Yoshiki Kimoto

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.

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.

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.

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.

Lidocaine Impairs Vasodilation Mediated by Adenosine Triphosphate-sensitive K+ Channels but Not by Inward Rectifier K+ Channels in Rat Cerebral Microvessels

Vasodilator effects of adenosine triphosphate (ATP)-sensitive, as well as inward rectifier, K+ channel openers have not been well demonstrated in cerebral microvessels. Although lidocaine impairs vasorelaxation via ATP-sensitive K+ channels in the rat aorta, the effects of this compound on K+ channels in the cerebral circulation have not been shown. We designed the present study to examine whether ATP-sensitive and inward rectifier K+ channels contribute to vasodilator responses in cerebral microvessels and whether the vasodilation mediated by these channels is inhibited by lidocaine. Rat brain slices were monitored using a computer-assisted videomicroscopy. Cerebral parenchymal arterioles (diameter, 5–10 μm) were contracted with prostaglandin F2&agr;, and thereafter potassium chloride (KCl), levcromakalim, or sodium nitroprusside was added to the perfusion chamber. Levcromakalim and KCl produced vasodilation of the cerebral parenchymal arterioles, which was abolished by an ATP-sensitive K+ channel antagonist, glibenclamide, or an inward rectifier K+ channel antagonist, barium chloride, respectively. Lidocaine (10−5 to 3 × 10−5 M) inhibited the dilation produced by levcromakalim but not by KCl or sodium nitroprusside. In parenchymal arterioles of the cerebral cortex, lidocaine seems to reduce vasodilation mediated by ATP-sensitive K+ channels but not by inward rectifier K+ channels.

Inhibitory Effects of Lidocaine and Mexiletine on Vasorelaxation Mediated by Adenosine Triphosphate–sensitive K+Channels and the Role of Kinases in the Porcine Coronary Artery

Background:Effects of antiarrhythmic drugs on coronary vasodilation mediated by K+ channels have not been studied. Modulator roles of protein kinase C and tyrosine kinase in the activity of K+ channels have also been unclear in the coronary artery. The current study examined whether lidocaine and mexiletine in the porcine coronary artery modify the vasorelaxation mediated by adenosine triphosphate–sensitive K+ channels via activation of protein kinase C and tyrosine kinase. Methods:Porcine coronary arteries without endothelium were suspended for isometric force recording, and vasorelaxation to levcromakalim (10−8 to 10−5 m) was obtained. Changes in membrane potentials produced by levcromakalim (10−5 m) were also recorded. Results:Glibenclamide completely abolished vasorelaxation as well as hyperpolarization in response to levcromakalim. Lidocaine and mexiletine significantly reduced these responses. Calphostin C, Gö 6976, genistein, and erbstatin A partly restored vasorelaxation or hyperpolarization in response to levcromakalim in arteries treated with mexiletine but not in those with lidocaine, whereas these inhibitors did not alter the vasorelaxation to levcromakalim. Phorbol 12-myristate 13-acetate produced reduction of vasorelaxation in response to levcromakalim, which is recovered by calphostin C or Gö 6976. Conclusions:Therefore, lidocaine and mexiletine inhibit vasorelaxation mediated by the activation of adenosine triphosphate–sensitive K+ channels in the coronary artery. Protein kinase C and tyrosine kinase seem to have roles in the inhibitory effect of mexiletine but not in that of lidocaine. Class Ib antiarrhythmic drugs may reduce coronary vasodilation mediated by adenosine triphosphate–sensitive K+ channels via the differential modulator effects on these kinases.

The Role of K Channels in Vasorelaxation Induced by Hypoxia and the Modulator Effects of Lidocaine in the Rat Carotid Artery

Hypoxia induces vasodilation, partly via the activation of K+ channels. Lidocaine impairs vasorelaxation mediated by a K+ channel opener, suggesting that this antiarrhythmic drug may inhibit hypoxia-induced vasodilation mediated by K+ channels. We designed the current study to determine whether, in the carotid artery, K+ channels contribute to vasorelaxation in response to hypoxia and whether lidocaine modulates vasorelaxation induced by K+ channels via pathophysiological and pharmacological stimuli. Rings of rat common carotid artery without endothelium were suspended for isometric force recording. During contraction to phenylephrine, hypoxia-induced vasorelaxation or concentration-response to an adenosine triphosphate-sensitive K+ channel opener was obtained changing control gas to hypoxic gas and the cumulative addition of levcromakalim, respectively. Hypoxia-induced vasorelaxation was significantly reduced by glibenclamide (5 &mgr;M) but not by iberiotoxin (0.1 &mgr;M), apamin (0.1 &mgr;M), BaCl2 (10 &mgr;M), or 4-aminopyridine (1 mM). Levcromakalim-induced vasorelaxation was completely abolished by glibenclamide. Lidocaine (10–100 &mgr;M) concentration-dependently inhibited this vasodilation, whereas it did not affect hypoxia-induced vasodilation. These results suggest that adenosine triphosphate-sensitive K+ channels play a role in hypoxia-induced vasodilation in the rat carotid artery and that lidocaine differentially modulates vasodilation via these channels activated by pathophysiological and pharmacological stimuli.