Katsutoshi Nakahata

Mild Hypercapnia Induces Vasodilation via Adenosine Triphosphate-sensitive K Channels in Parenchymal Microvessels of the Rat Cerebral Cortex

Background Carbon dioxide is an important vasodilator of cerebral blood vessels. Cerebral vasodilation mediated by adenosine triphosphate (ATP)-sensitive K+ channels has not been demonstrated in precapillary microvessel levels. Therefore, the current study was designed to examine whether ATP-sensitive K+ channels play a role in vasodilation induced by mild hypercapnia in precapillary arterioles of the rat cerebral cortex. Methods Brain slices from rat cerebral cortex were prepared and superfused with artificial cerebrospinal fluid, including normal (Pco2 = 40 mmHg; pH = 7.4), hypercapnic (Pco2 = 50 mmHg; pH = 7.3), and hypercapnic normal pH (Pco2 = 50 mmHg; pH = 7.4) solutions. The ID of a cerebral parenchymal arteriole (5–9.5 &mgr;m) was monitored using computerized videomicroscopy. Results During contraction to prostaglandin F2&agr; (5 × 10−7 m), hypercapnia, but not hypercapnia under normal pH, induced marked vasodilation, which was completely abolished by the selective ATP-sensitive K+ channel antagonist glibenclamide (5 × 10−6 m). However, the selective Ca2+-dependent K+ channel antagonist iberiotoxin (10−7 m) as well as the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (10−4 m) did not alter vasodilation. A selective ATP-sensitive K+ channel opener, levcromakalim (3 × 10−8 to 3 × 10−7 m), induced vasodilation, whereas this vasodilation was abolished by glibenclamide. Conclusion These results suggest that in parenchymal microvessels of the rat cerebral cortex, decreased pH corresponding with hypercapnia, but not hypercapnia itself, contributes to cerebral vasodilation produced by carbon dioxide and that ATP-sensitive K+ channels play a major role in vasodilator responses produced by mild hypercapnia.

Landiolol attenuates tachycardia in response to endotracheal intubation without affecting blood pressure

PURPOSE Beta-adrenergic receptor antagonists (beta-antagonists) have long been used to control perioperative tachyarrhythmias. The effects of a beta(1)-antagonist, landiolol, on perioperative hemodynamics are unknown. We aimed to determine the appropriate dosage of landiolol for the treatment of hemodynamic changes in response to endotracheal intubation. METHODS Sixty-four patients without heart disease or hypertension, were assigned to receive saline (group C) or landiolol (0.1 or 0.3 mg.kg(-1); groups L1 and L3). Anesthesia was induced with propofol (2 mg.kg(-1) iv) followed by saline or landiolol iv. After ventilation with facemask using 2% sevoflurane in 100% oxygen for 90 sec, endotracheal intubation was performed. After intubation, anesthesia was maintained using 1% sevoflurane in combination with 50% nitrous oxide. Values of heart rate and mean arterial blood pressure were recorded before induction to five minutes after intubation. RESULTS In group C, heart rate and mean blood pressure increased simultaneously after tracheal intubation, compared with baseline values. Heart rate values were attenuated immediately before as well as after intubation in group L3, compared with groups C and L1. Heart rate did not increase after tracheal intubation in group L1, compared with baseline. In contrast, mean arterial blood pressure values did not differ among groups. CONCLUSIONS The newly developed beta(1)-antagonist landiolol (0.1 and 0.3 mg.kg(-1)) may help prevent tachycardia without affecting blood pressure during the induction of anesthesia.PurposeBeta-adrenergic receptor antagonists (ß-antagonists) have long been used to control perioperative tachyarrhythmias. The effects of a ß1-antagonist, landiolol, on perioperative hemodynamics are unknown. We aimed to determine the appropriate dosage of landiolol for the treatment of hemodynamic changes in response to endotracheal intubation.MethodsSixty-four patients without heart disease or hypertension, were assigned to receive saline (group C) or landiolol (0.1 or 0.3 mg kg-1; groups L1 andL3). Anesthesia was induced with propofol (2 mg kg-1iv) followed by saline or landiololiv. After ventilation with facemask using 2% sevoflurane in 100% oxygen for 90 sec, endotracheal intubation was performed. After intubation, anesthesia was maintained using 1 % sevoflurane in combination with 50% nitrous oxide. Values of heart rate and mean arterial blood pressure were recorded before induction to five minutes after intubation.ResultsIn group C, heart rate and mean blood pressure increased simultaneously after tracheal intubation, compared with baseline values. Heart rate values were attenuated immediately before as well as after intubation in groupL3, compared with groups C and L1. Heart rate did not increase after tracheal intubation in group L1, compared with baseline. In contrast, mean arterial blood pressure values did not differ among groups.ConclusionsThe newly developed ß1-antagonist landiolol (0.1 and 0.3 mg·kg-1) may help prevent tachycardia without affecting blood pressure during the induction of anesthesia.RésuméObjectifLes antagonistes des récepteurs bêta-adrénergiques (ßantagonistes) ont été longtemps utilisés pour contrôler les tachyarythmies périopératoires. Les effets d’un ß 1-antagoniste, le landiolol, sur ïhémodynamique périopératoire sont inconnus. Nous voulions déterminer le dosage approprié de landiolol pour traiter les changements hémodynamiques provoqués par l’intubation endotrachéale.MéthodeSoixante-quatre patients sans cardiopathie, ni hypertension, ont reçu une solution saline (group C) ou du landiolol (0,1 ou 0,3 mg·kg-1; groupes L1 et L3). L’anesthésie a été induite avec du propofol (2 mg·kg-1 iv) suivi de la solution saline ou du landiolol iv. Après ventilation au masque, avec du sévoflurane à 2 % dans de l’oxygène à 100 pendant 90 s, l’intubation endotrachéale a été réalisée. Puis, l’anesthésie a été maintenue avec du sévoflurane à 1 % combiné à du protoxyde d’azote à 50 %. La fréquence cardiaque et la tension artérielle moyenne ont été enregistrées avant l’induction et jusqu’à cinq minutes après l’intubation.RésultatsDans le groupe C, la fréquence cardiaque et la tension artérielle moyenne ont augmenté simultanément après l’intubation endotrachéale, par rapport aux valeurs de base. La fréquence cardiaque a baissé immédiatement avant et après l’intubation dans le groupe L3 comparé aux groupes C et L1. La fréquence cardiaque n’a pas augmenté, sur les mesures de base, après l’intubation endotrachéale dans le groupe L1. Les valeurs de la tension artérielle moyenne étaient comparables entre les groupes. as]Conclusion p ]Le nouveau ß 1-antagoniste landiolol (0,1 et 0,3 mg·kg-1) peut aider à prévenir la tachycardie sans affecter la tension artérielle pendant l’induction de l’anesthésie.

Vasodilation mediated by inward rectifier K+ channels in cerebral microvessels of hypertensive and normotensive rats

Although inward rectifier K+ channels contribute to the regulation of cerebral circulation, dilation of cerebral microvasculature mediated by these channels has not been demonstrated in chronic hypertension. We designed the present study to examine the roles of inward rectifier K+ channels in the vasodilation produced by increased levels of extracellular K+ in cerebral parenchymal arterioles from hypertensive and normotensive rats. During constriction to prostaglandin F2&agr; (5 × 10−7 M), the arterioles within brain slices were evaluated using computer-assisted microscopy. Potassium chloride (KCl) induced vasodilation in cerebral arterioles from normotensive (5–10 mM) and hypertensive (5–15 mM) rats, whereas an inward rectifier K+ channel antagonist barium chloride (BaCl2; 10−5 M) completely abolished the vasodilation in both strains. In arterioles of hypertensive rats, vasodilator responses to KCl were augmented compared with those in normotensive rats. In contrast, the vasodilator responses induced by sodium nitroprusside (3 × 10−8 to 3 × 10−6 M) in these two strains were similar. These results suggest that in cerebral cortex parenchymal microvessels, inward rectifier K+ channels play a crucial role in vasodilation produced by extracellular K+ and that the dilation of cerebral arterioles via these channels is augmented in chronic hypertension.

Inhibitory Effect of High Concentration of Glucose on Relaxations to Activation of ATP-Sensitive K+ Channels in Human Omental Artery

Objective—The present study was designed to examine in the human omental artery whether high concentrations of D-glucose inhibit the activity of ATP-sensitive K+ channels in the vascular smooth muscle and whether this inhibitory effect is mediated by the production of superoxide. Methods and Results—Human omental arteries without endothelium were suspended for isometric force recording. Changes in membrane potentials were recorded and production of superoxide was evaluated. Glibenclamide abolished vasorelaxation and hyperpolarization in response to levcromakalim. D-glucose (10 to 20 mmol/L) but not l-glucose (20 mmol/L) reduced these vasorelaxation and hyperpolarization. Tiron and diphenyleneiodonium, but not catalase, restored vasorelaxation and hyperpolarization in response to levcromakalim in arteries treated with D-glucose. Calphostin C and Gö6976 simultaneously recovered these vasorelaxation and hyperpolarization in arteries treated with D-glucose. Phorbol 12-myristate 13 acetate (PMA) inhibited the vasorelaxation and hyperpolarization, which are recovered by calphostin C as well as Gö6976. D-glucose and PMA, but not l-glucose, significantly increased superoxide production from the arteries, whereas such increased production was reversed by Tiron. Conclusions—These results suggest that in the human visceral artery, acute hyperglycemia modulates vasodilation mediated by ATP-sensitive K+ channels via the production of superoxide possibly mediated by the activation of protein kinase C.

Roles of Phosphatidylinositol 3-Kinase-Akt and NADPH Oxidase in Adenosine 5′-Triphosphate–Sensitive K+ Channel Function Impaired by High Glucose in the Human Artery

The present study was designed to examine roles of the phosphatidylinositol 3-kinase-Akt pathway and reduced nicotinamide-adenine dinucleotide phosphate oxidases in the reduced ATP-sensitive K+ channel function via superoxide produced by high glucose in the human artery. We evaluated the activity of the phosphatidylinositol 3-kinase-Akt pathway, as well as reduced nicotinamide-adenine dinucleotide phosphate oxidases, the intracellular levels of superoxide and ATP-sensitive K+ channel function in the human omental artery without endothelium. Levels of the p85-α subunit and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits, including p47phox, p22phox, and Rac-1, increased in the membrane fraction from arteries treated with d-glucose (20 mmol/L) accompanied by increased intracellular superoxide production. High glucose simultaneously augmented Akt phosphorylation at Ser 473, as well as Thr 308 in the human vascular smooth muscle cells. A phosphatidylinositol 3-kinase inhibitor LY294002, as well as tiron and apocynin, restored vasorelaxation and hyperpolarization in response to an ATP-sensitive K+ channel opener levcromakalim. Therefore, it can be concluded that the activation of the phosphatidylinositol 3-kinase-Akt pathway, in combination with the translocation of p47phox, p22phox, and Rac-1, contributes to the superoxide production induced by high glucose, resulting in the impairment of ATP-sensitive K+ channel function in the human visceral artery.

Propofol Restores Brain Microvascular Function Impaired by High Glucose via the Decrease in Oxidative Stress

Background:Vascular dysfunction induced by hyperglycemia has not been studied in cerebral parenchymal circulation. The current study was designed to examine whether high glucose impairs dilation of cerebral parenchymal arterioles via nitric oxide synthase, and whether propofol recovers this vasodilation by reducing superoxide levels in the brain. Methods:Cerebral parenchymal arterioles in the rat brain slices were monitored using computer-assisted videomicroscopy. Vasodilation induced by acetylcholine (10−6 to 10−4 m) was obtained after the incubation of brain slices for 60 min with any addition of l-glucose (20 mm), d-glucose (20 mm), or propofol (3 × 10−7 or 10−6 m) in combination with d-glucose (20 mm). Superoxide production in the brain slice was determined by dihydroethidium (2 × 10−6 m) fluorescence. Results:Addition of d-glucose, but not l-glucose, reduced arteriolar dilation by acetylcholine, whereas the dilation was abolished by the neuronal nitric oxide synthase inhibitor S-methyl-l-thiocitrulline (10−5 m). Both propofol and the superoxide dismutase mimetic Tempol (10−4 m) restored the arteriolar dilation in response to acetylcholine in the brain slice treated with d-glucose. Addition of d-glucose increased superoxide production in the brain slice, whereas propofol, Tempol, and the nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase inhibitor apocynin (1 mm) similarly inhibited it. Conclusions:Clinically relevant concentrations of propofol ameliorate neuronal nitric oxide synthase–dependent dilation impaired by high glucose in the cerebral parenchymal arterioles via the effect on superoxide levels. Propofol may be protective against cerebral microvascular malfunction resulting from oxidative stress by acute hyperglycemia.

Synthetic peroxisome proliferator-activated receptor-gamma agonists restore impaired vasorelaxation via ATP-sensitive K+ channels by high glucose.

The present study was designed to examine whether in the human artery, synthetic peroxisome proliferator-activated receptor (PPAR)-γ agonists restore vasorelaxation as well as hyperpolarization via ATP-sensitive K+ channels impaired by the high concentration of d-glucose and whether the restoration may be mediated by the antioxidant capacity of these agents. The isometric force and membrane potential of human omental arteries without endothelium were recorded. The production rate of superoxide was evaluated using a superoxide-generating system with xanthine-xanthine oxidase in the absence of smooth muscle cells. Glibenclamide abolished vasorelaxation and hyperpolarization in response to levcromakalim. Addition of d-glucose (20 mM) but not l-glucose (20 mM) reduced this vasorelaxation and hyperpolarization. Synthetic PPAR-γ agonists (troglitazone and rosiglitazone) and/or an inhibitor of superoxide generation (4,5-dihydroxy-1,3-benzene-disulfonic acid, Tiron), but not a PPAR-α agonist (fenofibrate), restored vasorelaxation and hyperpolarization in response to levcromakalim in arteries treated with d-glucose. Troglitazone and rosiglitazone, but not fenofibrate, decreased the production rate of superoxide without affecting uric acid generation. These findings suggest that synthetic PPAR-γ agonists recover the function of ATP-sensitive K+ channels reduced by the high concentration of glucose in human vascular smooth muscle cells and that the effect of these agonists may be mediated in part by their antioxidant capacity.

Effects of bupivacaine enantiomers and ropivacaine on vasorelaxation mediated by adenosine triphosphate-sensitive K(+) channels in the rat aorta.

THE blockade of the ganglion impar, a single ganglion converged by the caudal ends of the two sympathetic trunks, has been described to relieve the intractable perineal pain of sympathetic origin in patients with rectal, anal, colon, bladder, or cervical cancer. The success rate of this method depends on the anatomical variability of the location of the ganglion, but its location has been variably reported from the anterior to the sacrococcygeal joint or the coccyx, to the tip of the coccyx. Accordingly, this study was performed to identify the location of the ganglion impar and to determine its shape and size and its topographic relation with the branch of the sacral nerve, in the hope that this might facilitate a more successful blockade of the ganglion.

Ketamine stereoselectively affects vasorelaxation mediated by ATP-sensitive K(+) channels in the rat aorta.

Background The effect of ketamine on vasodilation mediated by adenosine triphosphate (ATP)-sensitive K+ channels has not been studied. The present study was designed to determine whether ketamine might stereoselectively affect vasorelaxation induced by an ATP-sensitive K+ channel opener in the isolated rat aorta. Methods Rings of the rat aorta with or without endothelium were suspended for isometric force recording. During contraction to phenylephrine (3 × 10−7 m), vasorelaxation in response to an ATP-sensitive K+ channel opener levcromakalim (10−8 to 10−5 m) or a nitric oxide donor sodium nitroprusside (10−10 to 10−5 m) was obtained. Glibenclamide (10−5 m), S(+) ketamine (10−4 m), or ketamine racemate (10−5 to 10−4 m) was applied 15 min before addition of phenylephrine. Results Vasorelaxation induced by levcromakalim was completely abolished by an ATP-sensitive K+ channel antagonist glibenclamide (10−5 m) in the aorta with or without endothelium. Ketamine racemate (3 × 10−5 to 10−4 m) significantly inhibited this vasorelaxation in a concentration-dependent fashion, whereas S(+) ketamine did not affect the relaxation. However, the highest concentration of ketamine racemate and S(+) ketamine used in the present study did not alter vasorelaxation in response to sodium nitroprusside in the aorta without endothelium. Conclusion In the isolated rat aorta, clinically relevant concentrations of ketamine racemate can inhibit relaxation induced by an ATP-sensitive K+ channel opener, whereas S(+) ketamine did not produce any inhibitory effect on this vasorelaxation. These results suggest that ketamine stereoselectively alters vasodilation via ATP-sensitive K+ channels in the conduit artery.

Roles of neuronal nitric oxide synthase, oxidative stress, and propofol in N-methyl-d-aspartate-induced dilatation of cerebral arterioles

BACKGROUND It remains unclear whether N-methyl-D-aspartate (NMDA) receptors contribute to cerebral parenchymal vasodilatation, and any effects of clinically used anaesthetics on the dilatation. The present study was designed to examine whether NMDA induces neuronal nitric oxide synthase (NOS)-mediated dilatation, in the cerebral parenchymal arterioles, and whether propofol and superoxide modulate the dilatation in relation to the NMDA receptor activation. METHODS The cerebral parenchymal arterioles within rat brain slices were monitored by a computer-assisted microscopy, and the vasodilatation in response to NMDA (10(-7) to 10(-5) M) was evaluated. Immunofluorescence analysis to neuronal and endothelial NOS and measurement of levels of superoxide and nitric oxide within the arteriole were simultaneously performed. RESULTS Propofol, an NMDA receptor antagonist MK801, and a neuronal NOS antagonist S-methyl-l-thiocitrulline (SMTC) reduced NMDA-induced dilation, whereas a superoxide inhibitor, Tiron, and NADPH oxidase inhibitor, gp91ds-tat, augmented NMDA-induced dilatation. Immunofluorescence analysis revealed distribution of neuronal NOS in both endothelial and smooth muscle cells in addition to neuronal cells. NMDA-induced superoxide and nitric oxide within the parenchymal arterioles. The increased superoxide within the arteriole was similarly inhibited by MK801, SMTC, gp91ds-tat, propofol, and a neuronal NOS antagonist vinyl-l-NIO, whereas the level of nitric oxide was reduced by MK801, SMTC, propofol, and vinyl-l-NIO, and it was augmented by gp91ds-tat. CONCLUSIONS NMDA dilates cerebral parenchymal arterioles possibly via neuronal NOS activation, whereas it produces superoxide via NADPH oxidase. In these arterioles, propofol reduces both the dilatation and superoxide production in response to NMDA.