Effect of Antihypertensive Drugs on Uric Acid Metabolism in Patients with Hypertension: Cross-Sectional Cohort Study.

Background: Hypertension is a common complication in patients with gout and/or hyperuricemia. Besides, hyperuricemia is a risk factor of gout as well as ischemic heart disease in hypertensive patients. Moreover, the risk of gout is modified by antihypertensive drugs. However, it remains unclear how antihypertensive agents affect uric acid metabolism. Purpose: In the present study, we investigated the uric acid metabolism in treated hypertensive patients to find out whether any of them would influence serum levels of uric acid. Patients and methods: 751 hypertensive patients (313 men and 438 women) under antihypertensive treatment were selected. Blood pressure (BP), serum uric acid (SUA) and serum creatinine (Scr) were measured and evaluated statistically. Results: In patients treated with diuretics, beta-blockers and/or alpha-1 blockers SUA levels were significantly higher than in patients who were not taking these drugs. Besides, the estimated glomerular filtration rate (eGFR) in patients treated with diuretics, beta-blockers and/or alpha-1 blockers was negatively correlated with SUA level. There were gender differences in the effects of beta-blockers and alpha-1 blockers. Multiple regression analysis indicated that both diuretics and beta-blockers significantly contributed to hyperuricemia in patients with medication for hypertension. Conclusion: Diuretics, beta-blockers and alpha-1 blockers reduced glomerular filtration rate and raised SUA levels. Calcium channel blockers, ACE inhibitors and angiotensin receptor blockers, including losartan, did not increase SUA levels.

Modification of the N-terminal cysteine of plasma cholesteryl ester transfer protein selectively inhibits triglyceride transfer activity.

An invariant cysteine residue is found at the N-terminus of cholesteryl ester transfer protein (CETP) isolated from plasma of humans, rabbits and cynomolgus monkeys. We previously reported the expression of recombinant rabbit cholesteryl ester transfer protein in yeast (Kotake et al., J. Lipid Res. 1996; 37: 599-605). The recombinant CETP secreted into the medium contains an altered N-terminal sequence but was fully capable of facilitating both cholesteryl ester (CE) and triglyceride (TG) transfer between lipoproteins. We investigated the importance of the conserved N-terminal cysteine of plasma CETP in the lipid transfer activity by chemical modification of the free sulfhydryl groups of the recombinant CETP and CETP from human and rabbit plasma. The unmodified forms of these CETPs had similar specific activities of CE and TG transfer. Neither 5,5'-dithiobis-(2-nitrobenzoate) nor N-ethyl maleimide altered the lipid transfer activity. In contrast, p-chloromercuriphenyl sulfonate selectively inhibited the TG transfer activity of both human and rabbit plasma CETP. The TG and CE transfer activities of the recombinant CETP, which lacks the N-terminal cysteine residue, was not affected. These results demonstrate that the N-terminal cysteine residue of both human and rabbit plasma CETP is free and is likely to be involved in the construction of a critical part of the active site of CETP that can determine the selectivity of the lipid molecule for the transfer reaction.

T lymphocytes increase the synthesis of esterified cholesterol in human monocyte-derived macrophages by activation of the scavenger pathway.

Immunohistochemical analyses have shown the presence of T lymphocytes (T-cells) in atherosclerotic places in addition to macrophages and smooth muscle cells. To elucidate the role of T-cells in the formation of atherosclerotic lesions, we studied whether T-cells can stimulate the scavenger pathway and promote esterified cholesterol (EC) synthesis by [14C]oleate incorporation in macrophages. Macrophages and T-cells were co-cultured in two ways. In one culture, macrophages were in direct contact with T-cells (direct contact form). In the other, macrophages and T-cells were separated by Transwell membrane, but shared the same culture medium via the membrane (indirect contact form). Based on the incorporation of [14C]oleate into EC, macrophages strikingly increased EC synthesis in both forms of co-culture. This increase was proportional to the number of T-cells present and was inhibited by cyclosporin A. When macrophages were co-cultured indirectly in contact with T-cells in the presence of AcLDL for 24 h, and the T-cells were subsequently removed, EC synthesis in macrophages increased. However, this increase was not observed in macrophages that were rinsed twice with PBS. When macrophages, previously incubated with AcLDL for 24 h, were co-cultured indirectly in contact with T-cells for 24 h, the medium were prepared as activated T-cell-conditioned medium (aTCM). EC synthesis in macrophages cultured with aTCM increased. The ability of aTCM to increase EC synthesis disappeared upon repeated freezing/thawing, boiling and trypsin treatment. T-cells (indirect contact form) and aTCM similarly increased AcLDL-binding and -degradation in macrophages. These results indicated that T-cells secreted an active substance(s), protein in nature, which could activate the scavenger pathway and increase EC synthesis in macrophages. These observations suggest that T-cells can promote the uptake of modified lipoproteins by macrophages to induce foam cell-formation.

Human arterial smooth muscle cell proliferation in diabetes.

In the present study, we focus on the proliferation of human arterial smooth muscle cells (SMCs) from NIDDM patients (DM-SMCs) to clarify the reactivity to the growth factor(s) in fetal calf serum (FCS) and the factor(s) secreted by T-cells. The proliferation of DM-SMCs was significantly greater than SMCs from nondiabetic patients (nonDM-SMC). DM-SMC conditioned medium (DM-condMed) increased the growth of nonDM-SMCs. These results suggest that the growth factor is secreted from DM-SMCs as an autocrine system, which increases the proliferation of nonDM-SMCs. T-cells increased DNA synthesis of SMCs, and DM-SMCs strikingly reacted to T-cells. The present results support a function of T-cells in stimulating SMC growth. In conclusion, human arterial SMC proliferation is increased in diabetes in the same fashion as in experimentally induced diabetes in animals through responses to growth factors and an increased autocrine system. These results provide a mechanism for the increase in atherosclerotic disease in diabetes.

Significance of coronary artery tone in patients with vasospastic angina.

To investigate the relation between basal coronary artery diameter and development of coronary artery spasm, the diameters of the proximal, middle and distal segments of the three major coronary artery branches, together with that of the left main trunk, were measured on a control angiogram and after ergonovine and nitrate administration in 30 patients with vasospastic angina without significant organic stenosis, and in 35 patients without ischemic heart disease. The percent change in coronary diameter after ergonovine and nitrate administration compared with the control diameter was used as an index of coronary vasoreactivity. In patients with vasospastic angina, coronary artery responses to both ergonovine and nitrate were greater in the spastic segments than in the other segments (p less than 0.05), and those of the coronary arteries without spasm were greater than those of the coronary arteries in patients without ischemic heart disease (p less than 0.01). There were no significant differences between the coronary artery diameters in the two groups after nitrate administration, and the control diameters were less in patients with vasospastic angina than in patients without ischemic heart disease. These observations indicate that a coronary vasomotion disorder, which involves increased basal coronary artery tone and hypersensitivity to vasoconstrictive stimuli, not only at a localized segment but also in the entire coronary artery tree, is present in patients with vasospastic angina. Clinically, evaluation of basal coronary artery tone may be useful for predicting the occurrence and location of coronary artery spasm.

Antiarrhythmic effects of alpha-adrenoceptor antagonists in guinea pig ventricular myocardium.

Antiarrhythmic effects of alpha-adrenoceptor antagonists were assessed in the reserpinized guinea pig ventricular myocardium. Both bunazosin (1 to 3 x 10(-7) M), a new alpha 1-adrenoceptor antagonist, and yohimbine (1 to 3 x 10(-7) M), another adrenoceptor antagonist, suppressed the transient depolarization and triggered activity induced by a train of rapid stimuli in the solution containing low potassium ion (K+), high calcium ion (Ca2+) and strophanthidin (1 to 5 x 10(-7) M). Bunazosin (3 x 10(-6) M) abolished the facilitatory effect of hypoxia on beta-adrenoceptor mediated abnormal automaticity. To clarify the mechanisms underlying the antiarrhythmic properties of alpha-adrenoceptor antagonists, their electrophysiologic effects on the fast and slow action potentials were investigated. Alpha-adrenoceptor antagonists (bunazosin, yohimbine and phentolamine) suppressed the slow response in a dose-related manner. The voltage-dependent block and use-dependent block of the maximal rate of rise (Vmax) of action potentials by bunazosin (10(-5) to 10(-4) M) and yohimbine (10(-6) to 10(-5) M) were studied. The analysis of the onset and recovery kinetics from the use-dependent block of drugs showed that both bunazosin and yohimbine act as slow kinetic drugs. It is concluded that alpha-adrenoceptor antagonists seem to have an antiarrhythmic effect through the inhibition of fast sodium ion (Na+) and slow Ca2+ currents of the cell membrane independently of blockade of myocardial alpha-adrenoceptors.

Pacemaker current, membrane resistance, and K+ in sheep cardiac Purkinje fibres.

OBJECTIVE: The pacemaker current in cardiac Purkinje fibres has been attributed to either a decrease in potassium conductance or an increase in a non-specific (Na-K) conductance. The former mechanism would be associated with an increase in membrane resistance (Rm) and the latter with a decrease in Rm. The aim of this study was to obtain evidence in support of one or other mechanism by measuring Rm during the pacemaker current (Idd) under conditions where there is a small or no extracellular potassium depletion. METHODS: Hearts were obtained from anaesthetised sheep and thin strands of ventricular Purkinje fibres were shortened to less than or equal to 1.6 mm. Purkinje fibres were voltage clamped to potentials positive and negative to the potassium equilibrium potential (EK) using a two microelectrode technique. Small current pulses were superimposed on Idd to measure Rm changes. Procedures were used that decrease either the background potassium current IKl or Idd in order to dissect changes in Rm due to K depletion from those due to Idd. RESULTS: Rm increased during Idd, whether the pacemaker current increased or decreased as a function of time. Increasing [K]o from 2.7 to 5.4 mmol.litre-1 decreased Rm and during hyperpolarising steps increased the instantaneous current but did not change Idd amplitude. In 2.7 mmol.litre-1 K, caesium (Cs, 2 mmol.litre-1) increased the holding current (Ih), had little effect on the instantaneous current, and eliminated Idd and associated Rm changes. In 5.4 and 10.8 mmol.litre-1 K, Cs increased Ih and decreased Idd amplitude and in 10.8 mmol.litre-1 K Cs decreased the instantaneous current on hyperpolarisation. If the current was reversed, Cs decreased but did not abolish it. In normal [K]o, barium (Ba, 0.05-0.5 mmol.litre-1) increased Ih and Rm, reduced the instantaneous current but did not increase Idd amplitude. In high [K]o, Ba instead increased the amplitude and rate of development of Idd. When Cs was applied in the presence of Ba, Idd was reduced or eliminated depending on [K]o. CONCLUSIONS: The changes in membrane resistance during the pacemaker current cannot be accounted for by K depletion and suggest that in the range of diastolic depolarisation the pacemaker current results predominantly from a time dependent decrease in K conductance.

Effects of amoxapine on electrophysiological properties of rabbit sinoatrial node.

The effects of amoxapine on membrane potentials and membrane currents of rabbit sinoatrial node were studied using the double microelectrode voltage clamp method. Amoxapine (greater than 1 mumol.litre-1) decreased the heart rate and the maximum rate of rise and the rate of diastolic depolarisation in a dose dependent manner. Above 3 mumol.litre-1, amoxapine also decreased the action potential amplitude and prolonged the action potential duration at half amplitude. These electrophysiological changes induced by amoxapine were relatively reduced in a high calcium medium (extracellular calcium concentration 4.0 mmol.litre-1). In voltage clamp experiments amoxapine depressed the slow inward current, the time dependent potassium current, and the hyperpolarisation activated inward current. The major effect, however, was considered to be a reduction of the slow inward current. It is concluded that amoxapine produced an inhibitory action on the electrical activity of sinoatrial node, and this action is mainly explained by an inhibition of calcium influx through the cell membrane.

Inhibitory effect of 9-amino-1,2,3,4-tetrahydroacridine (THA) on the potassium current of rabbit sinoatrial node.

STUDY OBJECTIVE - To examine the effect of 9-amino-1,2,3,4-tetrahydroacridine (THA), a compound similar to the K+ blocker 4-aminopyridine, on potassium channels in the sinoatrial node. DESIGN - The pacemaking portion of rabbit sinoatrial nodes was studied using the double microelectrode voltage clamp method in the presence of THA at various concentrations. MEASUREMENTS AND RESULTS - Above 1 mumol.litre-1, THA prolonged the spontaneous cycle length and the transmembrane action potential duration at 50% repolarisation. Above 10 mumol.litre-1, the compound also decreased the maximum rate of rise, the action potential amplitude, and the rate of diastolic depolarisation. Under voltage clamp conditions, THA reduced the time dependent K+ current (IK) in a dose dependent manner. Neither the decay process of IK nor its activation process were altered by THA. CONCLUSIONS - THA depresses sinoatrial node IK without changing its kinetics. Thus it may inhibit the open state of the potassium channels.

Inhibitory action of 711389-S on the electrical activity of rabbit sinoatrial node.

The effects of 711389-S (0.1-10 mumol.litre-1) on membrane potentials and currents of rabbit sinoatrial node preparations were studied using a conventional double microelectrode voltage-clamp method. The agent 711389-S decreased the heart rate, the maximum rate of depolarisation, and the amplitude of the action potential and increased the action potential duration in a dose dependent manner. The slope of the diastolic depolarisation was also reduced. Of the current systems of sinoatrial node, 711389-S depressed the slow inward current (Isi), the potassium outward current (IK), and the hyperpolarisation activated current (Ih) dose dependently. The kinetics of IK were not altered significantly by the drug. It is concluded that 711389-S does not have an effect on a single current system but that the drug exerts a depressant effect on the electrical activity of the sinoatrial node.

Slow recovery of conduction velocity from use dependent inhibition induced by quinidine in guinea pig ventricular myocardium.

STUDY OBJECTIVE: The aim was to investigate whether the use dependent effects of antiarrhythmic drugs on the Na+ current could be applied to explain their effects on impulse conduction. DESIGN: Trains of rapid stimuli were applied to guinea pig papillary muscles via an electrode in the presence of quinidine (20 and 60 mumol.litre-1), and the conduction velocity was determined from the time difference between two signals of the maximal rate of rise (dV/dtmax) of the action potentials at two separate sites. The relationship of the time constants of the onset and recovery from the use dependent inhibition induced by quinidine was determined for the dV/dtmax and the conduction velocity. EXPERIMENTAL MATERIAL: Six male Hartley guinea pigs weighing 200 to 300 g were killed by a blow to the head and the papillary muscles were rapidly excised from the right ventricles. The preparations were superfused with Tyrode solution. MEASUREMENTS AND MAIN RESULTS: The rate of onset of the use dependent inhibition of conduction velocity and that of the square of conduction velocity were both faster than the simultaneously measured rate of onset of dV/dtmax inhibition induced by 20 mumol.litre-1 quinidine at high frequency stimulation. The relation between the rates of onset of the use dependent inhibition of conduction velocity (and the square of conduction velocity) and dV/dtmax became weak with low frequency stimulation and in the presence of 60 mumol.litre-1 quinidine. However, the recovery of conduction velocity (and the square of conduction velocity) from quinidine induced use dependent blockade, as measured by the extrastimulation method, appeared to be slower than the recovery of dV/dtmax. These results may be explained by a transient change in intracellular and intercellular conditions, such as an increase in internal resistance. CONCLUSIONS: The onset and recovery of the use dependent inhibition of conduction by antiarrhythmic drug may not always parallel the changes of the dV/dtmax of action potential in multicellular muscle preparations.

Inotropic effect of thyrotropin-releasing hormone on the guinea pig myocardium.

The inotropic effect of the physiological level of TRH on isolated guinea pig cardiac muscle was studied using a force transducer and standard microelectrode techniques. TRH increased the contractile force of muscles dose-dependently without changing the time course of contraction in normal Tyrode and a high K+ (27 mM) solution. The positive inotropic effect of TRH was associated with an augmentation of slow action potentials in high K+ solution and was reduced in the presence of diltiazem, verapamil, and manganese. TRH potentiated the response of contractile force to increasing extracellular Ca2+ concentration. The inotropic effect of TRH was suppressed by metoclopramide, phentolamine, and cimetidine, but was not affected by propranolol. TRH increased the contractile force even in the myocardium of reserpinized guinea pig. It is suggested that TRH has a positive inotropic effect at least partly due to an increase in the slow inward Ca2+ current.

Comparison of coronary responses to intracoronary and intraaortic ergonovine and isosorbide dinitrate in patients with atypical chest pain.

Fifty patients with atypical chest pain were studied to compare coronary responses to intracoronary and intraaortic ergonovine. The diameters of the proximal, middle (1) and (2) (proximal segments of segments 2 and 3 [AHA classification], respectively), and distal segments of the right coronary artery were measured before and after intracoronary ergonovine (4 micrograms/minute over 4 minutes) and isosorbide dinitrate (ISDN) (2 mg) in 24 patients, and before and after intraaortic ergonovine (0.2 mg) and ISDN (5 mg) in 26. Mean vasoconstriction by intracoronary and intraaortic ergonovine were 13 +/- 1.5% and 9 +/- 0.8%, respectively (p < 0.02). Irrespective of the methods of administration, the responses to ergonovine were similar in the 4 segments. Mean vasodilation by intracoronary and intraaortic ISDN, which were used to quantify the degree of basal coronary tone, were 25 +/- 2.2% and 27 +/- 1.5%, respectively (p = not significant [NS]). There were significant negative linear correlations between the responses to ergonovine and ISDN in the middle (2) (r = -0.51; p < 0.05) and distal (r = -0.53; p < 0.01) segments in patients with intracoronary injection, and the proximal (r = -0.41; p < 0.05), middle (1) (r = -0.66; p < 0.01) and middle (2) (r = -0.69; p < 0.01) segments in patients with intraaortic injection. These observations indicate that low-dose administration of intracoronary ergonovine produces sufficient coronary vasoconstriction, similar to or slightly greater than that of intraaortic ergonovine in patients with atypical chest pain, but basal coronary tone may influence the vasoreactivity to ergonovine.

Inhibitory actions of amoxapine, a tricyclic antidepressant agent, on electrophysiological properties of mammalian isolated cardiac preparations.

1. The electrophysiological effects of amoxapine were examined in guinea-pig isolated papillary muscles and rabbit sinoatrial nodes using a conventional microelectrode technique. 2. In papillary muscles, amoxapine above 10 microM caused a dose-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential and in the action potential amplitude (APA), whereas the action potential duration at 90% repolarization (APD90) was significantly prolonged. For a decrease in Vmax, amoxapine produced a negative shift of the curve relating Vmax to the resting potential (Em) along the voltage axis to more negative membrane potentials. 3. Amoxapine also decreased Vmax and the overshoot potential of K+-depolarized slow action potentials of papillary muscle preparations. 4. In spontaneously beating sinoatrial node preparations, amoxapine above 3 microM reduced the heart rate, Vmax, APA and the slope of phase 4 depolarization in a dose-dependent manner. 5. It was concluded that amoxapine exerts inhibitory actions on fast- and slow-response fibres of the heart and these actions can be mainly explained by inhibition of both fast Na+ and slow Ca2+ channels.

Electrical effects of okadaic acid extracted from black sponge on rabbit sinus node.

1. Effects of okadaic acid on electrical responses and spontaneous activity in the dominant pacemaker cells of rabbit sinus node were investigated by use of microelectrode techniques. 2. Okadaic acid (10(-5) M to 4 x 10(-5) M) caused a shortening of cycle length of spontaneous firing (SPCL) accompanied by increases in both maximum upstroke velocity at phase 0 (Vmax) and amplitude of action potential. 3. All of the effects of okadaic acid were relatively well preserved in a low-Ca2+ medium (0.12 mM). Okadaic acid restored the spontaneous activity of sinus node pacemaker cells even in a Ca2(+)-deficient medium. 4. The effects of okadaic acid were markedly inhibited or abolished in a low Na+ medium (24 mM or 70 mM) and in the presence of a slow channel blocking agent, verapamil (10(-6) M). 5. In voltage-clamp experiments using a two-microelectrode technique, okadaic acid (10(-5) M) caused an increase in the slow inward current without affecting the outward current. At a higher concentration (4 x 10(-5) M), the drug increased the outward current. 6. These results indicate that okadaic acid causes an increase in spontaneous activity of sinus node pacemaker cells mediated by an enhancement of slow inward current (Isi) through verapamil-sensitive Ca2+ channels.

Chronotropic effect of nizofenone fumarate in rabbit sino-atrial node in vitro.

1. The effects of nizofenone fumarate were studied on the membrane potentials and currents of rabbit sino-atrial node preparations by means of the double-microelectrode voltage clamp method. 2. In spontaneously firing pacemaker cells, nizofenone (above 1 microM) decreased the heart rate. Above 3 microM, nizofenone reduced the maximum upstroke velocity, the amplitude of the action potential and the slope of the phase 4 depolarization, and prolonged the action potential duration at 50% repolarization. 3. Under voltage clamp conditions, nizofenone decreased the slow inward current and the time-dependent potassium outward current in a dose-dependent manner. 4. These findings suggest that nizofenone exerts an inhibitory action on the automaticity of sinoatrial node preparations via effects on both inward and outward currents.

Use-dependent effects of pirmenol on Vmax and conduction in guinea-pig ventricular myocardium.

1. The use-dependent effects of pirmenol, a new antiarrhythmic drug, on the maximal rate of rise (Vmax) of the action potential, conduction velocity, and their corresponding recovery kinetics were studied in isolated papillary muscles of guinea-pig. Standard microelectrode techniques were used to monitor the conduction and action potential characteristics of the muscles. 2. Pirmenol decreased Vmax and the overshoot of action potentials in a dose-dependent fashion. Also, doses of pirmenol greater than 1 mM abolished the generation of action potentials. Low concentrations of pirmenol (3 and 10 microM) prolonged the action potential duration, while concentrations greater than 0.1 mM shortened it markedly. 3. The resting block of Vmax in the presence of 10 and 30 microM pirmenol was 9.48 +/- 3.12 and 20.36 +/- 3.61%, and that of conduction velocity 2.87 +/- 1.52 and 6.58 +/- 2.09%, respectively. 4. The degree of use-dependent block induced by 10 and 30 microM pirmenol during 0.2, 1, 2 and 3 Hz stimulations was dose- and rate-dependent. 5. In the presence of 30 microM pirmenol, mean values of time constants for the onset of the use-dependent inhibition of Vmax and conduction velocity during a 2 Hz stimulation were 1.32 +/- 0.15 and 1.28 +/- 0.09 s, respectively. The recovery time constants averaged 15.83 +/- 2.14 (for Vmax) and 27.80 +/- 8.74 (for conduction velocity) s in the presence of 30 microM pirmenol. 6. These results showed that the characteristics of the use-dependent inhibition of Vmax and conduction velocity induced by pirmenol are similar to those of slow kinetic drugs such as disopyramide rather than of fast ones.

Effect of bile acid on electrophysiological properties of rabbit sino-atrial node in vitro.

1 In order to examine the action of bile acid on cardiac pacemaker activity, the effect of sodium taurocholate (NTC) was studied on the membrane potential and current of rabbit sino-atrial node preparations by means of a double microelectrode voltage clamp technique. 2 In spontaneously beating sino-atrial node preparations, NTC (above 30 microM) decreased the maximum rate of rise of the action potential. Above 100 microM, the compound also exerted a bradycardiac effect and decreased the rate of diastolic depolarization significantly. 3 On the current systems, NTC produced dose-related decreases in the slow inward Ca2+ current and the time-dependent outward K+ current. 4 It is concluded that NTC depresses the spontaneous discharge of the sino-atrial node through decreases in both inward and outward current systems.

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.

The effect of TYB-3823, a new antiarrhythmic drug, on sodium current in isolated cardiac cells.

1. Sodium current (INa) blockade by TYB-3823, a newly synthesized antiarrhythmic agent, was investigated in isolated single ventricular myocytes by use of the whole cell patch-clamp technique. 2. TYB-3823 blocked INa under steady-state conditions (Kd,rest = 500 microM, Kd,i = 4.9 microM), findings consistent with a shift in the steady state INa availability curve to more negative potentials. 3. TYB-3823 produced use-dependent block at 2 Hz in conjunction with increase in pulse duration (5-300 ms), that was markedly enhanced at less negative holding potentials. 4. The time course of the onset of block was accelerated and the degree of use-dependent block was decreased at more negative holding potential. The time course of the onset of block was accentuated with enhancing block at more positive holding potentials. 5. The time course of recovery from use-dependent block was accelerated at more negative holding potentials but was accentuated at more positive holding potentials. 6. These results suggest that both tonic block and use-dependent block of sodium channels in cardiac tissue might result from an interaction of TYB-3832 with sodium channels mainly in the inactivated channel states and the kinetics of the interaction between drug and receptor may be modulated by the inactivation gate.