ω-3 and ω-6 polyunsaturated fatty acids block HERG channels

11 pages, 7 figures.Dietary polyunsaturated fatty acids (PUFAs) have been reported to exhibit antiarrhythmic properties, which have been attributed to their availability to modulate Na(+), Ca(2+), and several K(+) channels. However, their effects on human ether-a-go-go-related gene (HERG) channels are unknown. In this study we have analyzed the effects of arachidonic acid (AA, omega-6) and docosahexaenoic acid (DHA, omega-3) on HERG channels stably expressed in Chinese hamster ovary cells by using the whole cell patch-clamp technique. At 10 microM, AA and DHA blocked HERG channels, at the end of 5-s pulses to -10 mV, to a similar extent (37.7 +/- 2.4% vs. 50.2 +/- 8.1%, n = 7-10, P > 0.05). 5,6,11,14-Eicosatetrayenoic acid, a nonmetabolizable AA analog, induced effects similar to those of AA on HERG current. Both PUFAs shifted the midpoint of activation curves of HERG channels by -5.1 +/- 1.8 mV (n = 10, P O). Finally, both AA and DHA induced a use-dependent inhibition of HERG channels. In summary, block induced by AA and DHA was time, voltage, and use dependent. The results obtained suggest that both PUFAs bind preferentially to the open state of the channel, although an interaction with inactivated HERG channels cannot be ruled out for AA.This work was supported by Comisión Interministerial de Ciencia y Tecnología SAF2002-02160, SAF2004-06856, and CAM GR/SAL/0854/2004 and Red Temática de Investigación Cooperativa FIS C03/01 grants.Peer reviewe

ω-3 and ω-6 polyunsaturated fatty acids block HERG channels

11 pages, 7 figures.Dietary polyunsaturated fatty acids (PUFAs) have been reported to exhibit antiarrhythmic properties, which have been attributed to their availability to modulate Na(+), Ca(2+), and several K(+) channels. However, their effects on human ether-a-go-go-related gene (HERG) channels are unknown. In this study we have analyzed the effects of arachidonic acid (AA, omega-6) and docosahexaenoic acid (DHA, omega-3) on HERG channels stably expressed in Chinese hamster ovary cells by using the whole cell patch-clamp technique. At 10 microM, AA and DHA blocked HERG channels, at the end of 5-s pulses to -10 mV, to a similar extent (37.7 +/- 2.4% vs. 50.2 +/- 8.1%, n = 7-10, P > 0.05). 5,6,11,14-Eicosatetrayenoic acid, a nonmetabolizable AA analog, induced effects similar to those of AA on HERG current. Both PUFAs shifted the midpoint of activation curves of HERG channels by -5.1 +/- 1.8 mV (n = 10, P O). Finally, both AA and DHA induced a use-dependent inhibition of HERG channels. In summary, block induced by AA and DHA was time, voltage, and use dependent. The results obtained suggest that both PUFAs bind preferentially to the open state of the channel, although an interaction with inactivated HERG channels cannot be ruled out for AA.This work was supported by Comisión Interministerial de Ciencia y Tecnología SAF2002-02160, SAF2004-06856, and CAM GR/SAL/0854/2004 and Red Temática de Investigación Cooperativa FIS C03/01 grants.Peer reviewe

Ultrafast sodium channel block by dietary fish oil prevents dofetilide-induced ventricular arrhythmias in rabbit hearts

9 pages, 4 figures, 1 table.-- et al.Several epidemiologic and clinical studies show that following myocardial infarction, dietary supplements of omega-3 polyunsaturated fatty acids (omega3FA) reduce sudden death. Animal data show that omega3FA have antiarrhythmic properties, but their mechanisms of action require further elucidation. The effects of omega3FA supplementation were studied in female rabbits to analyze whether their antiarrhythmic effects are due to a reduction of triangulation, reverse use-dependence, instability, and dispersion (TRIaD) of the cardiac action potential (TRIaD as a measure of proarrhythmic effects). In Langendorff-perfused hearts challenged by a selective rapidly activating delayed rectifier potassium current inhibitor that has been shown to exhibit proarrhythmic effects (dofetilide; 1 to 100 nM), omega3FA pretreatment (30 days; n=6) prolonged the plateau phase of the monophasic action potential; did not slow the terminal fast repolarization; reduced the dofetilide-induced prolongation of the action potential duration; reduced dofetilide-induced triangulation; and reduced dofetilide-induced reverse use-dependence, instability of repolarization, and dispersion. Dofetilide reduced excitability in omega3FA-pretreated hearts but not in control hearts. Whereas torsades de pointes (TdP) were observed in five out of six in control hearts, none were observed in omega3FA-pretreated hearts. Docosahexaenoic acid (DHA) inhibited the sodium current with ultrafast kinetics. Dietary omega3FA supplementation markedly reduced dofetilide-induced TRIaD and abolished dofetilide-induced TdP. Ultrafast sodium channel block by DHA may account for the antiarrhythmic protection of the dietary supplements of omega3FA against dofetilide-induced proarrhythmia observed in this animal model.This work was funded by Solvay Pharma, Novartis, Grants CICYT SAF2004-06856 and SAF2007-65868 and Red Temática de Investigación Cooperativa Grant FIS RD06/0014/0006.Peer reviewe

Cryptanalysis of Dedicated Cryptographic Hash Functions

In this thesis we study the security of a number of dedicated cryptographic hash functions against cryptanalytic attacks. We begin with an introduction to what cryptographic hash functions are and what they are used for. This is followed by strict definitions of the security properties often required from cryptographic hash functions. FSB hashes are a class of hash functions derived from a coding theory problem. We attack FSB by modeling the compression function of the hash by a matrix in GF(2). We show that collisions and preimages can easily be found in FSB with the proposed security parameters. We describe a meet-in-the-middle attack against the FORK-256 hash function. The attack requires 2^112.8 operations to find a collision, which is a 38000-fold improvement over the expected 2^128 operations. We then present a method for finding slid pairs for the compression function of SHA-1; pairs of inputs and messages that produce closely related outputs in the compression function. We also cryptanalyse two block ciphers based on the compression function of MD5, MDC-MD5 and the Kaliski-Robshaw "Crab" encryption algorithm. VSH is a hash function based on problems in number theory that are believed to be hard. The original proposal only claims collision resistance; we demonstrate that VSH does not meet the other hash function requirements of preimage resistance, one-wayness, and collision resistance of truncated variants. To explore more general cryptanalytic attacks, we discuss the d-Monomial test, a statistical test that has been found to be effective in distinguishing iterated Boolean circuits from real random functions. The test is applied to the SHA and MD5 hash functions. We present a new hash function proposal, LASH, and its initial cryptanalysis.The LASH design is based on a simple underlying primitive, and some of its security can be shown to be related to lattice problems

La Flèche de la cathédrale. [Signé : Léon Guizy.]

Appartient à l’ensemble documentaire : HNormand1Avec mode text

A la mémoire de notre ami et F @ Benoist Coudy, hommage à sa triste veuve. [Signé : L. Guizy.]

Appartient à l’ensemble documentaire : HNormand1Avec mode text

Stereoselective interactions between local anesthetics and cardiac K + channels

Ionic channels are membrane proteins that can be blocked by many different types of drugs such as local anesthetics, antiarrhythmics, etc. Therefore, they are considered drug targets, whose topology, at the ion channel level, has been analyzed by studying the interactions of specific ion channel blockers and site-directed mutant ion channels. Stereoselective interactions are especially interesting because they can reveal three-dimensional relationships between drugs and channels with otherwise identical biophysical and physicochemical properties. Furthermore, stereoselectivity suggests direct and specific receptor-mediated action, and identification of such stereospecific interactions may have important clinical consequences. However, ≈25% of drugs used in clinical practice are racemic mixtures, the individual enantiomers of which frequently differ in both their pharmacodynamic and pharmacokinetic profile. Furthermore, these different effects induced by one of the enantiomers of a racemic drug may contribute to the undesired effects that can be similar or different to the pharmacological effect of the racemic drug. In other cases, the enantiomers on the molecular target are opposite. In this review, we focus on the stereoselective effects of bupivacaine on different Kv channels. Bupivacaine stereoselectively blocks Kv1.5 and Kv11.1 channels, whereas non-stereoselectively it blocks Kv2.1 and Kv4.3 channels. © 2005 Bentham Science Publishers Ltd.Peer Reviewe

Kvβ1.3 reduces the degree of stereoselective bupivacaine block of Kv1.5 channels

[Background]: Kvβ1.3 subunit modifies the gating and the pharmacology of Kv1.5 channels, decreasing their sensitivity to block induced by drugs, suggesting that Kvβ1.3 competes with them for a binding site at Kv1.5 channels. METHODS: Currents generated by the activation of Kv1.5 and Kv1.5 + Kvβ1.3 channels expressed in HEK293 cells and Xenopus oocytes were recorded by using whole cell patch clamp and voltage clamp techniques. [Results]: Block of Kv1.5, but not that produced on Kv1.5 + Kvβ1.3 channels, was voltage dependent. In both channels, bupivacaine block was time dependent. R(+)- and S(-)-bupivacaine blocked Kv1.5 with IC50 4.4 ± 0.5 μm (n = 15) and 39.8 ± 8.2 μm (n = 16; P < 0.05), respectively. These values increased fourfold for R(+)-bupivacaine (17.2 ± 2.2 μm) and twofold for S(-)-bupivacaine (71.9 ± 11.5 μm) in Kv1.5 + Kvβ1.3 channels. Therefore, the degree of stereoselectivity (θ) decreased from 9 to 4 in the presence of Kvβ1.3. The decrease in potency to block Kv1.5 + Kvβ1.3 channels was the result of a less stable interaction between bupivacaine enantiomers and channels. Differences in stereoselectivity in each situation were due to a more favorable interaction between the channel and R(+)-bupivacaine. In the presence of Kvβ1.3, stereoselectivity was abolished for V514A mutant channels (involved in bupivacaine binding but not in Kvβ1.3 binding) but not for L510A (part of Kvβ1.3 binding site). [Conclusions]: The degree of stereoselective block of Kv1.5 decreases from 9 to 4 when Kvβ1.3 is present. L510 is determinant for the modulation of bupivacaine block, because it is the only residue of the S6 segment that binds to both bupivacaine and Kvβ1.3. These findings support an overlapping binding site for drugs and Kvβ1.3. © 2007 American Society of Anesthesiologists, Inc.Peer Reviewe