Conductance Changes of Na+ Channels during the Late Na+ Current Flowing under Action Potential Voltage Clamp Conditions in Canine, Rabbit, and Guinea Pig Ventricular Myocytes

Late sodium current (INa,late) is an important inward current contributing to the plateau phase of the action potential (AP) in the mammalian heart. Although INa,late is considered as a possible target for antiarrhythmic agents, several aspects of this current remained hidden. In this work, the profile of INa,late, together with the respective conductance changes (GNa,late), were studied and compared in rabbit, canine, and guinea pig ventricular myocytes using the action potential voltage clamp (APVC) technique. In canine and rabbit myocytes, the density of INa,late was relatively stable during the plateau and decreased only along terminal repolarization of the AP, while GNa,late decreased monotonically. In contrast, INa,late increased monotonically, while GNa,late remained largely unchanged during the AP in guinea pig. The estimated slow inactivation of Na+ channels was much slower in guinea pig than in canine or rabbit myocytes. The characteristics of canine INa,late and GNa,late were not altered by using command APs recorded from rabbit or guinea pig myocytes, indicating that the different shapes of the current profiles are related to genuine interspecies differences in the gating of INa,late. Both INa,late and GNa,late decreased in canine myocytes when the intracellular Ca2+ concentration was reduced either by the extracellular application of 1 µM nisoldipine or by the intracellular application of BAPTA. Finally, a comparison of the INa,late and GNa,late profiles induced by the toxin of Anemonia sulcata (ATX-II) in canine and guinea pig myocytes revealed profound differences between the two species: in dog, the ATX-II induced INa,late and GNa,late showed kinetics similar to those observed with the native current, while in guinea pig, the ATX-II induced GNa,late increased during the AP. Our results show that there are notable interspecies differences in the gating kinetics of INa,late that cannot be explained by differences in AP morphology. These differences must be considered when interpreting the INa,late results obtained in guinea pig

Brane Junctions in the Randall-Sundrum Scenario

We present static solutions to Einstein's equations corresponding to branes at various angles intersecting in a single 3-brane. Such configurations may be useful for building models with localized gravity via the Randall-Sundrum mechanism. We find that such solutions may exist only if the mechanical forces acting on the junction exactly cancel. In addition to this constraint there are further conditions that the parameters of the theory have to satisfy. We find that at least one of these involves only the brane tensions and cosmological constants, and thus can not have a dynamical origin. We present these conditions in detail for two simple examples. We discuss the nature of the cosmological constant problem in the framework of these scenarios, and outline the desired features of the brane configurations which may bring us closer towards the resolution of the cosmological constant problem.Comment: 15 pages, LaTeX. 4 postscript figures included. Typo corrected and reference adde

A Standard Modell ellenőrzése elektron-pozitron és proton-proton ütközésekben = Test of the Standard Model in electron-positron and proton-proton collisions

A pályázat támogatásával csoportunk befejezte a CERN LEP gyorsítójának OPAL kísérletében korábban megkezdett munkáját, majd csatlakozott a rövidesen induló LHC CMS kísérletéhez. Az OPAL adatait analizálva egyebek között a töltött Higgs bozonokra adtunk alsó tömeghatárt, illetve a foton-foton ütközésekben történő hadronképződést vizsgáltuk. A CMS kísérletben a szuperszimmetrikus részecskéket kereső munkacsoport tevékenységébe kapcsolódtunk be, továbbá a kísérlet elosztott számítógépes hátterének (LHC Grid) magyarországi részét telepítettük és teszteltük. Jelenleg a CMS ún. T2 szintű számítási és adattárolási kapacitásának kb. 2%-át biztosítjuk, és az együttműködés többi résztvevőjével közösen folytatjuk a felkészülést az LHC indulásakor érkező adatok feldolgozására. | With this grant our group concluded its ongoing work in the OPAL experiment at CERN's LEP accelarator, and joined the CMS experiment of the starting LHC. Analysing OPAL data we gave, among others, a lower mass limit for charged Higgs bosons, and investigated hadron production in photon-photon collisions. In the CMS experiment we joined the group searching for supersymmetric particles, and we installed and tested the Hungarian part of the experiment's distributed computing infrastructure (LHC Grid). At the moment we cover about 2% of the T2 level CMS computing and storage capacity, and along with other participants of the collaboration we are continuing the preparations for handling the data that will arrive after the LHC startup

Selective Inhibition of Cardiac Late Na+ Current Is Based on Fast Offset Kinetics of the Inhibitor

The present study was designed to test the hypothesis that the selectivity of blocking the late Na+ current (INaL) over the peak Na+ current (INaP) is related to the fast offset kinetics of the Na+ channel inhibitor. Therefore, the effects of 1 µM GS967 (INaL inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on INaL and INaP were compared in canine ventricular myocardium. INaP was estimated as the maximum velocity of action potential upstroke (V+max). Equal amounts of INaL were dissected by the applied drug concentrations under APVC conditions. The inhibition of INaL by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V+max block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of INaL over INaP inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of INaL over INaP is related to the fast offset kinetics of the Na+ channel inhibitor