Biomedical subjects

I Hisatome

Publications and source records attributed to I Hisatome.

At least 55 records · Page 3Linked to original sources

PubMed1997

Different electrophysiological character of I-, ClO4-, and SCN- in the transport by Na+/I- symporter.

The electrophysiological characteristics of the Na+/I- symporter were examined using the Chinese hamster ovary (CHO) cell line, which was transfected with the rat Na+/I- symporter gene and stably expressed the Na+/I- symporter. In this cell line, iodide uptake was dependent on Na+, and kinetic studies revealed that the K(m) for iodide was 35 microM, similar to that of FRTL-5 cells. The maximal velocity at the cell protein level was 6- to 10-fold higher than in FRTL-5 cells. ClO-4 and SCN- dose-dependently inhibited iodide uptake in a competitive manner. Electrophysiological characteristics were examined using the whole-cell patch-clamp technique. The holding current at-40 mV rapidly shifted inwardly when the cells were perfused with 1 mEq I- or SCN-. The inward current induced by 1 mEq I- did not increase when bathing solution was replaced with a Tyrode solution with 10 mEq I-, indicating that 1 mEq I- was a saturating amount. The inward current induced by 1 mEq I- increased 1.5-fold by changing the bathing solution to a Tyrode solution containing 1 mEq I- and 1 mEq SCN-. The inward current induced by 0.5 mEq SCN- decreased when the bathing solution was changed to a Tyrode solution containing 0.5 mEq SCN- and 10 mEq I-. These findings indicated that the I- ion and the SCN- ion were carried by the NA+/ I- symporter with at least two Na+ ions. The current induced by the transport of SCN- was larger than that induced by the transport of I-, possibly because the number of Na+ ions that was carried with one SCN- ion was larger than the number of Na+ ions carried with one I- ion. Surprisingly, the perfusion of ClO-4 did not induce an inward current, indicating that ClO-4 bound to the Na+/I- symporter, but was not carried by it, or that one ClO-4 ion was carried with one Na+ ion.

Animals↗

PubMed1997

Responses of catecholamines, renin-angiotensin system, and atrial natriuretic peptide to exercise in untrained men and women.

1. Plasma norepinephrine (NE), epinephrine (E), renin activity (PRA), angiotensin II (ATII), aldosterone (ALD), and atrial natriuretic peptide (ANP) were measured in 20 male and 15 female subjects during submaximal treadmill test. 2. Exercise duration was not different between the two groups (male vs. female: 13.4 +/- 0.8 min vs. 11.6 +/- 0.7 min, ns). Female subjects had higher heart rate during exercise, while systolic blood pressure at peak exercise was higher in male subjects. 3. Plasma NE, E, ANP, and ATII responses were comparable between male and female subjects, but PRA both at rest and during exercise and ALD at rest were significantly higher in male subjects. 4. Cardiac responses to submaximal exercise were different between male and female subjects, but neurohormonal responses were comparable between the two groups except for the high PRA at rest and during exercise and high plasma ALD at rest in male subjects.

Adult↗

PubMed1997

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.

Animals↗

PubMed1997

A novel mutation causing complete deficiency of thyroxine binding globulin.

OBJECTIVE: 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. DESIGN: Exons of the TBG gene amplified by the polymerase chain reaction (PCR) were subcloned and sequenced. To examine for the presence of the same mutation in potentially affected individuals, we performed PCR using primer-directed mutagenesis or allele-specific amplification. PATIENTS: The index case was of Japanese ethnic origin, and was diagnosed as having TBG deficiency on the basis of undetectable serum TBG. The patient consented to this evaluation and the protocol was in accordance with IRB standards. MEASUREMENTS: Serum thyroid hormones, thyrotrophin binding inhibitory immunoglobulin and TBG concentrations were measured by conventional radio-immunoassay. Genomic DNA was extracted from white blood cells. RESULTS: In the index case exons 2, 3 and 4 were normal, but nucleotides 144 (cytosine) and 145 (thymine) in exon 1 were substituted with a single base (adenine) which induced a frame shift in the reading frame, resulting in an early stop codon at codon 51. The patient and his daughters were confirmed as having this mutation using primer-directed mutagenesis or allele-specific amplification. CONCLUSIONS: We have described a novel mutation in the TBG gene in a Japanese family. This results in a frame shift and premature stop codon, and was associated with undetectable serum TBG in the index case.

Exons↗

PubMed1997

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

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 (KdI = 3.3 microM in atrial myocytes, KdI = 10.3 microM in ventricular myocytes) than to those in the rested state (KdR = 91 microM in atrial myocytes, KdR = 180 microM 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.

Animals↗

PubMed1996

Amitriptyline inhibits the G protein and K+ channel in the cloned thyroid cell line.

We have reported that thyroid K+ channel is activated by extracellular application of the thyroid-stimulating hormone (TSH) using single channel recording method performed on cloned normal rat thyroid cell (FRTL-5) membrane. Treatment of dibutyryladenosine cyclic monophosphate (Bt2 cAMP) also activated the TSH-dependent K+ channel. These findings indicate that the thyroid K+ channel is activated through the TSH-adenosine cyclic monophosphate (cAMP)-protein kinase A system. We examined the effects of amitriptyline on TSH-guanosine triphosphate binding protein (G protein)-adenylate cyclase-cAMP-K+ channel system in the cloned normal rat thyroid cell line FRTL-5. Amitriptyline inhibited the cAMP production induced by TSH. Amitriptyline also inhibited the cAMP production induced by cholera toxin, indicating that amitriptyline inhibited the thyroid G protein. Amitriptyline had no effect on TSH-receptor binding and cAMP production by forskolin (adenylate cyclase stimulator). Amitriptyline inhibited the K+ channel activation by cAMP, indicating that the suppressing mechanism is not the inhibition of TSH receptor or G protein but the direct suppression of K+ channel. It was concluded that amitriptyline inhibited the thyroid G protein and K+ channel.

Amitriptyline↗

PubMed1996

Responses of plasma norepinephrine and renin-angiotensin-aldosterone system to dynamic exercise in patients with congestive heart failure.

BACKGROUND: Neurohormonal activation is present and neurohormonal responses to dynamic exercise are altered in congestive heart failure (CHF). Responses of plasma norepinephrine in various degrees of heart failure have been investigated, but the responses of the renin-angiotensin-aldosterone system have not been studied in relation to the severity of CHF. The aim of this study was to determine if the responses of the renin-angiotensin-aldosterone system to exercise are augmented according to the severity of CHF. METHODS AND RESULTS: Ventilatory and neurohormonal responses were assessed in 38 patients with CHF (New York Heart Association class: I, 13 patients; II, 14 patients; III, 11 patients) and 11 normal subjects during symptom-limited cardiopulmonary exercise testing. Plasma norepinephrine, renin activity, angiotensin II, and aldosterone were measured at rest and at peak exercise. The increments in neurohormones were divided by peak oxygen consumption, and these ratios (norepinephrine exercise ratio, plasma renin activity-exercise ratio, angiotensin II-exercise ratio, aldosterone-exercise ratio) were compared among groups. Peak oxygen consumption and anaerobic threshold decreased progressively with the severity of CHF. Neurohormonal profiles at rest showed that plasma norepinephrine levels were significantly higher, and the renin-angiotensin-aldosterone system was augmented only in patients with class III CHF. Neurohormones increased during exercise both in patients with CHF and in normal subjects, but patients with class III CHF had significantly higher plasma renin activity (10.11 +/- 2.32 ng/mL/h), angiotensin II (73.9 +/- 14.2 pg/mL), and aldosterone (265.2 +/- 61.1 pg/mL) than did normal subjects. Plasma renin activity-exercise ratio, angiotensin II-exercise ratio, and aldosterone-exercise ratio in patients with class III CHF were significantly higher compared to normal subjects. This augmentation of the renin-angiotensin-aldosterone system was not observed in class I or II patients. Peak plasma norepinephrine levels were not different among normal subjects and subgroups of CHF patients, but the norepinephrine-exercise ratio was significantly higher in classes II and III CHF compared to normal subjects. CONCLUSIONS: These data suggest that neurohormonal excitation during exercise increases along with the severity of CHF when normalized for peak exercise level.

Aldosterone↗

PubMed1996

RANTES and platelet-activating factor open Ca2+-activated K+ channels in eosinophils.

RANTES is a member of the low molecular cytokines and appears to be strictly a chemotactic and activating factor for eosinophils. We studied the effect of RANTES on the channel activity of the eosinophilic cell line (EoL-1 cells) using patch clamp techniques. Under cell-attached patch conditions, RANTES (20 ng/ml) activated channels in EoL-1 cells when applied to the recording pipette or to the bath. This channel was permeable to K+ with a unit conductance of 14 pS, and the reversal potential was close to the equilibrium potential for K+. The current-voltage relationship for this K+ channel was almost linear, showing little or no rectification. The open time and closed time histograms could he fitted to a single exponential function with time constants of 6.4 and 2.7 ms, respectively. Extracellular application of the calcium ionophore A23187 (1 microM) under cell-attached patch conditions or an increase in intracellular Ca2+ concentration under inside-out patch conditions increased K+ channel activity in a manner similar to that caused by RANTES, indicating that the RANTES-activated channel was the Ca2+ -activated K+ channel. Intracellular application of GTP gamma S (10 microM) opened the Ca2+V-activated K+ channels under inside-out patch conditions. Furthermore, RANTES failed to activate the K+ channels after the cells had been treated with pertussis toxin (100 ng/ml) for 2 h at 37 degrees C. These results suggest that RANTES opens the Ca2+ -activated K+ channels of EoL-1 cells through activation of G-proteins.

Calcium↗

PubMed1996

Catecholamines, renin-angiotensin-aldosterone system, and atrial natriuretic peptide at rest and during submaximal exercise in patients with congestive heart failure.

The aim of this study was to determine the responses of plasma catecholamines, renin-angiotensin-aldosterone (RAA) activity, and plasma atrial natriuretic peptide (ANP) to exercise in patients with congestive heart failure (CHF). Cardiac and neurohormonal responses were assessed during submaximal treadmill exercise testing in 23 patients with CHF (New York Heart Association classes I-III) and 13 control subjects (without CHF). Plasma norepinephrine, epinephrine, renin activity (PRA), angiotensin II (ATII), aldosterone, and ANP were measured at rest and immediately after exercise. Exercise duration was shorter in patients with CHF (control, 10.4 +/- 0.9 minute; CHF, 6.2 +/- 0.7 minute; P < 0.01). Heart rate and blood pressure responses were similar except for the smaller peak heart rate (control, 145 +/- 5 beats per minute; CHF, 129 +/- 4 beats per minute; P < 0.05) and higher systolic blood pressure at recovery stage (control, 122 +/- 4 mm Hg; CHF, 142 +/- 4 mm Hg; P < 0.01) in patients with CHF. At rest, plasma norepinephrine levels were insignificantly higher in patients with CHF (control, 110 +/- 10 pg/mL; CHF, 170 +/- 26 pg/mL; P = 0.09), and ANP levels (control, 40 +/- 5 pg/mL; CHF, 94 +/- 17 pg/mL; P < 0.05) and PRA levels (control, 0.77 +/- 0.11 ng/mL/hr; CHF, 4.33 +/- 1.25 ng/mL/hr; P < 0.05) were significantly higher. There were no differences in peak norepinephrine, epinephrine, or ANP between the two groups. Angiotensin II and aldosterone levels were similar between the two groups, although, in patients with CHF, there was a trend toward higher levels of ATII while at rest (control, 12.4 +/- 1.4 pg/mL; CHF, 20.3 +/- 3.3 pg/mL; P = 0.08) and at peak (control, 20.5 +/- 1.8 pg/mL; CHF, 41.0 +/- 9.4 pg/mL; P = 0.10). Peak values of PRA, ATII, and aldosterone positively correlated with respective resting values of PRA (r = 0.88 ng/mL/hr, P < 0.01), ATII (r = 0.63 pg/mL, P < 0.01), and aldosterone (r = 0.99, P < 0.01). Peak norepinephrine and peak ANP also positively correlated with respective resting values of norepinephrine (r = 0.58 pg/mL, P < 0.05) and ANP (r = 0.94, P < 0.01). Analysis of these results showed that patients with CHF had significantly higher levels of PRA and ANP at rest, and a trend toward augmentation in RAA system activity during exercise with less exercise workload. Basal level of neurohormones seemed to be an important determinant for the degree of exercise-induced neurohormonal activation in patients with CHF.

Atrial Natriuretic Factor↗

PubMed1996

Ammonia response to exercise in patients with congestive heart failure.

OBJECTIVE: To assess energy depletion in skeletal muscle in patients with congestive heart failure by measuring blood purine metabolites during exercise and, at the same time, determine the implications of the ammonia response to exercise in these patients. SETTING: Tottori University Hospital, Yonago, Japan. PATIENTS: 49 heart failure patients (New York Heart Association (NYHA) grades I-III) and 16 normal subjects. MAIN OUTCOME MEASURES: Blood lactate, ammonia, and hypoxanthine levels were measured during exercise with expired gas analysis. RESULTS: In normal exercising subjects as well as in each heart failure subgroup, the ammonia threshold was significantly higher than both the lactate threshold [control: 21.8 (SD 5.3) v 17.4 (3.3) ml/kg/min; NYHA class I: 18.9 (3.8) v 15.5 (2.6); class II: 14.8 (2.5) v 12.7 (2.4); class III: 13.5 (2.6) v 11.8 (2.5)] and the ventilatory threshold (P < 0.01). The difference between the ammonia and lactate thresholds was noted in all normal subjects and in all heart failure patients. The ammonia threshold, however, was significantly lower in heart failure patients than in normal subjects and it decreased with increasing NYHA class (P < 0.01). Maximum ammonia levels were lower in the heart failure group and decreased further with higher NYHA classifications [control: 198 (52) mg/dl; NYHA class I: 170 (74); class II: 134 (58); class III: 72 (15); P < 0.01]. There were significant correlations between maximum ammonia values and maximum lactate, oxygen consumption, and hypoxanthine levels (r = 0.74, 0.48, and 0.87, respectively; P < 0.001). CONCLUSIONS: The ammonia threshold may reflect the onset of ATP depletion in exercising skeletal muscles, as opposed to the onset of anaerobic respiration. It seems therefore that energy depletion in skeletal muscles during exercise occurs after attaining the anaerobic threshold. Both aerobic and anaerobic capacities of skeletal muscle are reduced in patients with congestive heart failure.

Adenosine Triphosphate↗

PubMed1996

A new type of familial central diabetes insipidus caused by a single base substitution in the neurophysin II coding region of the vasopressin gene.

We studied the genetic basis of familial neurohypophyseal diabetes insipidus in a Japanese family. The members had polyuria and a deficiency of plasma vasopressin (AVP). Polymerase chain reaction (PCR) amplified exons of the AVP-neurophysin-II gene were subcloned and sequenced. Exons 1 and 3 were normal, but nucleotide 1884 Guanine (G) in exon 2 was substituted with Thymine (T), which induced a substitution of glycine (Gly) for valine (Val). To examine the presence of this mutation in the affected subjects, we designed two mutated primers. One of them induced a new endonuclease restriction site in the PCR fragments from normal, and the other induced a new endonuclease restriction site from patients with the mutation. DNA fragments from two affected members of this family were amplified with this primer, and the PCR products were digested by endonuclease and resolved by electrophoresis. The results indicated that these subjects had both normal and mutant alleles, indicating that the mutation was heterozygous. We concluded that this mutation caused neurohypophyseal diabetes insipidus in this family.

Arginine Vasopressin↗

PubMed1996

Augmented response in plasma atrial natriuretic peptide to dynamic exercise in patients with congestive heart failure.

Neurohormonal activation is present and neurohormonal responses to dynamic exercise are altered in patients with congestive heart failure (CHF). The aim of this study was to determine if the responses of atrial natriuretic peptide (ANP) normalized for peak oxygen consumption (peak VO2) to exercise are augmented in patients with CHF. Ventilatory and ANP responses were assessed in 28 patients with CHF (NYHA classes II: 16, III: 12), 17 patients in NYHA class I, and 14 normal subjects during symptom-limited cardiopulmonary exercise testing. Plasma ANP was measured at rest and immediately after peak exercise. The increase in ANP was divided by peak VO2 and this ratio [ANP-Exercise Ratio: (peak ANP-rest ANP)/peak VO2] was compared among the 3 groups. Peak VO2 (Normal, NYHA I, CHF: 29.9 +/- 1.7, 24.0 +/- 1.3, 17.4 +/- 0.8 ml/min per kg), anaerobic threshold and peak work rate were lower in patients with CHF. The resting ANP level was significantly higher in patients with CHF (Normal, NYHA I, CHF: 35.4 +/- 4.6, 42.9 +/- 5.8, 80.8 +/- 12.9 pg/ml). The ANP level increased during exercise in all 3 groups, and patients with CHF had a significantly higher ANP level than normal subjects and NYHA class I patients (Normal, NYHA I, CHF: 65.3 +/- 10.7, 75.9 +/- 14.4, 141.6 +/- 20.1 pg/ml). The ANP-Exercise Ratio in patients with CHF was significantly higher than those in normal subjects and NYHA class I patients (Normal, NYHA I, CHF: 0.96 +/- 0.26, 1.32 +/- 0.38, 3.59 +/- 0.72). These data suggest that patients with CHF but not those in NYHA class I have an augmented ANP response, as reflected by both absolute ANP levels and by the exercise ratio, which was normalized by the peak exercise level.

Atrial Natriuretic Factor↗

PubMed1996

Renal handling of urate in a patient with familial juvenile gouty nephropathy.

We encountered a case of familial juvenile gouty nephropathy (FJGN) with an autosomal dominant transmission pattern. Hyperuricemia in the propositus was caused by renal underexcretion of urate although his erythrocyte purine enzyme was normal. A renal biopsy specimen from the propositus showed interstitial fibrosis with tubular atrophy. On pyrazinamide and probenecid tests, the tubular secretion of urate selectively decreased without changes in either presecretory or postsecretory reabsorption of urate when his renal function was normal. Probenecid increased the urinary urate excretion and Cur/Ccr. The serum urate concentration was poorly controlled by allopurinol. When his renal function deteriorated, the uricosuric effects of both probenecid and benzbromarone were attenuated. However, the combined administration of probenecid with allopurinol decreased the serum urate concentration. These data suggest that the tubular secretion of urate is selectively impaired in FJGN and at the stage of renal failure, the combination of an uricosuric agent with allopurinol might be effective in treating hyperuricemia in FJGN.

Adolescent↗

PubMed1996

[Renal hypouricemia].

Renal hypouricemia (serum urate < 2.0 mg/dl) is the inborn disorder due to the impaired tubular urate transport resulted in an increased urate excretion. The inheritance shows an autosomal recessive trait. The prevalence of renal hypouricemia is 0.15% in the outpatients. Based on the 4-component model, by using the pharmacological inhibitor, renal hypouricemia is classified into the 4 types as follows, 1) defective presecretory reabsorption, 2) defective postsecretory reabsorption, 3) enhanced urate secretion, and 4) both defective presecretory and postsecretory reabsorption including the three subtypes. Although renal hypouricemia has asymptomatic as usual, acute renal failure and urolithiasis (hematuria) have been reported as the complication. We further introduced the novel pathophysiology of the renal hypouricemia such as the aciduria correlating to the accelerated urate excretion and the hyperoxipurinemia in this review.

Acute Kidney Injury↗

PubMed1995

Possible mechanism of oxygen radical production by human eosinophils mediated by K+ channel activation.

Quinidine hydrochloride, as potent K+ channel blocker, reduced luminol-dependent chemiluminescence products evoked by the addition of the calcium ionophore A23187 to eosinophils from patients with hypereosinophilic syndrome (n = 3) in a concentration-dependent manner (10-5 mM quinidine). A23187 is known to cause increases in intracellular Ca2+ concentrations in eosinophils. Our results indicate that the production of reactive oxygen species by human eosinophils may be affected by Ca(+)-activated K+ channels.

Calcimycin↗

PubMed1995

Nicorandil suppressed myocardial purine metabolism during exercise in patients with angina pectoris.

To elucidate the effect of Nicorandil on myocardial energy metabolism and myocardial sympathetic activity, we administered Nicorandil orally to eight patients with angina pectoris prior to exercise testing. Arterial and coronary sinus levels of lactate, ammonia, hypoxanthine (HX), adrenaline and noradrenaline were measured during exercise in order to determine the irrespective myocardial extraction ratios (MER). Compared to placebo, Nicorandil increased the time to development of significant ST depression (322 vs 390 s) while decreasing the maximum amplitude of ST depression (0.244 vs 0.216 mV). Heart rate, systolic blood pressure, and the rate pressure product during exercise were not significantly affected. The MER of lactate, measured during exercise, was significantly higher after Nicorandil than placebo (13.6 vs 27.9). Similarly, the MERs of ammonia and HX were significantly higher after Nicorandil (-46.0 vs 7.4% and -47.0 vs 9.9% respectively). Nicorandil, had no apparent effect on myocardial sympathetic activity as the MERs of adrenaline and noradrenaline were essentially unaffected. We conclude that Nicorandil decreased myocardial ischaemia and suppressed myocardial accelerated purine metabolism (a marker of cellular energy metabolism) during exercise in patients with angina pectoris. This effect appears not to be related to myocardial sympathetic activity.

Administration, Oral↗

PubMed1995

Mechanism of inhibition of the sodium current by bepridil in guinea-pig isolated ventricular cells.

1. Effects of bepridil, a sodium-, calcium-, and potassium-antagonistic agent, on the Na+ current were studied by the whole cell voltage clamp technique (tip resistance = 0.5 MOhm, [Na]i and [Na]o 10 mmol l-1 at 20 degrees C). 2. Bepridil produced tonic block (Kdrest = 295.44 mumol l-1, Kdi = 1.41 mumol l-1; n = 4). 3. Bepridil (100 mumol l-1) shifted the inactivation curve in the hyperpolarization direction by 13.4 +/- 2.7 mV (n = 4) without change in the slope factor. 4. In the presence of 50 mumol l-1 bepridil, bepridil showed use-dependent block at 2 Hz, whereas changes in pulse duration did not significantly effect this use-dependent block (81% +/- 2% at 10 ms, 84% +/- 3% at 30 ms, 86% +/- 3% at 100 ms; n = 4). 5. After removal of fast inactivation of the Na+ current by 3 mmol l-1 tosylchloramide sodium, bepridil (50 mumol l-1) still showed use-dependent block which was independent of the holding potential. 6. The recovery time constant from the bepridil-induced use-dependent block was 0.48 s at holding potential of -100 mV and 0.51 s at holding potential of -140 mV. 7. These results indicate that bepridil could bind to the receptor in the sodium channel through the hydrophobic and the hydrophilic pathway and leave the receptor through the hydrophobic pathway in the lipid bilayer. The binding and dissociation kinetics of this drug were shown to be fast, and the accumulation of the drug in the sodium channel appeared to be small. Bepridil is presumed to be safe in terms of adverse effects that result from drug-accumulation in the sodium channel.

Animals↗

PubMed1995

A new class III antiarrhythmic drug, MS-551, blocks the inward rectifier potassium channel in isolated guinea pig ventricular myocytes.

We have studied the effects of MS-551 on the inward rectifier potassium channel (IK1) in isolated guinea-pig ventricular myocytes by use of whole-cell and single-channel recording techniques. MS-551 (5 microM) blocked the IK1 current. The percent blockade of the peak and steady-state IK1 current by MS-551 was constant at each test potential. In contrast 50 microM MS-551 failed to block either the sodium or the calcium current. Under cell-attached patch conditions, MS-551 reduced the open probability of IK1 channel activity by prolonging the interburst interval without changing either the unitary amplitude or the equilibrium potential. The blockade of IK1 was concentration-dependent. MS-551 did not change either the mean open time or mean closed time within a burst. Extracellular acidification (pH 6.4) strongly attenuated the effect of MS-551 on the open probability of IK1 channel activity when compared with its effect at pH 7.4. In summary, our results demonstrated that MS-551 blocked the IK1 channel. The neutral form of this drug molecules may penetrate the cardiac cell membrane via a hydrophobic pathway to block the steady-state IK1 current by reduction of open probability.

Animals↗