Biomedical subjects

I Kodama

Publications and source records attributed to I Kodama.

At least 37 records · Page 2Linked to original sources

PubMed2001

Oral estrogen replacement therapy increases forearm reactive hyperemia accompanied by increases in serum levels of nitric oxide in postmenopausal women.

The present study sought to determine the correlation between the vasodilator response of forearm resistance vessels and the circulating levels of nitric oxide (NO) after the administration of oral estrogen for 12 weeks to postmenopausal women. We classified postmenopausal women into two groups: those treated with conjugated equine estrogen (0.625 mg daily) orally for 12 weeks (n = 24) or those who received no treatment (control group, n = 8). Forearm blood flow was measured using strain-gauge plethysmography during hyperemia to evaluate endothelium-dependent vasodilation, and after sublingual nitroglycerin administration to evaluate endothelium-independent vasodilation. Serum levels of nitrite/nitrate (metabolites of NO) and lipid parameters were measured. Basal forearm blood flow, body weight and heart rate were similar in each group. After 12 weeks of estrogen administration, the maximal forearm blood flow response during reactive hyperemia and the serum level of nitrite/nitrate each showed a significant increase from 26.9 +/- 1.9 to 37.9 +/- 3.5 ml/min per 100 ml tissue (p < 0.01), and from 25.2 +/- 2.2 to 37.5 +/- 3.7 mumol/l (p < 0.05), respectively. No increases were seen in controls. The changes in forearm blood flow after sublingual nitroglycerin were similar before and after 12 weeks of estrogen administration. The increase in maximal forearm blood flow with reactive hyperemia was significantly correlated with the increase in nitrite/nitrate in the group administered estrogen (r = 0.48, p < 0.05). There was no significant correlation between maximal forearm blood flow with reactive hyperemia, nor any change in serum lipids, blood pressure or other parameters. In conclusion, the 12-week administration of oral estrogen increased forearm reactive hyperemia in postmenopausal women, probably via an increase in the production of NO.

Body Weight↗

PubMed2001

Carvedilol and vesnarinone: new antiarrhythmic approach in heart failure therapy.

Carvedilol and vesnarinone are drugs attracting recent interest in the treatment of chronic heart failure. Electrophysiologic studies have revealed that these drugs cause a moderate prolongation of action potential duration (APD) of ventricular muscles with minimal "reverse frequency-dependence" through different ionic mechanisms. Carvedilol blocks L-type Ca2+ current (ICa), transient outward K+ current (Ito), and delayed rectifier K+ current (IK) preferentially for the rapidly activating component (IKr). Vesnarinone is a selective blocker of IK with a unique drug-channel interaction. From the voltage- and time-dependence of IK inhibition, vesnarinone is considered to bind the IK (mainly IKr) channel during the activated state and unbind during the closed state. These electropharmacologic profiles provide a new approach for the development of an ideal antiarrhythmic drugs in patients with structural heart diseases.

Action Potentials↗

PubMed2000

Remodeling of gap junctional coupling in hypertrophied right ventricles of rats with monocrotaline-induced pulmonary hypertension.

The present study investigates the remodeling of gap junctional organization in relation to changes in anisotropic conduction properties in hypertrophied right ventricles (RVs) of rats with monocrotaline (MCT)-induced pulmonary hypertension. In contrast to controls that showed immunolocalization of connexin43 (Cx43) labeling largely confined to the intercalated disks, RV myocytes from MCT-treated rats showed dispersion of Cx43 labeling over the entire cell surface. The disorganization of Cx43 labeling became more pronounced with the progression of hypertrophy. Desmoplakin remained localized to the intercalated disks, as in controls. In RV tissues, the proportion of Cx43 label at the intercalated disk progressively decreased. Quantitative analysis of en face views of intercalated disks revealed a significant decrease in the disk gap junctional density in RV tissues of MCT-treated rats (control, 0.18 versus MCT-treated, 0.14 at 2 weeks; control, 0.16 versus MCT-treated, 0.11 at 4 weeks). Conduction velocity in RVs parallel to the fiber orientation was significantly lower (30.2% [n=9]) in MCT-treated rats at 4 weeks than in control rats, whereas there was no significant difference observed in the conduction velocity across the fiber orientation between control and MCT-treated rats. The anisotropic ratio of MCT-treated rats (1.38+/-0.10) was significantly lower than that of control rats (1.98+/-0.12). These results suggest that RV hypertrophy induced by pressure overload is associated with both disorganization of gap junction distribution and alteration of anisotropic conduction properties.

Animals↗

PubMed2000

The effect of hormone replacement therapy on metabolism of lipoprotein remnants in postmenopausal women.

OBJECTIVE: The measurement of remnant-like particles reflects chylomicron and very low density lipoprotein remnants which are most likely atherogenic particles. We investigated the effects of menopausal status and postmenopausal hormone replacement on metabolism of remnant lipoprotein-cholesterol. METHODS: We measured remnant lipoprotein-cholesterol by an immunoseparation assay in 20 premenopausal, 40 postmenopausal, and 30 bilaterally oophorectomized women. Of 70 postmenopausal subjects, 21 surgically menopausal women (with total hysterectomy) were started on hormone replacement with conjugated equine estrogen, 0.625 mg/day, and 36 naturally postmenopausal women were begun on a combination of conjugated equine estrogen 0.625 mg/day, plus medroxyprogesterone acetate, 2.5 mg/day. Plasma levels of remnant lipoprotein-cholesterol and other common lipids were measured after 6 and 12 months of treatment. RESULTS: Plasma remnant lipoprotein-cholesterol levels in postmenopausal and surgically menopausal women were significantly higher than in premenopausal women (P < 0.005). Plasma total and low-density lipoprotein cholesterol levels decreased and high-density lipoprotein cholesterol increased significantly (P < 0.01) in both treatment groups, respectively. Plasma triglyceride levels were not changed by treatment; however, remnant lipoprotein-cholesterol levels decreased in both treatment groups (estrogen group; P = 0.07, estrogen-progestin group; P < 0.05). No side effects of therapy were consistently reported. CONCLUSIONS: We confirmed that remnant lipoprotein-cholesterol increases after menopause. Hormone replacement therapy improves disordered lipoprotein metabolism and exerts a favorable effect on lipoprotein remnant metabolism in postmenopausal women.

Adult↗

PubMed2000

Voltage-gated K(+)Channel, Kv4.2, localizes predominantly to the transverse-axial tubular system of the rat myocyte.

Kv4.2 subunit, a member of K(+)channel gene family, is considered to play a major role in the formation of depolarization-activated transient outward K(+)current channels in the mammalian heart. We investigated the subcellular localization of Kv4.2 subunit in the rat heart by immunofluorescence and immunoelectron microscopy. In atrial cells, Kv4.2 immunofluorescent staining was intensely observed in the peripheral sarcolemma and the intercalated disks, but seldom found in transverse tubules, which are rare or absent in atrial cells. In ventricular cells, the labeling of Kv4.2 immunofluorescent staining was found throughout the entire cell membrane, and the staining was stronger in the transverse-axial tubular system than in the peripheral sarcolemma. Correlative immunoconfocal and immunoelectron microscopy using FluoroNanogold confirmed that Kv4.2 distributed in the transverse-axial tubular system including the longitudinally oriented axial tubules. Immunogold electron microscopy of ultrathin cryosections revealed that Kv4.2 was distributed on the plasma membranes of the T-tubules. The extensive distribution of Kv4.2 on the entire cell membrane of myocytes would provide rat myocardial cells with a large capability for the transport of K(+)ions through the channels in the repolarization phase.

Animals↗

PubMed2000

Characterisation of the transient outward K+ current in rabbit sinoatrial node cells.

OBJECTIVE: To (i) characterise the electrophysiological and pharmacological properties of the transient outward K+ current, I(to), (ii) determine the relationship between the density of I(to) and cell size, and (iii) determine the role of I(to) in electrical activity in rabbit sinoatrial node cells at 35 degrees C. METHODS: Rabbit sinoatrial node cells were studied using whole-cell voltage and current clamp techniques. RESULTS: I(to) showed half activation and inactivation at +11 and -49 mV, respectively. I(to) was blocked by 4-aminopyridine (4-AP) as well as the class I agents, quinidine and flecainide, with EC50 values of 326, 21 and 19 microM, respectively. The densities of the transient and sustained components of 4-AP-sensitive current were significantly correlated with cell capacitance, a measure of cell size, and were greater in cells with a larger capacitance. Block of I(to) by 4-AP affected both the action potential and pacemaker activity of sinoatrial node cells and the effects were greater in cells with a larger capacitance. CONCLUSIONS: I(to) in sinoatrial node cells shows similar electrophysiological and pharmacological properties to I(to) in atrial and ventricular cells. The expression of I(to) in sinoatrial node cells is heterogeneous and differs in large and small cells (likely to be from the periphery and centre of the sinoatrial node, respectively). I(to) plays an important role in action potential configuration and pacemaker activity in sinoatrial node cells, especially in larger cells.

4-Aminopyridine↗

PubMed2000

The sinoatrial node, a heterogeneous pacemaker structure.

This article focuses on the regional heterogeneity of the mammalian sinoatrial (SA) node in terms of cell morphology, pacemaker activity, action potential configuration and conduction, densities of ionic currents (i(Na), i(Ca,L), i(to), i(K,r), i(K,s) and i(f)), expression of gap junction proteins (Cx40, Cx43 and Cx45), autonomic regulation, and ageing. Experimental studies on the single SA node cell to the whole animal are reviewed. The heterogeneity is considered in terms of the gradient model of the SA node, in which there is gradual change in the intrinsic properties of SA node cells from periphery to centre, and the alternative mosaic model, in which there is a variable mix of atrial and SA node cells from periphery to centre. The heterogeneity is important for the dependable functioning of the SA node as the pacemaker for the heart, because (i) via multiple mechanisms, it allows the SA node to drive the surrounding atrial muscle without being suppressed electrotonically; (ii) via an action potential duration gradient and a conduction block zone, it promotes antegrade propagation of excitation from the SA node to the right atrium and prevents reentry of excitation; and (iii) via pacemaker shift, it allows pacemaking to continue under diverse pathophysiological circumstances.

Action Potentials↗

PubMed2000

Cell-to-cell interaction prevents cell death in cultured neonatal rat ventricular myocytes.

OBJECTIVES: Loss of cardiac cells and the anatomical or functional remodeling of intercellular coupling occur under several pathological conditions. We have assessed the significance of intercellular coupling for cell death. METHODS AND RESULTS: Ventricular cells obtained from 1 day old Wistar rats were cultured. Apoptosis was detected by nick-end labeling. Cells were plated at low and high cell density (3x10(4)/ml and 12x10(4)/ml, respectively). Cultured myocytes died spontaneously by apoptosis in a time dependent manner. The increase of the apoptotic cell population in a culture with high cell density on day 4 (1+/-1.2%, n=4) was significantly lower than that in a culture with low cell density (20+/-5.5%, n=4). The progression of apoptosis in the culture of low cell density was prevented in part after application of the medium extract from the culture of high cell density; the apoptotic cell population on day 6 decreased from 57+/-8.0% (n=4) to 36+/-3.8% (n=4). Treatment of the cultured myocytes at high cell density with antisense oligonucleotide for connexin43 (Cx43) for 24 h on day 2 resulted in a significant decrease in Cx43 expression as judged by Western blot, dye transfer and immunocytochemistry using mouse monoclonal antibody for Cx43. In association with the down-regulation of Cx43, the progress of apoptosis was accelerated; the apoptotic cell population on day 5 in the antisense-treated cultures (27+/-5.7%, n=4) was significantly higher than the sense-treated cultures (5+/-1.1%, n=4). The effect of Cx43 antisense treatment to promote apoptosis was not reversed by application of high cell-density culture medium. CONCLUSIONS: These findings suggest that cell-cell communication through gap junction formation and some humoral factors play important roles in the survival of cultured myocytes.

Actinin↗

PubMed2000

Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreases in calcium and transient outward currents in rabbit ventricle.

OBJECTIVE: Heart failure in patients and in animal models is associated with action potential prolongation of the ventricular myocytes. Changes in several membrane currents have been already demonstrated to underlie this prolongation. However, information on the two components (I(Kr) and I(Ks)) of the delayed rectifier potassium current (I(K)) in rapid pacing induced heart failure is lacking. METHODS AND RESULTS: Action potentials and whole-cell currents, I(K), I(to1), I(K1), and I(Ca-L) were recorded in apical myocytes of left ventricle from 10 rabbits subjected to left ventricular pacing at 350-380 beats/min for 3-4 weeks and 10 controls with sham operation. Action potential duration at 90% repolarization (APD(90)) was prolonged in myocytes from failing hearts compared to controls at both cycle lengths of 333 and 1000 ms. Both E-4031-sensitive and -resistant components of I(K) (I(Kr), I(Ks)) in myocytes from failing hearts were significantly less than those of control hearts; tail current densities of I(Kr) and I(Ks) following depolarization to +50 mV were 0.62+/-0.05 vs. 0.96+/-0.12 pA/pF (P<0.05), and 0.27+/-0.08 vs. 0.52+/-0.08 pA/pF (P<0.05), respectively. There was no significant difference between control and failing myocytes in the voltage- and time-dependence of activation of total I(K), I(Kr) and I(Ks). The peak of L-type Ca(2+) current (I(Ca-L)) was significantly reduced in myocytes from failing hearts (at +10 mV, -9.29+/-0.52 vs. -12.28+/-1.63 pA/pF, P<0.05), as was the Ca(2+)-independent transient outward current (I(to1); at +40 mV, 4.8+/-0.9 vs. 9.6+/-1.3 pA/pF, P<0.05). Steady state I-V curve for I(K1) was similar in myocytes from failing and control hearts. CONCLUSIONS: Decrease of I(K) (both I(Kr) and I(Ks)) in addition to reduced I(to1), may underly action potential prolongation at physiological cycle length and thereby contribute to arrhythmogenesis in heart failure.

Action Potentials↗

PubMed2000

Three-year study of estrogen alone versus combined with progestin in postmenopausal women with or without hypercholesterolemia.

This study compares the effects of long-term hormone replacement therapy on the lipid profile of postmenopausal women with or without hypercholesterolemia, with a comparison of 2 different regimens over a 3-year period. A total of 209 women were enrolled in this prospective, nonrandomized trial. They were classified into 2 groups according to baseline serum levels of total cholesterol and low-density lipoprotein (LDL) cholesterol. The hypercholesterolemic group consisted of 83 subjects with a total cholesterol level of 220 mg/dL or higher and LDL cholesterol 140 mg/dL or higher. The normocholesterolemic group consisted of 126 subjects with normal total and LDL cholesterol levels. Therapy was assigned as follows: 44 subjects in the hypercholesterolemic group and 67 in the normal cholesterol group with a total hysterectomy received conjugated equine estrogen (CEE) 0.625 mg/d, while 39 subjects in the hypercholesterolemic group and 59 in the normal cholesterol group with a physiological menopause received CEE 0.625 mg/d plus medroxyprogesterone acetate 2.5 mg/d. Fasting blood samples were monitored periodically for 3 years. Nine women withdrew from the study. Hormone replacement therapy had a more favorable effect in the hypercholesterolemic group versus the normal cholesterol group by decreasing total and LDL cholesterol, 7.0% and 16.6%, versus the normal cholesterol group, 0.8% and 3.9%. Serum levels of high-density lipoprotein (HDL) cholesterol were increased in both groups (hypercholesterolemic, 14.4%; normal cholesterol group, 26.5%), with the increase being larger in the normal cholesterol group. These changes were similar with both treatments and were maintained over 3 years. Serum levels of triglyceride were also increased in both groups, with the increase being statistically significant only in the group with normal cholesterol levels at baseline. There were no consistently reported side effects of therapy. The effects of postmenopausal hormone replacement therapy, estrogen with or without progestin, on the lipid profile appear to be related to the subject's baseline lipid values. Thus, such therapy may have a more favorable effect on LDL cholesterol in postmenopausal women with hypercholesterolemia, with the beneficial effect being maintained over 3 years.

Aged↗

PubMed2000

Regional differences in arrhythmogenic aftereffects of high intensity DC stimulation in the ventricles.

Regional differences of the aftereffects of high intensity DC stimulation were investigated in isolated rabbit hearts stained with a voltage-sensitive dye (di-4-ANEPPS). Optical action potential signals were recorded from the epicardial surface of the right and left ventricular free wall (RVep, LVep) and from the right endocardial surface of the interventricular septum (IVS). Ten-millisecond monophasic DC stimulation (S2, 20-120 V) was applied to the signal recording spots during the early plateau phase of the action potential induced by basic stimuli (S1, 2.5 Hz). There was a linear relationship between S2 voltage and the S2 field intensity (FI). S2 caused postshock additional depolarization, giving rise to a prolongation of the shocked action potential. With S2 > or = 40 V (FI > or = approximately 20 V/cm), terminal repolarization of action potential was inhibited, and subsequent postshock S1 action potentials for 1-5 minutes were characterized by a decrease in the maximum diastolic potential and a decrease in the amplitude and a slowing of their upstroke phase. The higher the S2 voltage, the larger the aftereffects. The changes in postshock action potential configuration in RVep were significantly greater than those observed in LVep and IVS when compared at the same levels of S2 intensity. In RVep, 12 of 20 shocks of 120 V resulted in a prolonged refractoriness to S1 (> 1 s), and the arrest was often followed by oscillation of membrane potential. Ventricular tachycardia or fibrillation ensued from the oscillation in five cases. No such long arrest or serious arrhythmias were elicited in LVep and IVS. These results suggest that RVep is more susceptible than LVep and IVS for arrhythmogenic aftereffects of high intensity DC stimulation.

Animals↗

PubMed2000

Action potential remodeling in the human right atrium with chronic lone atrial fibrillation.

It has been shown in animal experiments that recurrent induction of atrial fibrillation (AF) or long-lasting atrial pacing causes a shortening of the atrial effective refractory period (ERP) and action potential duration (APD) and a loss of their physiological adaptation to rate. Much remains to be clarified as to the electrical remodeling in human patients with chronic AF. We recorded monophasic action potentials (MAPs) from the right atrium at pacing cycle lengths (CLs) of 300, 333, 400, 500, 600, and 750 ms after external cardioversion in 13 patients with chronic lone AF. Their configuration was compared with those obtained from 13 control patients. APDs at 50% and 90% repolarization (APD50, APD90) at the shortest CL (300 ms) in control and AF patients were 131 +/- 14, 211 +/- 19 ms and 136 +/- 12, 210 +/- 22 ms, respectively (mean +/- SD). APDs in control patients increased linearly with increases of CL, reaching maximal values of 174 +/- 30 ms (APD50) and 277 +/- 38 ms (APD90) at a CL of 750 ms. In AF patients, the steady-state CL-APD relation was shifted downward and flattened at CLs > 500 ms; APD50 and APD90 at a CL of 750 ms were 158 +/- 19 ms, 232 +/- 28 ms, respectively. APD90s at CLs of 600 and 750 ms were significantly shorter in AF than in control patients. No statistically significant difference was obtained in APD50 between the two groups at any CL tested. MAP configuration in AF patients was characterized by an acceleration of the late repolarization. The difference between APD90 and APD50 (APD90-50) in control patients was increased with increases of CL, reaching a plateau at a CL of 600 ms. This CL dependent slowing of the late repolarization of MAPs was abolished in AF patients. The atrial ERP, measured at CLs of 400 and 600 ms, showed changes parallel to those of APD90. ERP at a CL of 600 ms in AF patients (224 +/- 13 ms) was significantly shorter than that in control patients (247 +/- 25 ms). We conclude that chronic lone AF leads to electrical remodeling in the human atrium, which causes a loss of rate response of the late repolarization of action potential, leading to a shortening of APD and ERP at slower heart rates.

Action Potentials↗

PubMed2000

Mathematical models of action potentials in the periphery and center of the rabbit sinoatrial node.

Mathematical models of the action potential in the periphery and center of the rabbit sinoatrial (SA) node have been developed on the basis of published experimental data. Simulated action potentials are consistent with those recorded experimentally: the model-generated peripheral action potential has a more negative takeoff potential, faster upstroke, more positive peak value, prominent phase 1 repolarization, greater amplitude, shorter duration, and more negative maximum diastolic potential than the model-generated central action potential. In addition, the model peripheral cell shows faster pacemaking. The models behave qualitatively the same as tissue from the periphery and center of the SA node in response to block of tetrodotoxin-sensitive Na(+) current, L- and T-type Ca(2+) currents, 4-aminopyridine-sensitive transient outward current, rapid and slow delayed rectifying K(+) currents, and hyperpolarization-activated current. A one-dimensional model of a string of SA node tissue, incorporating regional heterogeneity, coupled to a string of atrial tissue has been constructed to simulate the behavior of the intact SA node. In the one-dimensional model, the spontaneous action potential initiated in the center propagates to the periphery at approximately 0.06 m/s and then into the atrial muscle at 0.62 m/s.

Action Potentials↗

PubMed2000

Presence of the Kv1.5 K(+) channel in the sinoatrial node.

The aim of this study was to establish, using immunolabeling, whether the Kv1.5 K(+) channel is present in the pacemaker of the heart, the sinoatrial (SA) node. In the atrial muscle surrounding the SA node and in the SA node itself (from guinea pig and ferret), Western blotting analysis showed a major band of the expected molecular weight, approximately 64 kD. Confocal microscopy and immunofluorescence labeling showed Kv1.5 labeling clustered in atrial muscle but punctate in the SA node. In atrial muscle, Kv1.5 labeling was closely associated with labeling of Cx43 (gap junction protein) and DPI/II (desmosomal protein), whereas in SA node Kv1.5 labeling was closely associated with labeling of DPI/II but not labeling of Cx43 (absent in the SA node) or Cx45 (another gap junction protein present in the SA node). Electron microscopy and immunogold labeling showed that the Kv1.5 labeling in atrial muscle is preferentially associated with desmosomes rather than gap junctions.

Animals↗

PubMed2000

Adriamycin causes dual inotropic effects through complex modulation of myocardial Ca2+ handling.

Effects of adriamycin (ADR) on the twitch contraction of isolated guinea pig cardiac muscles were examined to elucidate its actions on intracellular Ca2+ mobilization. In right ventricular papillary muscles, ADR (100-300 micromol/L) caused positive inotropy when the muscles were constantly stimulated at low frequencies (0.1-0.5 Hz), whereas it caused negative inotropy when the muscles were stimulated at higher frequencies (2.0-3.0 Hz). Action potential duration was prolonged significantly by ADR, especially at the lower frequencies. The potentiation of twitch contraction of the first beat (B 1) following a short rest period (2-10 s) in ventricular muscles was inhibited by ADR. In untreated papillary muscles, B1 contraction showed time-dependent decay in response to a prolongation of the preceding rest period up to 120 s. ADR (300 micromol/L) caused ryanodin-like acceleration for the early B1 decay with rest period less than 20 s, but a substantial deceleration for the later B1 decay (> or =30 s). In left atrial muscles stimulated constantly, ADR had significant negative inotropy throughout the entire range of stimulation frequencies tested (0.1-4.0 Hz). The post-rest potentiation of B 1 contraction of atrial muscle in the presence of nifedipine was also inhibited by ADR. These findings suggest that ADR has dual inotropic effects through a complex modulation of myocardial Ca2+ handling, which may involve (1) an increase of Ca2+ influx through a prolongation of action potential duration, (2) ryanodine-like inhibition of Ca2+ release from the sarcoplasmic reticulum, and (3) inhibition of sarcolemmal Ca2+ extrusion probably through the Na+/Ca2+ exchange.

Animals↗

PubMed2000

Study of lymphatic metastatic patterns in gastric carcinoma according to tumor location.

A total of 226 cases of advanced gastric cancer which occupied only one third of the stomach were analyzed in order to clarify whether and how lymphatic spread differed according to the tumor location and gross type of tumor. Out of the 226 patients, 45 cases had tumor in the upper third, 74 cases had it in the middle third, and 107 cases had it in the lower third of the stomach. The incidence of lymph node metastasis was found to be much higher for the tumors located in the lesser curvature (51.6%), greater curvature and posterior wall (54.4%), as compared to the tumors located in the anterior wall (28.0%). The tumors located in the upper third of the stomach did not show any metastasis in the N3 node, while the tumors located in the lower third of the stomach did not show any metastasis in the left cardial nodes, short gastric nodes, and the nodes along the left gastroepiploic vessels. Similarly, the tumors from the middle third of the stomach did not invade the left cardial nodes.

Adult↗

PubMed1999

Amiodarone: ionic and cellular mechanisms of action of the most promising class III agent.

Amiodarone is the most promising drug in the treatment of life-threatening ventricular tachyarrhythmias in patients with significant structural heart disease. The pharmacologic profile of amiodarone is complex and much remains to be clarified about its short- and long-term actions on multiple molecular targets. This article reviews electrophysiologic effects of amiodarone based on previous reports and our own experiments in single cells and multicellular tissue preparations of mammalian hearts. As acute effects, amiodarone inhibits both inward and outward currents. The inhibition of inward sodium and calcium currents (I(Na), I(Ca)) is enhanced in a use- and voltage-dependent manner, resulting in suppression of excitability and conductivity of cardiac tissues especially when stimulated at higher frequencies and in those with less-negative membrane potential. Both voltage- and ligand-gated potassium channel currents (I(K), I(K,Na), I(K,ACh)) are also inhibited at therapeutic levels of drug concentrations. Acutely-administered amiodarone has no consistent effect on the action potential duration (APD). The major and consistent long-term effect of the drug is a moderate APD prolongation with minimal frequency dependence. This prolongation is most likely due to a decrease in the current density of I(K) and I(to). Chronic amiodarone was shown to cause a down-regulation of Kv1.5 messenger ribonucleic acid (mRNA) in rat hearts, suggesting a drug-induced modulation of potassium-channel gene expression. Tissue accumulation of amiodarone and its active metabolite (desethylamiodarone) may modulate the chronic effects, causing variable suppression of excitability and conductivity of the heart through the direct effects of the compounds retained at the sites of action. Amiodarone and desethylamiodarone could antagonize triiodothyronine (T3) action on the heart at cellular or subcellular levels, leading to phenotypic resemblance of long-term amiodarone treatment and hypothyroidism.

Amiodarone↗

PubMed1999

Carvedilol blocks the repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes.

Carvedilol ((+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]am ino]-2-propanol), a beta-adrenoceptor-blocking agent with vasodilator properties, has been reported to produce dose-related improvements in left ventricular function and reduction in mortality in patients with chronic heart failure. However, its electrophysiological effects have not been elucidated. We studied ion channel and action potential modulation by carvedilol in rabbit ventricular preparations using whole-cell voltage-clamp and standard microelectrode techniques. In ventricular myocytes, carvedilol blocked the rapidly activating component of the delayed rectifier K+ current (I(Kr)) in a concentration-dependent manner (IC50 = 0.35 microM). This block was voltage- and time-independent; a prolongation of the depolarizing pulses from a holding potential of -50 mV to +10 mV within the range of 100-3000 ms did not affect the extent of I(Kr) block. Carvedilol also inhibited the L-type Ca2+ current (I(Ca)), the transient outward K+ current (I(to)) and the slowly activating component of the delayed rectifier K+ current (I(Ks)) with IC50 of 3.59, 3.34, and 12.54 microM, respectively. Carvedilol (0.3-30 microM) had no significant effects on the inward rectifier K+ current. In papillary muscles from rabbits pretreated with reserpine, action potential duration was prolonged by 7-12% with 1 microM and by 12-24% with 3 microM carvedilol at stimulation frequencies of 0.1-3.0 Hz. No further action potential duration prolongation was observed at concentrations higher than 3 microM. These results suggest that concomitant block of K+ and Ca2+ currents by carvedilol resulted in a moderate prolongation of action potential duration with minimal reverse frequency-dependence. Such electrophysiological effects of carvedilol would be beneficial in the treatment of ventricular tachyarrhythmias.

Action Potentials↗