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 microm) was monitored using computerized videomicroscopy. Results During contraction to prostaglandin F2alpha (5 x 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 x 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 x 10(-8) to 3 x 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.

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 x 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 x 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 ATP-sensitive K(+) channels in the conduit artery.

Background Inducible nitric oxide synthase (iNOS) is induced by endotoxin or cytokines, such as interleukin (IL)-1, through a protein synthesis pathway. Halothane reportedly inhibits protein synthesis in various tissues. The aim of the current study was to examine the effect of halothane on the IL-1beta-evoked induction of NOS in vascular smooth muscle. Methods After removal of the endothelium, arterial rings of rat aorta were mounted in an isometric force recording system. The effects of halothane (1.0-3.0%) or isoflurane (3.0%) on IL-1beta (20 ng/ml)-induced inhibition of the contractile responses to KCl (30 mM) and phenylephrine (10(-9)-10(-5) M) were studied. The cyclic guanosine monophosphate and cyclic adenosine monophosphate contents were determined by radioimmunoassay. Expression of iNOS and iNOS mRNA were measured by Western or Northern blot analysis, respectively. Results Halothane (1.0-3.0%) but not isoflurane (3%) significantly reduced the ML-1beta-induced inhibition of contraction in a concentration-dependent manner. The cyclic guanosine monophosphate content of the vascular smooth muscle increased significantly after a 5-h exposure to IL-1beta. Halothane at 3.0% significantly inhibited the increase in cyclic guanosine monophosphate content induced by IL-1beta. Halothane had no effect on cyclic adenosine monophosphate content. IL-1beta-induced expression of iNOS and iNOS mRNA in the rat aorta were inhibited significantly by halothane. Conclusion The current study demonstrated that halothane but not isoflurane inhibits IL-1beta-stimulated hyporesponsiveness to vasoconstrictive agents in vascular smooth muscle and that this inhibitory effect of halothane involves the inhibition of iNOS mRNA expression. Thus, these findings suggest that halothane may have some sites to affect nitric oxide-signaling pathway.

Background The 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. Methods Rings 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 x 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. Results Relaxations 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. Conclusions These 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.

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 Ca2+ 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 Ca2+ 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 Ca2+ release mechanism is not involved in activating this enzyme. Halothane can inhibit the nitric oxide-cyclic GMP mechanism only when Ca2+ release is greatly involved in the activation of constitutive nitric oxide synthase.