Hemos comparado las prevalencias de grupos sanguíneos entre los pacientes que acudieron al Servicio de Emergencia del Hospital Nacional Cayetano Heredia (Lima, Perú) durante el mes de abril de 1991 con diarrea aguda severa con aislamiento de Vibrio cholerae en los coprocultivos, con la de un grupo control conformado por los donantes del Banco de Sangre del mismo hospital, apareados por distritos de residencia. La prevalencia de grupo sanguíneo O entre los 136 pacientes con coprocultivos positivos (todo a V. Cholerae O1 biotipo Inaba) fue de 94.9% mientras que entre los 544 controles fue de 79.2% (similar a la reportada en otros estudios sobre prevalencia de grupos sanguíneos en nuestra población).Aunque el diseño del estudio tiende a subestimar el real riesgo relativo, encontramos un riesgo relativo estimado de 4.832 (IC95=2.196, 10.628) de presentar diarrea aguda severa por V.cholerae entre las personas con grupo sanguíneo O (p<0.00002). Queda por descubrir la base fisiopatológica de esta asociación y el impacto que puede tener en la morbilidad y mortalidad de la presente epidemia de cólera en el Perú, país con alta prevalencia de grupo sanguíneo O.
In long term treatment, thiazide diuretics such as hydrochlorothiazide (HCTZ) lower blood pressure by decreasing peripheral resistance rather than by their diuretic effect. This action has been attributed to the opening of Ca2+-activated K+ channels in vascular smooth muscle cells. However, little is known about their cardiac cellular actions. Here we investigated the possible actions of HCTZ on action potential and contraction of rat ventricular muscle strips and on the ionic currents of isolated rat ventricular cardiomyocytes. HCTZ depressed ventricular contraction with an IC30 of 1.85 microM (60% decrease at 100 microM). Action potential duration at -60 mV and maximal rate of depolarization were, however, only slightly decreased by 12% and 22%, respectively, at 100 microM. At the single cell level, HCTZ (100 microM) depressed the fast Na+ current (INa) and the L-type Ca2+ current (ICaL) by 30% and 20%, respectively. The effects on ICaL were not voltage-or frequency-dependent. In cells intracellularly perfused with 50 microM cyclic adenosine, monophosphate HCTZ reduced ICaL by 33%. The transient (Ito), the delayed rectifier and the inward rectifier potassium currents were decreased by 20% at 100 microM HCTZ. The effects on Ito were voltage-dependent. In conclusion, HCTZ at high concentrations possesses a negative inotropic action that could be in part due to its blocking action on INa and ICaL. The actions of HCTZ on multiple cardiac ionic currents could explain its weak effect on action potential duration.
sensor movement may underlie the destabilization of the fast-inactivated state in NaV1.5. To test this, we expressed NaV1.5 channels in Xenopus oocytes and recorded gating currents using a cut-open voltage clamp with extracellular solution titrated to either pH 7.4 (control) or pH 6.0. At pH 6.0, compared to pH 7.4, the V1/2 of the Q(V) curve was significantly depolarized (from À57.854.3 mV to À40.855.1 mV). Additionally, the slow time constant of charge recovery was significantly reduced from 16.155.0 ms at pH 7.4 to 9.754.2 ms at pH 6.0. These data suggest a molecular basis for the increased persistent and window currents previously shown in NaV1.5 channels at reduced extracellular pH. Specifically, protons may electrostatically affect the rate of voltage sensor movement, either by directly binding to extracellular residues (e.g. H880) or indirectly by binding to carboxylates in the pore domain (Kahn et al., J Physiol. 2002, 543).
mu-Conotoxin (muCTX) KIIIA is of special interest both functionally and structurally because (1) it blocks neuronal voltage-gated sodium (Na v ) channels involved in pain signalling (Zhang et al., 2007, J. Biol. Chem.) and (2) unlike previously discovered muCTXs (most >22 amino acids), KIIIA has only 16 amino acids, missing amino acids in the N-terminal section. We have performed preliminary molecular dynamics simulations of muCTX KIIIA docking to a model of the Na v 1.4 outer vestibule (Choudhary et al, 2007, Channels). The results are consistent with a possible binding orientation in Na v 1.4 with K7 facing down into the pore, interacting with the outer ring charges (E403 & E758) in domains I and II. To exam this possible orientation, single-channel bilayer recordings from rat brain (preparation includes Na v 1.1, 1.2, 1.3 and 1.6) and rat skeletal muscle (muscle, predominantly Na v 1.4) preparations demonstrated that when lysine-7 (K7) is neutralized, channels show an increase in fractional residual current (f res ) upon KIIIA[K7A] addition (brain, 4853% & muscle, 4559%) compared to wild type KIIIA (brain, 1953%, muscle 1953%). The wild-type non-zero f res hints that the lack of N-terminal residues or the use of a lysine residue (instead of arginine) to occlude the pore in KIIIA leads to incomplete toxin block, suggesting KIIIA has a ''looser'' interaction with the channel, with the key basic residue, K7, playing a smaller role in toxin block than in GIIIA and PIIIA. This data is supported by whole-cell experiments looking at KIIIA and KIIIA[K7A] interactions with multiple Na v isoforms. The single-channel and whole-cell data suggest KIIIA binds to the outer vestibule with the lysine at position 7 blocking current through the pore, similar to R13 in GIIIA (skeletal muscle specific) and R14 in PIIIA (blocks both skeletal and neuronal channels).
Voltage-gated sodium channels undergo alternative mRNA splicing. In the human neuronal Nav1.1 channel encoded by SCN1A, a common genetic variant affecting an intron splice donor site alters the proportion of transcripts that incorporate the canonical exon 5 (exon 5A) or an alternative (exon 5N) encoding portions of the S3 and S4 segments of domain 1. Epileptic subjects with this genetic variant require lower doses of anticonvulsant drugs such as phenytoin compared with individuals lacking this variant. Because this genetic variant is associated with a larger proportion of exon 5N containing transcripts in brain, we hypothesized that differences in function and pharmacology of Nav1.1 channels containing either exon 5N or 5A account for the observed divergence in anticonvulsant dose requirements. To examine differences in drug efficacy of SCN1A splice variants, we performed whole-cell recording on tsA201 cells transiently co-transfected with either Nav1.1-5A or Nav1.1-5N and two accessory subunits (b1,b2). We examined voltage-dependence of activation, steady-state inactivation, and recovery from fast inactivation and observed no significant differences between splice variants. We also measured both steady-state block and use-dependent block (10Hz) by phenytoin, carbamazepine, and lamotrigine. Nav1.1-5N channels exhibited greater steady-state block by phenytoin(100mM) (1655% vs. 256%) and lamotrigine(200mM) (2554% vs. 1452%) compared to Nav1.1-5A. Additionally, Nav1.1-5N exhibited greater use-dependent block by phenytoin (3955% vs. 2454%) and lamotrigine (2956% vs. 1852%). We tested cells stably transfected with either Nav1.1-5A or Nav1.1-5N and both b subunits using an automated planar patch clamp system (Patchliner, Nanion Inc.) to perform concentration-response curves to determine steady-state and inactivated state affinities for lamotrigine. Similar to conventional patch clamp experiments, lamotrigine exhibited greater steady-state and inactivated state affinity for Nav1.1-5N than Nav1.1-5A. These results suggest SCN1A transcripts containing the alternative exon 5N encode channels that are more sensitive to multiple anticonvulsant drugs.
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