Hiroshi Iranami

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.

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.

A beta-adrenoceptor agonist evokes a nitric oxide-cGMP relaxation mechanism modulated by adenylyl cyclase in rat aorta : Halothane does not inhibit this mechanism

Background The objective of this study was to characterize the effects of halothane on the agonist-induced nitric oxide-cyclic GMP (NO-cGMP) mechanisms by comparing the intracellular signal transduction mediating isoproterenol- and acetylcholine-induced nitric oxide formation. Methods Isoproterenol-induced relaxations of rat aortic rings with and without endothelia were examined in the absence and presence of halothane. Studies were also done in the presence of inhibitors of nitric oxide-synthase, adenylyl cyclase, calmodulin, protein kinase A, and intracellular Calcium2+ release mechanism. The relaxations under some of these conditions were compared with those induced by acetylcholine. Cyclic nucleotide contents of the rings were also measured. Results Isoproterenol relaxed aortic rings via the endothelium-dependent nitric oxide-cyclic GMP mechanism. Inhibition of adenylyl cyclase or of protein kinase A attenuated the isoproterenol-induced relaxations significantly but did not affect those induced by acetylcholine. Inhibition of intracellular Calcium2+ release abolished the acetylcholine-induced relaxations but did not affect those induced by isoproterenol. Calmodulin inhibition attenuated both agonist-induced relaxations significantly. Unlike acetylcholine-induced relaxation, that induced by isoproterenol was not affected by halothane. Isoproterenol increased both the cyclic adenosine monophosphate and cGMP contents of rings significantly when endothelia were intact. Inhibition of nitric oxide synthase attenuated the isoproterenol-induced cGMP content increases significantly but did not affect the cyclic adenosine monophosphate content increases. Halothane (2%) did not affect isoproterenol-induced increases in nucleotide content. Conclusions Isoproterenol-induced nitric oxide formation requires the activation of constitutive nitric oxide synthase, but the Calcium sup 2+ release mechanism is not involved in activating this enzyme. Halothane can inhibit the nitric oxide-cyclic GMP mechanism only when Calcium2+ release is greatly involved in the activation of constitutive nitric oxide synthase.

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.

Fentanyl added to propofol anesthesia elongates sinus node recovery time in pediatric patients with paroxysmal supraventricular tachycardia.

BACKGROUND: In some types of pediatric supraventricular tachycardia, reentrant mechanisms are sensitive to enhanced vagal tone. Propofol is a feasible anesthetic for pediatric electrophysiological study and radiofrequency catheter ablation. Although fentanyl and propofol infusions both enhance cardiac vagal tone, it is unclear whether the combination of propofol and fentanyl has a potential to enhance it. In this study, we evaluated the hypothesis that fentanyl combined with propofol could alter cardiac electrophysiological activities in pediatric patients undergoing electrophysiological study and radiofrequency catheter ablation. METHODS: Twenty-seven pediatric patients (9 Wolff-Parkinson-White syndrome, 7 concealed accessory pathway and 11 atrioventricular nodal reentry tachycardia) were enrolled in this study. Anesthesia was induced with propofol 2.0 mg/kg and was maintained with a continuous infusion of propofol at a rate of 100–167 &mgr;g · kg−1 · min−1. During a stable anesthetic state, the calculated sinoatrial conduction time and corrected sinus node recovery time (CSNRT) were measured before and after fentanyl administration. The fentanyl dose consisted of an initial 2.0 &mgr;g/kg IV bolus and subsequent continuous infusion of 0.075 &mgr;g · kg−1 · min−1. RESULTS: Bispectral Index scores and systemic blood pressure remained unchanged throughout the examinations. Fentanyl administration significantly prolonged CSNRT (P = 0.005) but not calculated sinoatrial conduction time (P = 0.35). CONCLUSION: Since an enhanced cardiac vagal tone is one of the causative factors for prolonged CSNRT, our findings greatly support the hypothesis that fentanyl combined with propofol has a potential to enhance cardiac vagal tone.

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.

Mild Alkalinization and Acidification Differentially Modify the Effects of Lidocaine or Mexiletine on Vasorelaxation Mediated by ATP-sensitive K+Channels

BackgroundThe previous study by the authors showed that the class Ib antiarrhythmic drug lidocaine impairs but mexiletine augments vasorelaxation mediated by adenosine triphosphate–sensitive K+ channels. Lidocaine and mexiletine have different values of the negative logarithm of the drug-proton dissociation constant, indicating that the ion channel–blocking effects of these drugs under different pH levels may vary. However, the role of pH in the effects of lidocaine and mexiletine on vasodilation mediated by K+ channels has not been studied. Therefore, the current study was designed to examine whether the inhibition and augmentation of vasorelaxation in response to an adenosine triphosphate–sensitive K+ channel opener, levcromakalim, by the clinically relevant concentrations of lidocaine or mexiletine are modified by mild alkalinization or acidification in the isolated rat aorta. MethodsRings of the rat aorta without endothelium were suspended for isometric force recording. Three types of modified Krebs-Ringer solutions (pH 7.2, 7.4, and 7.6) were prepared by changing the composition of NaCl and NaHCO3. During contractions in response to phenylephrine (3 × 10−7 m), relaxations in response to levcromakalim (10−8 to 10−5 m) were obtained. Lidocaine (10−5 to 10−4 m), mexiletine (10−5 to 10−4 m), or glibenclamide (10−5 m) was applied 15 min before addition of phenylephrine. ResultsRelaxations in response to levcromakalim, which are abolished by the selective adenosine triphosphate–sensitive K+ channel antagonist glibenclamide (10−5 m), were not different among the three pH groups. In the normal Krebs-Ringer solution of pH 7.4, lidocaine significantly reduced these relaxations in a concentration-dependent fashion. Alkalinization of pH 7.6 augmented the inhibitory effect of lidocaine on these relaxations, whereas acidification of pH 7.2 substantially abolished this effect. In contrast, mexiletine pH independently augmented relaxations in response to levcromakalim. Glibenclamide (10−5 m) abolished these relaxations in arteries treated with mexiletine (10−4 m) in any pH group. ConclusionsThese results suggest that even under conditions of such mild alkalosis or acidosis, vasorelaxation via adenosine triphosphate–sensitive K+ channels is dependent on pH in the presence of clinically relevant concentrations of lidocaine but not mexiletine.

High-dose remifentanil suppresses sinoatrial conduction and sinus node automaticity in pediatric patients under propofol-based anesthesia.

BACKGROUND: We sought to determine the effect of remifentanil on sinus node function and the atrial-His (AH) interval in pediatric patients undergoing radiofrequency catheter ablation. METHODS: Sixty pediatric patients with Wolff-Parkinson-White syndrome were prospectively enrolled in this study. General anesthesia was induced and maintained with a continuous infusion of propofol. We recorded the calculated sinoatrial conduction time (CSACT), corrected sinus node recovery time (CSNRT), and AH interval when the patients were in a stable anesthetic state and compared the values before and during remifentanil administration at a moderate dose (0.2 &mgr;g · kg−1 · min−1) or a high dose (0.4 &mgr;g · kg−1 · min−1). Data are expressed as mean (95% confidence interval). RESULTS: At the moderate dose, remifentanil prolonged CSNRT (from 177 [117–237] milliseconds to 245 [167–322] milliseconds after administration; P = 0.016), but had no effect on either CSACT (P = 0.59) or AH interval (P = 0.11). However, high-dose remifentanil prolonged both CSNRT (from 201 [144–260] milliseconds to 307 [232–382] milliseconds after administration; P = 0.019) and CSACT (from 48 [31–65] milliseconds to 78 [59–96] milliseconds after administration; P = 0.038), but had no effect on the AH interval (P = 0.058). The interaction in CSNRT between remifentanil administration and its dose was not different (P = 0.44). CONCLUSION: Remifentanil may inhibit both intraatrial conduction and sinus node automaticity, but it has no effect on conduction through the atrioventricular node. Dose dependency was not observed within the range of 0.2 to 0.4 &mgr;g · kg−1 · min−1 of remifentanil.

Halothane inhibition of acetylcholine-induced relaxation in rat mesenteric artery and aorta.

PurposeT1he effect of halothane was compared on acetylcholine (ACh)-induced relaxation of the mesentenc artery and the aorta in ratsMethodsThe responses of isolated rat aortic and mesentenc artenal nng segments precontracted with phenylephnne to ACh (10−8– 10−5M), in the presence of halothane 0–3%. were compared using isometric force tension recordings. Effects of NG -nitro-l-arginine (L-NOARG, 3 × 10−5), methylene blue (MB, 5 × 10−6 M), oxyhaemoglobin (OxyHB, 10−7 M), and vanous potassium channel inhibitors; tetraethylammonium (TEA, 10−5 M. 10−3 M), apamin (AP, 10−7 M), charybdotoxin (ChTx, 10−7M) and glibenclamide (GC, 10−5M) on ACh-induced relaxation in mesentenc artery were tested. Using radioimmunoassay, ACh (10−6M)-induced guanosine 3′:5′-cyclic monophosphate (cGMP) accumulation of mesentenc arterial rings pretreated with L-NAORG were also measured.ResultsL-NOARG partially inhibited ACh-induced relaxation in mesentenc arterial rings (P < 0.05. maximum relaxation reduced by approximately 50%), whereas it abolished them in aortic rings. The remaining relaxation resistant to L-NOARG in mesentenc artenal rings was insensitive to additional MB or OxyHB, and was not accompanied by increases in cGMP contents of rings. Halothane inhibited endothelium-dependent relaxation in aorta and mesentenc artenal rings. This inhibitory effect was larger in aorta. Halothane also inhibited NO independent EDHF-dependent relaxation in the mesentenc arterial rings.ConclusionDespite a similar inhibitory effect on the EDHF relaxing pathway, halothane has a larger effect on endothelium-dependent relaxation in the aorta (NO dependent mainly) than in the mesenteric rings (NO and EDHF dependent).RésuméObjectifComparer sur l’artère mésenténque et sur l’aorte du rat l’influence de l’halothane sur la vasodilatation induite par l’acétylcholine (ACh).MéthodesOn a comparé les réactions d’anneaux arténels isolés de segments d’aorte et d’artère mésentérique préalablement contractés avec de la phényléphnne à l’ACh (10−8–10−5M), en présence d’halothane à 0 à 3% sur des enregistrements de la force de la tension isométrique. On a vérifié les effets de la NG-nitro-l-arginine (L-NOARG, 3 × 10−5 M), du bleu de méthylène (MB. 5 × 10−6 M), de l’oxyhémoglobine (OxyHB, 10−7 M) et de plusieurs inhibiteurs des canaux potassiques: le tétraéthylammonium (TEA, 10−5M, 10−3 M), l’apamine (AP, 10−7M), la charybdotoxine (ChTx, 10−7 M) et le glibenclamide (GC, 10−5M) sur la vasodilatation de l’artère mésentérique induite par l’ACh. Le radioxmmunodosage a servi en outre à mesurer l’accumulation de guanosine 3′:′5 — monophosphatase cyclique (cGMP) dans les anneaux arténels mésentériques prétraités à la L-NOARG.RésultatsLa L-NOARG n’abolissart que partiellement la vasodilatation des anneaux arténels mésentériques induite par l’ACh (P < 0,05. réduction de la dilatation maximale d’environ 50%) alors qu’elle abolissait celle des anneaux aortiques. La vasodilatation résiduelle L-NOARG-résistante des anneaux artériels mésentériques ne réagissait pas à l’ajout de MB ou d’OxyHB et ne s’accompagnait pas d’une augmentation du contenu en cGMP des anneaux. L’inhibition par l’halothane de la vasodilatation endothélium-dépendante des anneaux aortiques et artériels mésentériques était plus importante dans l’aorte. L’halothane inhibait aussi la vasodilatation NO-indépendante EDHP-dépendante des anneaux mésentériques.ConclusionMalgré des effets inhibiteurs similaires sur les voies de la vasodilation EDHF, l’halothane a un effet plus prononcé sur la vasodilatation endothélium-dépendante au niveau de l’aorte (principalement NO-dépendante) qu’au niveau des anneaux mésentériques (NO-et EDHF-dépendante).