PubMed Health⌕ Search

Biomedical subjects

N Homma

Publications and source records attributed to N Homma.

At least 19 recordsLinked to original sources
PubMed2001

Electrophysiologic effects of an antiarrhythmic agent, bidisomide, on sodium current in isolated rat ventricular myocytes: comparison with mexiletine and disopyramide.

The effects of bidisomide, an antiarrhythmic agent, on sodium current (I(Na)) in isolated rat ventricular myocytes were investigated using a whole cell voltage clamp method. Bidisomide blocked I(Na) with a Ki of 214 microM at a holding potential of -140 mV. The blockade of I(Na) was enhanced at a less negative holding potential of -100 mV with a Ki of 21 microM. Bidisomide shifted the steady state inactivation curve to a negative potential direction by 20 mV without a significant change in the slope factor. Bidisomide slowed the time course of recovery of I(Na) at a holding potential of -140 mV with a slow recovery phase. The time constant of recovery phase for bidisomide, disopyramide and mexiletine were 2703, 1858 and 757 ms, respectively. The development of the block of I(Na) consisted of two phases in the presence of bidisomide. The fast and slow time constants were 11 and 648 ms. Bidisomide produced a use-dependent block of I(Na) when the depolarizing pulse was repeated at 1-3 Hz. Our results indicate that bidisomide binds to rat cardiac sodium channels and that the dissociation kinetics of bidisomide from the inactivated sodium channel is slower than that of disopyramide.

Animals↗
PubMed2000

Both alpha(1A)- and alpha(1B)-adrenergic receptor subtypes couple to the transient outward current (I(To)) in rat ventricular myocytes.

1. Regulation of transient outward current (I(To)) by alpha(1)-adrenergic (alpha(1)AR) plays a key role in cardiac repolarization. alpha(1)ARs comprise a heterogeneous family; two natively expressed subtypes (alpha(1A) and alpha(1B)) and three cloned subtypes (alpha(1a), alpha(1b) and alpha(1d)) can be distinguished. We have examined the electrophysiological role of each alpha(1)AR subtype in regulating I(To) in isolated rat ventricular myocytes. 2. Reverse transcription-PCR study revealed the presence of three subtype mRNAs (alpha(1a), alpha(1b) and alpha(1d)) in rat myocytes. 3. Radioligand binding assay using [(125)I]-HEAT showed that the inhibition curves for alpha(1A)AR-selective antagonists (WB4101, 5-methylurapidil, (+)-niguldipine and KMD-3213) in rat ventricles best fit a two-site model, with 30% high and 70% low affinity binding sites. The high affinity sites were resistant to 100 microM chloroethylclonidine (CEC), while the low affinity sites were highly inactivated by CEC. 4. Whole cell voltage clamp study revealed that methoxamine reduced a 4-aminopyridine(4-AP)-sensitive component of I(To) in the isolated rat ventricle myocytes. Lower concentrations of KMD-3213 (1 nM) or 5-MU (10 nM) did not affect the methoxamine-induced reduction of I(To). On the other hand, CEC treatment (100 microM) of isolated myocytes reduced the methoxamine-induced reduction of I(To) by 46%, and the remaining response was abolished by lower concentrations of KMD-3213 or 5-MU. 5. The results indicate that rat ventricular myocytes express transcripts of the three alpha(1)AR subtypes (alpha(1a), alpha(1b) and alpha(1d)); however, two pharmacologically distinct alpha(1)AR subtypes (alpha(1A) and alpha(1B)) are predominating in receptor populations, with approximately 30% alpha(1A)AR and 70% alpha(1B)AR. Although both alpha(1A) and alpha(1B)AR subtypes are coupled to the cardiac I(To), alpha(1B)ARs predominantly mediate alpha(1)AR-induced effect.

Adrenergic alpha-Agonists↗
PubMed1999

The anti-ischemic effects of CP-060S during pacing-induced ischemia in anesthetized dogs.

CP-060 S, (-)-( S)-2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[N-methyl-N-[2-(3 ,4-methylenedioxyphenoxy)ethyl]-amino]propyl]-1,3-thiazolidin++ +-4-one hydrogen fumarate, is a novel cardioprotective drug which prevents Na+-, Ca2+-overload and has Ca2+ channel blocking activity. We compared the anti-ischemic effects of CP-060S with those of diltiazem, a Ca2+ channel blocker, and R56865, N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazo lamine, a Na+-, Ca2+-overload inhibitor, in a canine pacing-induced ischemia model. CP-060S 100 microg kg(-1) significantly suppressed the pacing-induced ischemic epicardial ST-segment elevation by maximally 75%, while diltiazem 100 microg kg(-1) suppressed it by maximally 35%. R56865 100 microg kg(-1) significantly suppressed the ST-segment elevation by maximally 30%. In addition, diltiazem 100 microg kg(-1) caused synergistic suppression of ST-segment elevation by 70% when administered simultaneously with R56865 100 microg kg(-1). These results suggest that a Na+-, Ca2+-overload preventive action and a Ca2+ channel blocking action independently contribute to the suppression of the ST-segment elevation. Therefore, CP-060S may suppress pacing-induced ST-segment elevation by a dual action by preventing Na+-, Ca2+-overload and the Ca2+ channel blockade.

Anesthesia↗
PubMed1998

A particle-receptor model for the insulin-induced closure of connexin43 channels.

Connexin43(Cx43) channels can be regulated by a variety of factors, including low pHi. Structure/function studies from this laboratory have demonstrated that pH gating follows a particle-receptor mechanism, similar to the "ball-and-chain" model of voltage-dependent inactivation of ion channels. The question whether the particle-receptor model is applicable only to pH gating or to other forms of Cx43 regulation as well remains. To address this question, we looked at the uncoupling effects of insulin and of insulin-like growth factor-1 (IGF) on Cx43 channels expressed in Xenopus oocytes. These agonists do not induce changes in pHi. Junctional conductance (Gj) was measured by the dual 2-electrode voltage-clamp technique. Control studies showed that relative Gj did not change spontaneously as a function of time. Continuous exposure of Cx43-expressing oocytes to insulin (10 micro/L) led to a decrease in Gj. After 80 minutes, Gj was 54+/-5% from control (n= 12). Exposure of oocytes to IGF (10 nmol/L) caused an even more pronounced change in Gj (37+/-4% of control, n=6). The time course of the IGF-induced uncoupling was similar to that observed after insulin exposure. The effect of insulin was abolished by truncation of the carboxyl-terminal domain of Cx43 at amino acid 257 (M257). Interestingly, as in the case of pH gating, coexpression of the carboxyl-terminal domain (amino acids 258 to 282) together with M257 rescued the ability of insulin to reduce coupling (Gj, 39+/-12% from control; n=6). Structure/function experiments using various deletion mutants of the carboxyl-terminal domain showed that insulin treatment does not modify Gj if amino acids 261 to 280 are missing from the Cx43 sequence. Our results suggest that a particle-receptor (or ball-and-chain) mechanism, similar to that described for pH gating, also applies to chemical regulation of Cx43 by other factors.

Amino Acid Sequence↗
PubMed1996

Flow cytometry analysis of alpha1-adrenoceptor subtypes.

To characterize the alpha1-adrenoceptor subtypes, we developed a flow cytometry method using the fluorescent ligand BODIPY-FL prazosin and the anti-peptide antibody against the alpha1b-adrenoceptor amino terminus (designated 1B-N1-C) as probes. Three alpha1-adrenoceptors (alpha1a, alpha1b and alpha1d) expressed in CHO cells were detected by BODIPY-FL prazosin; however, only alpha1b-adrenoceptor subtype was detected by the anti-peptide antibody 1B-N1-C. Furthermore, the flow cytometry analysis with 1B-N1-C specifically identified alpha1b-adrenoceptor in native cells of hamster DDT1-MF2 cells, rat hepatocytes and cardiomyocytes.

Amino Acid Sequence↗
PubMed1993

A new therapeutic approach to dialysis amyloidosis: intensive removal of beta 2-microglobulin with adsorbent column.

Amyloidosis, in which amyloid protein consists of beta 2-microglobulin (beta 2-M), is both a common and a serious complication of long-term hemodialysis. The mechanism of its development is not completely understood. Since beta 2-M is an amyloid protein, it is essential to try to remove as much of it as possible. A specific adsorbent of beta 2-M has been developed for use in direct hemoperfusion. The adsorbent is a porous cellulose bead to which hydrophobic organic compound is bound covalently. A combination of a high-flux membrane dialyzer and an adsorption column (BM-01) would make it possible to efficiently eliminate beta 2-M. Dialysis with a combination of direct hemoperfusion (DHP) and an adsorption column led to the elimination of more than 200-300 mg of beta 2-M. We observed 5 patients who received treatment with this column (BM-01) in combination with high-flux dialysis 3 times a week for periods of 1 week (3 patients), 6 months (1 patient), or 14 months (1 patient). It is demonstrated that the adsorbent column (BM-01) provides an intensive method to eliminate beta 2-M from the blood with no serious adverse effect. It thus has the potential to suppress the progression of dialysis amyloidosis. The use of this adsorbent column (BM-01) in combination with a high-flux dialyzer may present an improved approach to removing beta 2-M from the body.

Adsorption↗
PubMed1993

Long-term complications of dialysis: pathogenic factors with special reference to amyloidosis.

Amyloidosis, caused by amyloid containing beta 2-microglobulin (beta 2m), is a frequent complication of long-term hemodialysis. The precise mechanism of its pathogenesis is not known. While beta 2m is an amyloid protein, other factors likely are involved in the pathogenesis of such amyloidosis. In treating patients with dialysis-related amyloidosis, it is essential to remove as much beta 2m from the blood as possible. In this respect, progress has been made in developing a column to adsorb beta 2m from the blood. Using a combination of a high-flux dialyzer and an adsorption column, it becomes possible to efficiently eliminate beta 2m. We have treated four patients with this column in combination with a high-flux dialyzer three times a week for periods of one month or one year. The absorbent column eliminates beta 2m from the blood, and may thus halt or slow the progression of beta 2m-related amyloidosis. However, such treatment is still in a preliminary phase; long-term studies are required to determine clinical efficacy.

Amyloidosis↗
PubMed1992

Cystic radiolucencies of carpal bones, distal radius and ulna as a marker for dialysis-associated amyloid osteoarthropathy.

Patients on long-term hemodialysis (HD) are known to develop amyloid osteoarthropathy, evidenced as cystic radiolucencies on X-rays of the affected joints. To study the relationship between cystic radiolucencies and amyloid osteoarthropathy in 394 patients, we classified the severity of the cystic radiolucencies seen in the wrist joint on a 4-point scale and evaluated the association between lesion severity (grade) and several parameters. Biopsy was performed in 8 patients with 11 bone cysts of the wrist joint who had been operated for carpal tunnel syndrome. HD for 10 years or longer, age 50 or older and the presence of carpal tunnel syndrome were associated with severe cyst rating. There was no association between lesion grade and serum level of PTH-C, aluminum or beta 2-microglobulin (B2M). Ten of the 11 biopsied bone cysts in 8 patients with carpal tunnel syndrome demonstrated amyloid deposits which reacted with B2M. We conclude that a cystic radiolucency observed in the wrist joint of a patient undergoing HD indicates the deposition of amyloid. The cyst grade provides a useful marker for the severity of amyloid osteoarthropathy in HD patients.

Adult↗
PubMed1990

Anticholinergic action of quinidine sulfate in the rabbit atrioventricular node.

Anticholinergic action of quinidine sulfate was electrophysiologically studied by recording spontaneous action potentials and membrane current of the rabbit atrioventricular node. In the presence of 0.1 mumol/l carbachol, the spontaneous activity of the atrioventricular nodal preparations was markedly inhibited, whereas subsequent addition of 1, 5 and 20 mumol/l quinidine restored automaticity in a concentration-dependent manner. In some preparations, quinidine at concentrations of 5 mumol/l and higher slowed the spontaneous activity by its direct membrane action even in the presence of carbachol. The dose-response curve for acetylcholine action on the spontaneous firing frequency showed that one molecule of acetylcholine bound to one muscarinic receptor of the atrioventricular node cell (Hill coefficient = 1.2). A parallel shift of this curve towards higher acetylcholine concentrations was observed at 0.03, 0.1 and 0.3 mumol/l but not at 1 and 3 mumol/l quinidine, suggesting a noncompetitive antagonism of quinidine against acetylcholine. Voltage clamp experiments revealed that 5 mumol/l quinidine reduced the slow inward current, hyperpolarization-activated inward current, and delayed rectifying K+ current, through its membrane actions. Quinidine at this concentration almost completely suppressed the acetylcholine-activated K+ current, which showed a relaxation phenomenon. Hence, the direct blockage of the acetylcholine-activated K+ current by quinidine was considered responsible for the anticholinergic action of this drug. We conclude that quinidine is a non-specific ionic channel blocker that inhibits all the membrane currents in the atrioventricular node including the acetylcholine-activated K+ current.

Action Potentials↗