The currents through single Na' channels from the sarcolemma of ventricular cells dissociated from adult rat hearts were studied using the patch-clamp technique. All patches had several Na' channels ; most had 5-10, while some had up to 50 channels . At 10°C, the conductance of the channel was 9.8 pS . The mean current for sets of many identical pulses inactivated exponentially with a time constant of 1 .7 ± 0.6 ms at -40 mV . Careful examination of the mean currents revealed a small, slow component of inactivation at pulse potentials ranging from -60 to -30 mV . The time constant of the slow component was between 8 and 14 ms . The channels that caused the slow component had the same conductance and reversal potential as the fast Na' currents and were blocked by tetrodotoxin . The slow currents appear to have been caused by repeated openings of one or more channels . The holding potential influenced the frequency with which such channel reopening occurred . The slow component was prominent during pulses from a holding potential of -100 mV, while it was very small during pulses from -140 mV . Ultraslow currents through the Na' channel were observed occasionally in patches that had large numbers of channels . They consisted of bursts of 10 or more sequential openings of a single channel and lasted for up to 150 ms . We conclude that the single channel data cannot be explained by standard models, even those that have two inactivated states or two open states of the channel. Our results suggest that Na' channels can function in several different "modes," each with a different inactivation rate .

Na' currents were measured during 0.4-s depolarizing pulses using the cell-attached variation of the patch-clamp technique. Patches on Csdialyzed segments of sartorius muscle of Rana pipiens contained an estimated 25-500 Na' channels . Three distinct types of current were observed after the pulse onset: (a) a large initial surge of inward current that decayed within 10 ms (early currents), (b) a steady "drizzle" of isolated, brief, inward unitary currents (background currents), and (c) occasional "cloudbursts" of tens to hundreds of sequential unitary inward currents (bursts) . Average late currents (background plus bursts) were 0.12% of peak early current amplitude at -20 mV . 85% of the late currents were carried by bursting channels. The unit current amplitude was the same for all three types of current, with a conductance of 10 .5 pS and a reversal potential of +74 mV. The magnitudes of the three current components were correlated from patch to patch, and all were eliminated by slow inactivation . We conclude that all three components were due to Na+ channel activity . The mean open time of the background currents was -0 .25 ms, and the channels averaged 1 .2 openings for each event. Neither the open time nor the number of openings of background currents was strongly sensitive to membrane potential. We estimated that background openings occurred at a rate of 0 .25 Hz for each channel. Bursts occurred once each 2,000 pulses for each channel (assuming identical channels). The open time during bursts increased with depolarization to 1-2 ms at -20 mV, whereas the closed time decreased to <0 .2 ms . The fractional open time during bursts was fitted with mW using standard Na + channel models . We conclude that background currents are caused by a return of normal Na' channels from inactivation, while bursts are instances where the channel's inactivation gate spontaneously loses its function for prolonged periods.

Limited data are available on direct-acting antivirals for treating hepatitis C virus (HCV) infection in patients with severe renal impairment. The aim of this study was to evaluate the effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) in patients with stage 4 or 5 chronic kidney disease (CKD) and HCV genotype 1 or 4 infection in real clinical practice, and to investigate pharmacological interactions. This retrospective study included patients treated with OBV/PTV/r+DSV±RBV or OBV/PTV/r+RBV with CKD stage 4 (eGFR: 15-29 mL/min/1.73m ) or 5 (eGFR<15 mL/min/1.73m or requiring dialysis) and HCV infection by genotypes 1 and 4 between April 2015 and October 2015 in nine Spanish centres. Sustained virological response at 12 weeks (SVR12) was assessed, and clinical and laboratory data, fibrosis stage, adverse events and pharmacological interactions were reported. Forty-six patients were included: 10 (21.7%) had CKD stage 4 and 36 (78.2%) CKD stage 5. Seventeen (36.9%) had cirrhosis. SVR12 rate in the intention-to-treat population was 95.7%. Twenty-one (45.6%) received RBV, which was discontinued in two (9.5%) patients. Anaemia (haemoglobin <10 g/dl) occurred in 12 patients (57.1%) with RBV vs 10 (40.0%) without RBV (P=.246). Renal function remained stable during antiviral therapy. Nine patients (19.5%) experienced serious adverse events unrelated to antiviral therapy. Concomitant medication was discontinued or modified in 41.3% of patients. In conclusion, the effectiveness of OBV/PTV/r±DSV±RBV in patients with CKD 4-5 was similar to that observed in those with normal renal function and was not associated with severe adverse events.

Single voltage-activated Na+ channel currents were obtained from membrane patches on internally dialyzed skeletal muscle segments of adult frogs. The high channel density in these membranes permitted frequent observation of the "bursting mode" of individual Na+ channels during 400-ms records. We examined the opentimes within and between bursts on individual membrane patches. We used a new nonparametric statistical procedure to test for heterogeneity in the opentime distributions. We found that although 80% of all bursts consisted of opentimes drawn from a single distribution, the opentime distribution varied significantly from burst to burst. Significant heterogeneity was also detected within the remaining 20% of individual bursts. Our results indicate that the gating kinetics of individual Na+ channels are heterogeneous, and that they may occasionally change in a single channel.

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