropivacaine and bupivacaine fluidized membranes in increasing order of intensity, which agreed with their clinical potency. The relative degree of membrane fluidization correlated with that of retention on an octadecyl stationary phase more significantly than the other phases. Both membrane-fluidizing effects and capacity factors decreased by lowering the reaction and mobile phase pH, being consistent with the hypothesis that anesthetic potency is reduced in inflammation because of tissue acidity. Reversed-phase liquid chromatography appears to be useful for estimating the structure-specific and pH-dependent membrane-fluidizing effects of local anesthetics.

Anesthetics, Local↗
PubMed2004

Local anesthetics adsorbed onto infusion balloon.

We compared the adsorption of different local anesthetics onto infusion balloons and studied one of the possible mechanisms for adsorption. After injection of lidocaine, bupivacaine, ropivacaine, and mepivacaine solutions (1 mM each; pH 7.4) into balloons of 100-mL volume, their concentrations in effluents flowing out at 4 mL/h were determined over time by high-performance liquid chromatography. All were adsorbed in a structure-dependent manner, and the concentration decreased by 6%-14% within 5 min. Bupivacaine was most strongly adsorbed, followed by lidocaine, ropivacaine, and mepivacaine. QX-314, a quaternary ammonium derivative of lidocaine, was only weakly adsorbed compared with the parent compound lidocaine. The extent of adsorption of local anesthetics was related to their hydrophobicity (evaluated by reversed-phase chromatography) and was much more at pH 7.4 than at pH 6.0. A hydrophobic interaction with balloon materials appears to be responsible for the adsorption of local anesthetics. When infusion balloons are used for the continuous administration of local anesthetics, attention should be paid to the possibility that their actual concentrations in effluents are smaller than those present when they are initially prepared.

Adsorption↗
PubMed2003

Deactivation of norepinephrine by peroxynitrite as a new pathogenesis in the hypotension of septic shock.

BACKGROUND: Vascular hyporeactivity to catecholamines limits successful treatment of hypotension in septic shock. Large amounts of nitric oxide (NO) and superoxide anion (O(2)(-1).) are produced in response to bacterial endotoxins and/or inflammatory cytokines. NO reacts with O(2)(-1). to form the potentially toxic NO metabolite, peroxynitrite (ONOO(-1)). The purpose of this study was to investigate whether ONOO(-1) decreases the vasocontractile activity of norepinephrine. METHODS: Norepinephrine was treated with ONOO(-1) or 3-morpholinosydonimine-N-ethyl-carbamine (SIN-1; an ONOO(-1) producer) in a 5 x 10(-2) m sodium phosphate buffer solution at pH 7.4, and absorbance of the product was measured spectrophotometrically at 295 and 370 nm. Norepinephrine pretreated with ONOO(-1) was administered to isolated rat thoracic aortas to observe contractions in functional experiments. The rate constant between norepinephrine and ONOO(-1) was determined via a competition assay with cysteine in functional experiments. Norepinephrine pretreated with ONOO(-1) was injected intravenously into anesthetized rats to measure blood pressure. RESULTS: Norepinephrine pretreated with ONOO(-1) was confirmed spectrally as oxidized norepinephrine. Norepinephrine pretreated with ONOO(-1) decreased its vasocontractile force in an ONOO(-1) (10(-6), up to 3 x 10(-4) m) concentration-dependent manner (EC(50) = 5.1 x 10(-5) m). The decrease in its force was lower at pretreatment with ONOO(-1) in a lower pH buffer. A rate constant for the ONOO(-1)-norepinephrine reaction was 6 x 10(2) m/s. Norepinephrine (10(-7) m) incubated with SIN-1 (10(-3) m) decreased its vasocontractile force in an incubation time-dependent manner. Administration of norepinephrine pretreated with ONOO(-1) to anesthetized rats caused no significant change in arterial blood pressure. CONCLUSIONS: These results indicate that norepinephrine was oxidized and deactivated by ONOO(-1). This deactivation may, at least in part, account for the hyporeactivities of vasocontraction to norepinephrine in septic shock.

Anesthesia↗
PubMed2003

Peroxynitrite decreases dopamine's vasoconstrictive activity.

UNLABELLED: Peroxynitrite (ONOO(-1)) reacts with dopamine to form an oxidized derivative. To investigate the vasoconstrictive activity of this derivative, we performed functional examinations with dopamine treated with ONOO(-1) or 3-morpholinosydonimine-N-ethyl-carbamine (SIN-1; an ONOO(-1) producer) on isolated strips of rat thoracic aorta. To exclude the direct effect of ONOO(-1), the strips were pretreated with methylene blue, a guanylyl cyclase inhibitor. Dopamine induced concentration-dependent contraction, but dopamine pretreated with ONOO(-1) decreased the contraction in an ONOO(-1)-concentration-dependent manner. Both maximum contractions and 50% effective concentration values for dopamine-induced vasocontraction were significantly decreased by pretreatment with ONOO(-1). Dopamine incubated with SIN-1 also decreased the contraction, the decrease being dependent on the incubation time. ONOO(-1) formation is a favored reaction and occurs easily when cellular production of both nitric oxide and superoxide increases, as in septic shock. These results may, at least in part, account for dopamine's limitation as a vasoconstrictor in septic shock. IMPLICATIONS: Peroxynitrite (ONOO(-1)) reacts with dopamine to form an oxidized derivative. We investigated the vasoconstrictive activity of this derivative with functional examinations using rat thoracic aorta and found the activity decreased. As ONOO(-1) formation increases in septic shock, our results may account for dopamine's limitation as a vasoconstrictor in septic shock.

Animals↗
PubMed2002

Modification of alpha1 -adrenoceptors by peroxynitrite as a possible mechanism of systemic hypotension in sepsis.

OBJECTIVE: It is well known that nitric oxide synthase is induced by endotoxin or inflammatory cytokines, and consequently large amounts of nitric oxide cause vascular hyporeactivity to vasoconstrictor agents and myocardial dysfunction, hence hypotension. However, there is considerable controversy as to whether these pathologic cardiovascular features are mediated directly by nitric oxide or also through the formation of secondary reaction products such as peroxynitrite (ONOO-1). Our objective was to investigate inhibitory effects of ONOO-1 on alpha1-adrenoceptors. DESIGN: Prospective, controlled, in vitro, laboratory study. SETTING: Laboratory of a health sciences university. SUBJECTS: Chinese hamster ovary cells that expressed the human recombinant alpha1a-, alpha1b-, or alpha1d-adrenoceptors, rat aorta strips. INTERVENTIONS: Binding experiments of [3H]prazosin were done in the Chinese hamster ovary cell membranes pretreated with 100 microM to 3 mM ONOO-1. Displacement experiments with noradrenaline or 3-nitro-l-tyrosine also were conducted. Mobilization of intracellular Ca2+ evoked by 1 nM to 10 microM noradrenaline was monitored in a fluorescence spectrophotometer with dual excitation at 340 nm/380 nm and emission at 500 nm in fura-2/AM-loaded Chinese hamster ovary cells. Contractile force produced by noradrenaline was monitored in rat aorta strips that have alpha1a- and alpha1d-adrenoceptors, pretreated with 1 mM ONOO-1. Either 0.3 N NaOH or the decomposed ONOO-1 was used as the control. MEASUREMENTS AND MAIN RESULTS: The specific binding of [3H]prazosin to alpha1a- and alpha1d-adrenoceptor was inhibited by ONOO-1 in a concentration-dependent manner. We found that 3 mM ONOO-1 decreased maximum binding sites by 40% to 50% in alpha1a- and alpha1d-adrenoceptors. Binding affinities for prazosin and noradrenaline were not affected by 1 mM ONOO-1 in all subtypes. We found that 3-nitro-l-tyrosine did not affect the prazosin binding to three adrenoceptor subtypes. Noradrenaline increased intracellular Ca2+ concentration ([Ca2+]i) concentration-dependently, which was inhibited by ONOO-1 in alpha1a- and alpha1d-adrenoceptors. ONOO-1 had no effect on alpha1b-adrenoceptor. Contractile force produced by noradrenaline decreased significantly in aorta strips pretreated with ONOO-1. CONCLUSION: ONOO-1 reduces the binding capacity of alpha1a- and alpha1d- but not alpha1b-adrenoceptors without changing the affinities. Treatment with ONOO-1 attenuates noradrenaline-stimulated increase in [Ca2+]i in alpha1a- and alpha1d-adrenoceptors but not in alpha1b-adrenoceptor. ONOO-1 also weakens noradrenaline-induced contractions in rat aorta that has alpha1a- and alpha1d-adrenoceptors. Cardiovascular hyporeactivity to catecholamines in septic shock may be caused in part by the inactivation of alpha-adrenoceptors by ONOO-1.

Adrenergic alpha-Antagonists↗