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Background and Purpose At present there are no small molecule inhibitors that show strong selectivity for the Na +/Ca 2+ exchanger ( NCX). Hence, we studied the electrophysiological effects of acute administration of ORM-10103, a new NCX inhibitor, on the NCX and L-type Ca2+ currents and on the formation of early and delayed afterdepolarizations. Experimental Approach Ion currents were recorded by using a voltage clamp technique in canine single ventricular cells, and action potentials were obtained from canine and guinea pig ventricular preparations with the use of microelectrodes. Key Results ORM-10103 significantly reduced both the inward and outward NCX currents. Even at a high concentration (10 μ M), ORM-10103 did not significantly change the L-type Ca2+ current or the maximum rate of depolarization ( dV/dtmax), indicative of the fast inward Na+ current. At 10 μ M ORM-10103 did not affect the amplitude or the dV/dtmax of the slow response action potentials recorded from guinea pig papillary muscles, which suggests it had no effect on the L-type Ca2+ current. ORM-10103 did not influence the Na+/ K+ pump or the main K+ currents of canine ventricular myocytes, except the rapid delayed rectifier K+ current, which was slightly diminished by the drug at 3 μ M. The amplitudes of pharmacologically- induced early and delayed afterdepolarizations were significantly decreased by ORM-10103 (3 and 10 μ M) in a concentration-dependent manner. Conclusions and Implications ORM-10103 is a selective inhibitor of the NCX current and can abolish triggered arrhythmias. Hence, it has the potential to be used to prevent arrhythmogenic events. Linked Article This article is commented on by Terracciano and Hancox, pp. 765-767 of this issue. To view this commentary visit [ABSTRACT FROM AUTHOR]

Aim: In diabetes mellitus, several cardiac electrophysiological parameters are known to be affected. In rodent experimental diabetes models, changes in these parameters were reported, but only limited relevant information is available in other species, having cardiac electrophysiological properties more resembling the human, including the rabbit. The present study was designed to analyse the effects of experimental type 1 diabetes on ventricular repolarization and the underlying transmembrane potassium currents in rabbit hearts. Methods: Diabetes was induced by a single injection of alloxan (145 mg kg−1 i.v.). After the development of diabetes (3 weeks), electrophysiological studies were performed using whole cell voltage clamp and ECG measurements. Results: The QTc interval in diabetic rabbits was moderately but statistically significantly longer than measured in the control animals (155 ± 1.8 ms vs. 145 ± 2.8 ms, respectively, n = 9–10, P < 0.05). This QTc-lengthening effect of diabetes was accompanied by a significant reduction in the density of the slow delayed rectifier K+ current, IKs (from 1.48 ± 0.35 to 0.86 ± 0.17 pA pF−1 at +50 mV, n = 19–21, P < 0.05) without changes in current kinetics. No differences were observed either in the density or in the kinetics of the inward rectifier K+ current ( IK1), the rapid delayed rectifier K+ current ( IKr), the transient outward current ( Ito) and the L-type calcium current ( ICaL) between the control and alloxan-treated rabbits. Conclusion: It is concluded that type 1 diabetes mellitus, although only moderately, lengthens ventricular repolarization. Diabetes attenuates the repolarization reserve by decreasing the density of IKs current, and thereby may enhance the risk of sudden cardiac death. [ABSTRACT FROM AUTHOR]

Effects of stilbene disulfonates on single KATP channel currents were investigated in inside-out and outside-out membrane patches from guinea pig ventricular myocytes. All drugs tested, 4,4'-diisothiocyanatostilbene,2,2'-disulfonic acid (DIDS), 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS), 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS), and 4,4'-diaminostilbene-2,2'-disulfonic acid (DADS), inhibited the KATP channel when they were applied to the intracellular, but not extracellular side of the membrane patch. Inhibitory actions of DIDS and SITS were irreversible, whereas those induced by DNDS and DADS were reversible. KATP channel inhibition was concentration dependent with an order of potency of DIDS > SITS approximately DNDS > DADS; the Hill coefficient was close to unity for each drug. No change in channel conductance was observed during exposure to DIDS or DNDS; however, channel kinetics was altered. Distribution of the open time within bursts and that between bursts could be described by a single exponential relation in the absence and presence of DIDS or DNDS. The time constant of the open time within bursts was not altered, but that between bursts was decreased by DIDS (from 40.0 +/- 8.1 to 29.8 +/- 6.7 msec, P < 0.05) and by DNDS (from 43.1 +/- 9.3 to 31.9 +/- 7.1 msec, P < 0.05). Distributions of closed time within bursts were also fitted to a single exponential function both in the absence and presence of drugs, while those of the closed time between bursts were fitted to a single exponential function in the absence of drugs, but a double exponential function was required in the presence of drugs. The rates of onset and development of channel inhibition by DIDS and DNDS appeared to be concentration dependent; a longer time was required to reach a new steady-state of channel activity as drug concentration was decreased. Inhibition by DIDS or DNDS was regulated by intracellular pH; inhibition was greater during acidic conditions. For DIDS (0.1 mM), the open probability (Po) expressed as a fraction of the value before drug application was 42.9 +/- 8.3% at pH 7.4 and 8.2 +/- 6.6% at pH 6.5 (P < 0.01); corresponding values for DNDS (1 mM) were 39.6 +/- 17.6 and 8.9 +/- 5.8%, respectively (P < 0.01). From these data, we conclude that stilbene disulfonates block the KATP channel by binding to their target site with one-to-one stoichiometry. Similar to glibenclamide, the binding of stilbene disulfonates may reflect interpolation in an "intermediate lipid compartment" between the cytosolic drug and the site of drug action. [ABSTRACT FROM AUTHOR]