Mariko Tsuboi

Mitochondrial DNA deletion associated with the reduction of adenine nucleotides in human atrium and atrial fibrillation

Background Structural changes in the number, size, and shape of mitochondria (mt) have been observed in the atrial muscles of patients with atrial fibrillation (AF) and of animals with rapid atrial pacing, however, it is not known whether the mitochondrial function is impaired in human atrium with AF.

Differences in the electrophysiological response to I− and the inhibitory anions SCN∮- and C1O4−, studied in FRTL-5 cells

The electrophysiological properties of the Na+/I- symporter (NIS) were examined in a cloned rat thyroid cell line (FRTL-5) using the whole-cell patch-clamp technique. When the holding potential was between -40 mV and -80 mV, 1 mM NaI and NaSCN induced an immediate inward current which was greater with SCN- than with I-. The reversal potential for I- and SCN- induced membrane currents was +50 mV. This is close to the value of +55 mV calculated by the Nernst equation for Na+. These results are consistent with I- and SCN- translocation via the NIS that is energized by the electrochemical gradient of Na+ and coupled to the transport of two or more Na+. There was no change in the membrane current recording with ClO-4 indicating that ClO-4 was either not transported into the cell, or the translocation was electroneutral. ClO-4 addition, however, did reverse the inward currents induced by I- or SCN-. These effects of I-, SCN- and ClO-4 on membrane currents reflect endogenous NIS activity since the responses duplicated those seen in CHO cells transfected with NIS. There were additional currents elicited by SCN- in FRTL-5 cells under certain conditions. For example at holding potentials of 0 and +30 mV, 1 mM SCN- produced an increasingly greater outward current. This outward current was transient. In addition, when SCN- was washed off the cells a transient inward current was detected. Unlike SCN-, 1-10 mM I- had no observable effect on the membrane current at holding potentials of 0 and +30 mV. The results indicate FRTL-5 cells may have a specific SCN- translocation system in addition to the SCN- translocation by the I- porter. Differences demonstrated in current response may explain some of the complicated influx and efflux properties of I-, SCN- and ClO-4 in thyroid cells.

A novel mutation causing complete deficiency of thyroxine binding globulin

Thyroxine binding globulin (TBG) is a serum protein that transports thyroxine. Three naturally occurring mutations have been reported to produce complete deficiency of TBG (TBG‐CD). The first to be reported was TBG‐CD5 in caucasian families of French‐Canadian origin and consists of substitutions in exons 2 and 3. TBG‐CD of English ethnic origin (TBG‐CD6) is characterized by a thymine deletion in codon 165 (exon 1). In Japanese families with TBG‐CD (TBG‐CDJ), a variant has been characterized with a deletion of the first base of the codon for amino acid 352 (exon 4) in the common type TBG. In this communication we report a new type of TBG‐CD in a family of japanese ethnic origin that is characterized by a single nucleotide substitution in place of two nucleotides in exon 1. This is an uncommon mutation which we have been unable to find in other genes.

Tonic block of the Na+ current in single atrial and ventricular guineapig myocytes, by a new antiarrhythmic drug, Ro 22-9194

Summary— Ro 22‐9194 reduced the Na+ current in the atrial myocytes as well as ventricular myocytes in a tonic block fashion. Ro 22‐9194 had a higher affinity to the inactivated state Na+ channels (Kd1 = 3.3 μM in atrial myocytes, Kd1 = 10.3 μM in ventricular myocytes) than to those in the rested state (KdR = 91 μM in atrial myocytes, KdR = 180 μM in ventricular myocytes), which indicated that Ro 22‐9194 had a higher affinity to the Na+ channels in atrial myocytes than in ventricular myocytes. Ro 22‐9194 shifted the inactivation curve in the hyperpolarized direction in both atrial and ventricular myocytes. These findings suggest that Ro 22‐9194 more strongly inhibited the Na+ channel of the atrial myocytes of the diseased hearts with the depolarized membranes potentials than the Na+ channels in ventricular myocytes.

Influence of extracellular H+ and Ca2+ on Ro 22-9194-induced block of sodium current in cardiac myocytes.

1. Ro 22-9194 reduced the Na current in ventricular myocytes in either a tonic block or phasic block manner. 2. Ro 22-9194 had a higher affinity to the inactivated state (Kdi = 10.3 microM) than to the rested state (Kdrest = 180 microM). 3. Extracellular acidification enhanced the tonic block but reduced the phasic block. 4. Elevation of extracellular Ca2+ inhibited the enhancing effects of extracellular acidification. 5. These findings suggest that Ro 22-9194 strongly inhibits Na+ channels of the ventricular myocytes of the diseased hearts, characterized by the depolarized cell membranes and by acid conditions.

Quinidine enhances intracellular Ca2+ accumulation during rapid stimulation

1. The quinidine-induced modification of intracellular Ca2+ concentration ([Ca2+]i) was studied in guinea-pig myocardium using fura-2. Quinidine reduced the systolic fluorescence signal level for [Ca2+]i and enhanced the end-diastolic signal level during a stimulation train. 2. The diastolic decay of [Ca2+]i fitted 2 exponential curves. Quinidine distorted the stimulation frequency-dependent acceleration of rapid [Ca2+]i decay, and prolonged the mean time constant of rapid decay after 2 Hz stimulation, from 154.4 to 205.3 msec (20 microM), and to 259.7 msec (60 microM quinidine). The time constant of slow recovery from [Ca2+]i accumulation after the stimulation train was not affected by stimulation frequency, or by quinidine, or caffeine. 3. These results suggest that quinidine modulates [Ca2+]i via a balance between the slowing of rapid [Ca2+]i decay and the reduction of the systolic [Ca2+]i. This effect may contribute to the anti-arrhythmic and pro-arrhythmic effects exerted by quinidine in some conditions.