Evaluation of cutoff scores for the Parkinson's disease sleep scale-2.

BACKGROUND: The Parkinson's Disease Sleep Scale (PDSS)-2 is a recently developed tool for evaluating disease-related nocturnal disturbances in patients with Parkinson's disease (PD). However, its cutoff score has not been clinically assessed. We determined the optimal cutoff score of the Japanese version of the PDSS-2. METHODS: Patients with PD (n = 146) and controls (n = 100) completed the PDSS-2 and the Pittsburgh Sleep Quality Index (PSQI). Poor sleepers were defined as having global PSQI scores >5. Optimal cutoff scores for determining poor sleepers were assessed using the receiver operating characteristic curve. RESULTS: A PDSS-2 total score ≥ 14 exhibited 82.0% sensitivity and 70.6% specificity, whereas a PDSS-2 total score ≥ 15 provided 72.1% sensitivity and 72.9% specificity in distinguishing poor sleepers (PSQI score >5) from good sleepers (PSQI ≤ 5). Nocturnal disturbances were more frequently observed in patients with PD than in controls (PDSS-2 total score ≥ 14 or ≥ 15; 51.4% vs 20%; 45.9% vs 19%). Nocturnal disturbances were associated with higher Hoehn and Yahr stages and Unified Parkinson's Disease Rating Scale motor scores, impaired quality of life, daytime sleepiness, and depressive symptoms. CONCLUSION: We suggest that PDSS-2 total scores ≥ 15 are useful for detecting poor sleepers among patients with PD.

High levels of a major histocompatibility complex II-self peptide complex on dendritic cells from the T cell areas of lymph nodes.

T lymphocytes recirculate continually through the T cell areas of peripheral lymph nodes. During each passage, the T cells survey the surface of large dendritic cells (DCs), also known as interdigitating cells. However, these DCs have been difficult to release from the lymph node. By emphasizing the use of calcium-free media, as shown by Vremec et al. (Vremec, D., M. Zorbas, R. Scollay, D.J. Saunders, C.F. Ardavin, L. Wu, and K. Shortman. 1992. J. Exp. Med. 176:47-58.), we have been able to release and enrich DCs from the T cell areas. The DCs express the CD11c leukocyte integrin, the DEC-205 multilectin receptor for antigen presentation, the intracellular granule antigens which are recognized by monoclonal antibodies M342, 2A1, and MIDC-8, very high levels of MHC I and MHC II, and abundant accessory molecules such as CD40, CD54, and CD86. When examined with the Y-Ae monoclonal which recognizes complexes formed between I-Ab and a peptide derived from I-Ealpha, the T cell area DCs expressed the highest levels. The enriched DCs also stimulated a T-T hybridoma specific for this MHC II-peptide complex, and the hybridoma underwent apoptosis. Therefore DCs within the T cell areas can be isolated. Because they present very high levels of self peptides, these DCs should be considered in the regulation of self reactivity in the periphery.

The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro.

B7-2 is a recently discovered, second ligand for the CTLA-4/CD28, T cell signaling system. Using the GL-1 rat monoclonal antibody (mAb), we monitored expression of B7-2 on mouse leukocytes with an emphasis on dendritic cells. By cytofluorography, little or no B7-2 was detected on most cell types isolated from spleen, thymus, peritoneal cavity, skin, marrow, and blood. However, expression of B7-2 could be upregulated in culture. In the case of epidermal and spleen dendritic cells, which become highly immunostimulatory for T cells during a short period of culture, the upregulation of B7-2 was dramatic and did not require added stimuli. Lipopolysaccharide did not upregulate B7-2 levels on dendritic cells, in contrast to macrophages and B cells. By indirect immunolabeling, the level of staining with GL-1 mAb exceeded that seen with rat mAbs to several other surface molecules including intercellular adhesion molecule 1, B7-1, CD44, and CD45, as well as new hamster mAbs to CD40, CD48, and B7-1/CD80. Of these accessory molecules, B7-2 was a major species that increased in culture, implying a key role for B7-2 in the functional maturation of dendritic cells. B7-2 was the main (> 90%) CTLA-4 ligand on mouse dendritic cells. When we applied GL-1 to tissue sections of a dozen different organs, clear-cut staining with B7-2 antigen was found in many. B7-2 staining was noted on liver Kupffer cells, interstitial cells of heart and lung, and profiles in the submucosa of the esophagus. B7-2 staining was minimal in the kidney and in the nonlymphoid regions of the gut, and was not observed at all in the brain. In the tongue, only rare dendritic cells in the oral epithelium were B7-2+, but reactive cells were scattered about the interstitial spaces of the muscle. In all lymphoid tissues, Gl-1 strongly stained certain distinct regions that are occupied by dendritic cells and by macrophages. For dendritic cells, these include the thymic medulla, splenic periarterial sheaths, and lymph node deep cortex; for macrophages, the B7-2-rich regions included the splenic marginal zone and lymph node subcapsular cortex. Splenic B7-2+ cells were accessible to labeling with GL-1 mAb given intravenously. Dendritic cell stimulation of T cells (DNA synthesis) during the mixed leukocyte reaction was significantly (35-65%) blocked by GL-1.(ABSTRACT TRUNCATED AT 400 WORDS)

Ventroptin: a BMP-4 antagonist expressed in a double-gradient pattern in the retina.

In the visual system, the establishment of the anteroposterior and dorsoventral axes in the retina and tectum during development is important for topographic retinotectal projection. We identified chick Ventroptin, an antagonist of bone morphogenetic protein 4 (BMP-4), which is mainly expressed in the ventral retina, not only with a ventral high-dorsal low gradient but also with a nasal high-temporal low gradient at later stages. Misexpression of Ventroptin altered expression patterns of several topographic genes in the retina and projection of the retinal axons to the tectum along both axes. Thus, the topographic retinotectal projection appears to be specified by the double-gradient molecule Ventroptin along the two axes.

Vital capacity and selected metabolic diseases in middle-aged Japanese men.

OBJECTIVE: To elucidate the association between vital capacity and the presence of selected metabolic diseases in middle-aged Japanese men. METHODS: A cross-sectional analysis of the associations among forced vital capacity (FVC), static vital capacity as a percentage of that predicted (%VC) and the presence of metabolic diseases was performed. RESULTS: In a univariate linear regression analysis, FVC and %VC were inversely associated with poor vegetable intake, cigarette smoking and body mass index, but not with physical activity or ethanol consumption. In a logistic regression analysis adjusted for lifestyle factors, body mass index and age, the odds ratios for the presence of metabolic disease per 0.54 L (1 SD) decrease in FVC were 1.24 (95% CI 1.03 to 1.50) for type II diabetes, 1.21 (95% CI 1.02 to 1.42) for hypertension, 1.34 (95% CI 1.11 to 1.63) for hypertriglyceridemia, 1.23 (95% CI 1.03 to 1.46) for high gamma-glutamyl transferase levels and 1.63 (95% CI 1.10 to 2.41) for an episode of cardiovascular disease. FVC did not correlate with hyperhomocysteinemia, hypercholesterolemia or high white blood cell count. Similar results were also obtained for the association between %VC and metabolic diseases. CONCLUSIONS: A decrease in FVC or %VC was associated with the presence of some metabolic diseases. The association may partly explain the reported association between low FVC and cardiovascular disease.

Identification of RALDH-3, a novel retinaldehyde dehydrogenase, expressed in the ventral region of the retina.

In the developing retina, a retinoic acid (RA) gradient along the dorso-ventral axis is believed to be a prerequisite for the establishment of dorso-ventral asymmetry. This RA gradient is thought to result from the asymmetrical distribution of RA-generating aldehyde dehydrogenases along the dorso-ventral axis. Here, we identified a novel aldehyde dehydrogenase specifically expressed in the chick ventral retina, using restriction landmark cDNA scanning (RLCS). Since this molecule showed enzymatic activity to produce RA from retinaldehyde, we designated it retinaldehyde dehydrogenase 3 (RALDH-3). Structural similarity suggested that RALDH-3 is the orthologue of human aldehyde dehydrogenase 6. We also isolated RALDH-1 which is expressed in the chick dorsal retina and implicated in RA formation. Raldh-3 was preferentially expressed first in the surface ectoderm overlying the ventral portion of the prospective eye region and then in the ventral retina, earlier than Raldh-1 in chick and mouse embryos. High level expression of Raldh-3 was also observed in the nasal region. In addition, we found that Pax6 mutants are devoid of Raldh-3 expression. These results suggested that Raldh-3 is the key enzyme in the formation of an RA gradient along the dorso-ventral axis during the early eye development, and also in the development of the olfactory system.

Exogenous and endogenous type I interferons inhibit interferon-gamma-induced nitric oxide production and nitric oxide synthase expression in murine peritoneal macrophages.

We investigated the effect of type I IFNs (IFN-alpha and IFN-beta) on IFN-gamma-induced nitric oxide (NO) production by murine peritoneal macrophages. It was found that exogenous and also endogenous type I IFNs suppressed IFN-gamma-induced NO production, cytosolic inducible NO synthase (iNOS) activity, and iNOS mRNA accumulation in macrophages. Furthermore, we show here that type I IFNs prevent the NO-mediated deterioration of mitochondrial respiratory activity in macrophages. These results seem to indicate a possible protective role of type I IFNs against the NO-mediated immunosuppressive and/or cytotoxic effect of macrophages.

Calcitonin gene-related peptide enhances apoptosis of thymocytes.

The effect of calcitonin gene-related peptide (CGRP), a neuropeptide, on the apoptosis of murine thymocytes was investigated. CGRP enhanced apoptosis of thymocytes beyond the spontaneous level at concentrations of 10(-11) M or higher, and the effect attained a plateau at 10(-9) M, mainly by stimulating cAMP formation. Implication of cAMP-independent mechanism was also suggested in the CGRP-induced apoptosis. Flow cytometric analysis revealed that CGRP caused apoptosis preferentially in CD4+8+ thymocytes. In addition, RNA and protein synthesis was required for apoptosis induced by CGRP.

Antiarrhythmic drugs, clofilium and cibenzoline are potent inhibitors of glibenclamide-sensitive K+ currents in Xenopus oocytes.

1. The novel K+ channel opener, Y-26763 induced outward K+ currents in voltage-clamped follicle-enclosed Xenopus oocytes in a concentration-dependent manner with an EC50 value of 58 microM. 2. The Y-26763-induced K+ current was completely and reversibly blocked by glibenclamide (an ATP-sensitive K+ channel blocker) in a concentration-dependent manner (IC50 140 nM). Effects of several antiarrhythmic drugs on Y-26763-induced glibenclamide-sensitive K+ currents were investigated. 3. (+/-)-Cibenzoline, RS-2135, pirmenol, lorcainide and KW-3407 (class I antiarrhythmic drugs, Na+ channel blockers) suppressed Y-26763 responses in a concentration-dependent manner with IC50 values (in microM) of 6.6, 54, 68, 71 and 370, respectively. 4. Clofilium, E-4031, MS-551 and bretylium (class III antiarrhythmic drugs which increase the action potential duration) also suppressed Y-26763 responses concentration-dependently, IC50 values (in microM) were 3.3, 660, 980 and > or = 2000, respectively. N-acetylprocainamide (class III antiarrhythmic drug) scarcely suppressed Y-26763 responses. 5. The glibenclamide-sensitive K+ currents elicited by KRN2391 were also suppressed by all these antiarrhythmic drugs. 6. The antiarrhythmic drugs, clofilium and (+/-)-cibenzoline block glibenclamide-sensitive K+ channels in Xenopus oocytes at concentrations comparable to their therapeutic plasma levels.

Blockade by antiarrhythmic drugs of glibenclamide-sensitive K+ channels in Xenopus oocytes.

1. The outward K+ current induced by KRN2391 (K+ channel opener) in Xenopus oocytes is blocked by glibenclamide. We have investigated the effects of various classes (I-IV) of antiarrhythmic drugs on this KRN2391-induced response. 2. All class I antiarrhythmic drugs (Na+ channel blockers) tested concentration-dependently suppressed KRN2391-induced responses with the rank order of potency (IC50 in microM), disopyramide (17.8) > aprindine (29.5) > propafenone (63.1) > ajmaline (145) > quinidine (151). Flecainide, SUN1165, lignocaine, mexiletine and procainamide were much less potent (IC50, 450- > 1000 microM) than quinidine. 3. The class II antiarrhythmic drugs (beta-blockers), timolol, (-)- and (+/-)- propranolol, and (+)- propranolol (a non-beta-blocker) inhibited KRN2391-induced K+ currents in a concentration-dependent manner with values for IC50 (microM) of 79, 131, 151 and 129, respectively, whilst butoxamine, oxprenolol, alprenolol, pindolol, nadolol, metoprolol and acebutolol were either weak (IC50, 300 microM-600 microM) or virtually inactive (IC50, > 1000 microM). 4. The class III antiarrhythmic drugs, amiodarone and (+)-sotalol scarcely affected KRN2391 responses. 5. All class IV drugs (Ca2+ antagonists) tested suppressed KRN2391-induced responses in a concentration-dependent manner with an IC50 of 6.3 microM for bepridil, 38 microM for prenylamine, 85 microM for verapamil and 135 microM for diltiazem. 6. In conclusion, antiarrhythmic drugs of classes I, II and IV potently blocked glibenclamide-sensitive K+ channels in Xenopus oocytes.

GABAB receptors expressed in Xenopus oocytes by guinea pig cerebral mRNA are functionally coupled with Ca2(+)-dependent Cl- channels and with K+ channels, through GTP-binding proteins.

Transmembrane currents induced by (-)-baclofen (BAC), a specific agonist of the gamma-aminobutyric acid-B (GABAB) receptor, in Xenopus oocytes injected with guinea pig cerebral mRNA were electrophysiologically and pharmacologically characterized under a voltage-clamp condition. The oocytes injected with mRNA acquired responsiveness to BAC and showed two types of currents at a holding potential of -50 mV. One was the slow and smooth inward current which had a short latency and associated with a decrease in membrane conductance, and its amplitude was decreased by hyperpolarization and increased by depolarization. The other was the large fast oscillatory inward current with a long-latency, which was decreased in amplitude by depolarization and reversed at -26 mV. Both currents were not blocked by bicuculline but were depressed by 2-hydroxysaclofen (2-OH-SAC), though the smooth current was less sensitive to 2-OH-SAC; about 40% blockade at the 2-OH-SAC concentration capable of abolishing the oscillatory current. The smooth current was depressed by Ba2+. The oscillatory current was time-dependently attenuated and almost abolished by intracellularly injected pertussis toxin (PTX), while the smooth current was not depressed by this toxin even when the oscillatory current was nearly abolished. The intracellular injection of GTP-gamma-S into oocytes attenuated both oscillatory and smooth currents. These results suggest the possibility that GABAB receptors expressed in Xenopus oocytes by cerebral mRNA are functionally coupled with two signal transduction systems, one is the opening of Ca2(+)-dependent Cl- channels mediated by PTX-sensitive GTP-binding protein(s) and the other is the closure of K+ channels through PTX-insensitive GTP-binding protein(s).

Vanadate-induced oscillatory inward Cl- currents in Xenopus laevis oocytes.

Extracellularly applied sodium orthovanadate (30-3000 microM) evoked oscillatory inward Cl- currents in defolliculated Xenopus laevis oocytes. The current responses were attenuated by microinjection of EGTA into the oocytes and by treatment of the oocytes with pertussis toxin (2 micrograms/ml). The vanadate responses were not affected by preceding vanadate (1 mM) responses or an angiotensin II (200 nM) response, or by pre-application of atropine (5 microM). Intracellular injection of vanadate was ineffective. These results suggest that vanadate stimulates Ca2+ mobilization in Xenopus oocytes possibly by activating surface membrane receptors, which is coupled to pertussis toxin-sensitive G-protein.

Potentiation by insulin and insulin-like growth factor-1 of glibenclamide-sensitive K+ currents in follicle-enclosed Xenopus oocytes.

Effects of insulin and IGF-1 (insulin-like growth factor-1) on K+ channel opener-induced/glibenclamide-sensitive K+ currents were studied using follicle-enclosed Xenopus oocytes. Both insulin (4 x 10(-9)-4 x 10(-6) M) and IGF-1 (4 x 10(-10)-4 x 10(-7) M) increased the cromakalim-induced K+ currents in a concentration-dependent manner. The current-facilitating effect of IGF-1 was about ten times as potent as that of insulin. Treatment of the oocyte with pertussis toxin (2 micrograms/ml) suppressed the current-potentiating effects of insulin and IGF-1 by about 60%. Although phenylarsine oxide (1-100 microM), a putative inhibitor of protein tyrosine phosphatase, also facilitated the K+ currents, the current enhancing effects were not affected by pertussis toxin. These results suggest that insulin and IGF-1 potentiate the glibenclamide-sensitive K+ current by activating IGF-1 receptor and that pertussis toxin-sensitive G-protein may be associated with these effects.

Inhibition by histamine H1 receptor antagonists of endogenous glibenclamide-sensitive K+ channels in follicle-enclosed Xenopus oocytes.

Effects of histamine receptor ligands on the glibenclamide-sensitive K+ currents induced by K+ channel openers, cromakalim and Y-26763, were examined in follicle-enclosed Xenopus oocytes. Histamine H1 receptor antagonists, promethazine, dimethindene and chlorpheniramine all decreased cromakalim-induced K+ currents with IC50 values of 31.5 microM, 29.5 microM and 138 microM, respectively. These compounds also blocked Y-26763-induced K+ currents with comparable IC50 values. Histamine (1 mM) and histamine H2 receptor antagonists, cimetidine (0.5 mM) and ranitidine (1 mM) had little effect on these K+ currents. These results suggest that histamine H1 receptor antagonists inhibit glibenclamide-sensitive K+ currents by a mechanism other than the histamine H1 receptor antagonism. The inhibitory effects might explain, in part, the reported actions of histamine H1 receptor antagonists in ischemia.

Activation by KRN2391 and nicorandil of glibenclamide-sensitive K+ channels in Xenopus oocytes.

KRN2391 (N-cyano-N'-(2-nitroxyethyl)-3-pyridine-carboximidamide methanesulfonate) and nicorandil, a new class of K+ channel openers, each with an NO2 moiety, induced outward K+ currents in follicle-enclosed Xenopus oocytes. These K+ currents were suppressed concentration-dependently and reversibly by glibenclamide, phentolamine and trifluoperazine, all known to inhibit ATP-sensitive K+ channels. The nicorandil-induced K+ current was virtually abolished by defolliculation of oocytes, while the KRN2391 response was little affected by defolliculation. These results suggest that Xenopus oocyte has at least two types of glibenclamide-sensitive K+ channels, one is selectively sensitive to KRN2391 and is probably localized in the oocyte, and the other is sensitive to nicorandil and distributed in the follicle cells surrounding an oocyte.

Inhibition by imidazoline and imidazolidine derivatives of glibenclamide-sensitive K+ currents in Xenopus oocytes.

The effects of imidazoline and imidazolidine derivatives on glibenclamide-sensitive K+ currents induced by the novel K+ channel opener, Y-26763 ((+)-(3S,4R)-4-(N-acetyl-N-benzyloxyamino)-6-cyano-3,4-dihydro-2,2 -dimethyl-2H-1-benzopyran-3-ol), were investigated in voltage-clamped follicle-enclosed Xenopus oocytes. Of 14 imidazoline derivatives and seven imidazolidine derivatives tested, phenotalmine, (-)-cibenzoline, (+)-cibenzoline, alinidine, oxymetazoline, antazoline, midaglizole, xylometazoline, tramazoline and ST91 (2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride) potently suppressed Y-26763-induced K+ currents (IC50 < 80 microM). The compounds which lack an aromatic ring in their structure, 2-methyl-2-imidazole and 2-hydrazino-2-imidazoline, did not affect the K+ currents. Clonidine and idazoxan, which both bind to imidazoline-preferring binding sites with high affinity in various tissues, showed only a small inhibitory effect on Y-26763-induced K+ currents (IC50 780 microM and 955 microM, respectively). The non-imidazoline/non-imidazolidine alpha-adrenoceptor antagonists, WB-4101 (2-(2,6-dimethoxy-phenoxyethyl)-aminomethyl-1,4-benzodioxane hydrochloride), yohimbine and rauwolscine, showed suppressive effects on Y-26763-induced K+ currents (IC50 203 microM, 813 microM and 832 microM, respectively). Octopamine (1 mM), a non-imidazoline/non-imidazolidine alpha-adrenoceptor agonist, was inactive. The results suggest that (1) an aromatic ring or aromatic rings are an essential moiety for imidazoline or imidazolidine derivatives to block glibenclamide-sensitive K+ currents in oocytes, and (2) the K+ current-blocking ability of imidazolines and imidazolidines is related to the alkylation of the benzene ring and the existence of a tertiary amine structure. The K+ current-blocking effects of imidazolines or imidazolidines may not be mediated by alpha-adrenoceptors, at least in follicle-enclosed Xenopus oocytes.

Inhibition by SKF 525A and quinacrine of endogenous glibenclamide-sensitive K+ channels in follicle-enclosed Xenopus oocytes.

Effects of local anesthetics-related drugs, SKF 525A (proadifen, a cytochrome P450 inhibitor) and quinacrine (a phospholipase A2 inhibitor) on glibenclamide-sensitive K+ currents were investigated using native Xenopus oocytes. SKF 525A and quinacrine suppressed cromakalim-induced/glibenclamide-sensitive K+ currents with IC50 values of 9.8 microM and 4.4 microM, respectively. Inhibitors of either cytochrome P450 or phospholipase A2, which are structurally unrelated to local anesthetics, however, did not affect the K+ currents. Similar results were obtained for Y-26763-induced/glibenclamide-sensitive K+ currents. SKF 525A and quinacrine block the glibenclamide-sensitive K+ currents by a mechanism irrelevant to the inhibition of cytochrome P450 or phospholipase A2 in oocytes.

Effects of Ca2+ channel antagonists and their isomers on glibenclamide-sensitive K+ currents in follicle-enclosed Xenopus oocytes.

Several Ca2+ channel antagonists were shown to inhibit glibenclamide-sensitive K+ currents in follicle-enclosed Xenopus oocytes. We have investigated the stereoselectivity of the effects of Ca2+ channel antagonists on the glibenclamide-sensitive K+ currents induced by Y-26763 (a K+ channel opener) in follicle-enclosed Xenopus oocytes. (-)-Bepridil and (+)-bepridil similarly suppressed Y-26763-induced K+ currents with IC50 values of 7.8 microM and 7.4 microM, respectively. The Ca2+ channel antagonists, (-)- and (+/-)-verapamil, and inactive (+)-verapamil suppressed Y-26763-induced K+ currents to similar extents and their IC50 values were 63.1 microM and 55.0 microM, respectively. The Ca2+ channel antagonist, SD-3211 and its less potent (-)-isomer, SD-3212, suppressed Y-26763-induced K+ currents with similar IC50 values of 10.7 microM and 8.9 microM, respectively. Of all the Ca2+ channel antagonists tested, only diltiazem exhibited stereoselectivity. The rank order of potencies (IC50 in microM) of four isomers of diltiazem to block Y-26763-induced K+ currents was (+)-trans (4.2) > (-)-trans (13.3) > (-)-cis (35.8) > (+)-cis (75.9), which was, however, opposite to that of their potencies as Ca2+ channel antagonists. These results indicate that blockade by Ca2+ channel antagonists of glibenclamide-sensitive K+ currents in follicle-enclosed Xenopus oocytes is not mediated by Ca2+ channel antagonism.

Atrial natriuretic factor potentiates glibenclamide-sensitive K+ currents via the activation of receptor guanylate cyclase in follicle-enclosed Xenopus oocytes.

The effect of the atrial natriuretic factor (ANF) on K+ channel opener-induced glibenclamide-sensitive K+ currents was studied using follicle-enclosed Xenopus oocytes. K+ currents induced by the K+ channel opener Y-26763 were potentiated by ANF (0.5-50 nM) in a concentration-dependent manner. 50 nM ANF increased the peak amplitude of the current by 59.4 +/- 9.9% (mean +/- S.E., n = 8). ANF (1-1000 nM) increased the cGMP contents of follicle-enclosed oocytes; about 13-fold increase was achieved by 100 nM ANF, showing a peak at 5 min. The ANF-stimulated accumulation of cGMP was suppressed by HS-142-1 (a non-peptide antagonist of the ANF receptor), at concentrations of 3-300 micrograms/ml. The K+ current-potentiating effect of ANF was mimicked by membrane-permeable cGMP (1 mM 8-bromo cGMP). These results suggest that ANF potentiates glibenclamide-sensitive K+ currents via the activation of receptor guanylate cyclase and consequent accumulation of cGMP in follicle-enclosed Xenopus oocytes.

Effects of local anesthetics and related drugs on endogenous glibenclamide-sensitive K+ channels in Xenopus oocytes.

Effects of local anesthetics and structurally related drugs on the glibenclamide-sensitive K+ currents evoked by Y-26763 (a K+ channel opener) were investigated in native Xenopus oocytes. The K+ current induced by Y-26763 (100 microM) was reversibly suppressed by all six local anesthetics tested in a concentration-dependent manner with the rank order of potencies (IC50 in microM): bupivacaine (67) > dibucaine (136) > tetracaine (845) > lidocaine (1710) = mepivacaine (1945) > procaine (3112). (+)-Propranolol and mexiletine also suppressed Y-26763-induced K+ currents with IC50 values of 115 microM and 789 microM, respectively. These results suggest that a suppressive action on glibenclamide-sensitive K+ channels is the common property of local anesthetics.