Biomedical subjects

I Kodama

Publications and source records attributed to I Kodama.

At least 19 recordsLinked to original sources

PubMed2003

Sarcoplasmic reticulum Ca2+ release is not a dominating factor in sinoatrial node pacemaker activity.

Recent work on isolated sinoatrial node cells from rabbit has suggested that sarcoplasmic reticulum Ca2+ release plays a dominant role in the pacemaker potential, and ryanodine at a high concentration (30 micromol/L blocks sarcoplasmic reticulum Ca2+ release) abolishes pacemaking and at a lower concentration abolishes the chronotropic effect of beta-adrenergic stimulation. The aim of the present study was to test this hypothesis in the intact sinoatrial node of the rabbit. Spontaneous activity and the pattern of activation were recorded using a grid of 120 pairs of extracellular electrodes. Ryanodine 30 micromol/L did not abolish spontaneous activity or shift the position of the leading pacemaker site, although it slowed the spontaneous rate by 18.9+/-2.5% (n=6). After ryanodine treatment, beta-adrenergic stimulation still resulted in a substantial chronotropic effect (0.3 micromol/L isoproterenol increased spontaneous rate by 52.6+/-10.5%, n=5). In isolated sinoatrial node cells from rabbit, 30 micromol/L ryanodine slowed spontaneous rate by 21.5+/-2.6% (n=13). It is concluded that sarcoplasmic reticulum Ca2+ release does not play a dominating role in pacemaking in the sinoatrial node. The full text of this article is available at http://www.circresaha.org.

Action Potentials↗

PubMed2001

Heterogeneous expression of the delayed-rectifier K+ currents i(K,r) and i(K,s) in rabbit sinoatrial node cells.

1. The electrical activity of sinoatrial node cells is heterogeneous. To understand the reasons for this, the density of the delayed-rectifier K+ current and its two components, i(K,r) and i(K,s), as a function of the size (as measured by cell capacitance) of rabbit sinoatrial node cells was investigated using the whole-cell voltage-clamp technique at 35 degrees C. 2. i(K,r) and i(K,s) were isolated using E-4031 and 293B. Features of the E-4031-sensitive and 293B-insensitive currents corresponded well to those of i(K,r), while features of the E-4031-insensitive and 293B-sensitive currents corresponded well to those of i(K,s). 3. The densities of the outward current under control conditions and the drug-sensitive and -insensitive currents were significantly (P < 0.01) correlated with cell capacitance, with current densities being greater in larger cells. 4. The effects of partial blockade of i(K,r) by 0.1 microM E-4031 on spontaneous action potentials were greater in smaller cells. 5. It is concluded that there are cell size-dependent differences in the density of the i(K,r) and i(K,s) components, and these may be involved in the heterogeneity of the electrical activity of single sinoatrial node cells as well as that of the intact sinoatrial node.

Action Potentials↗

PubMed2001

Density and kinetics of I(Kr) and I(Ks) in guinea pig and rabbit ventricular myocytes explain different efficacy of I(Ks) blockade at high heart rate in guinea pig and rabbit: implications for arrhythmogenesis in humans.

BACKGROUND: Class III antiarrhythmic agents commonly exhibit reverse frequency-dependent prolongation of the action potential duration (APD). This is undesirable because of the danger of bradycardia-related arrhythmias and the limited protection against ventricular tachyarrhythmias. The effects of blockade of separate components of delayed rectifier K(+) current (I(K)) may help to develop agents effective at high heart rate. METHODS AND RESULTS: We assessed the density and kinetics of the 2 components of the delayed rectifier K(+) current, I(Kr) and I(Ks), in rabbit and guinea pig ventricular myocytes. The effects of their specific blockers (chromanol 293B for I(Ks) and E-4031 for I(Kr)) on the action potential was studied at different heart rates by use of whole-cell patch-clamp techniques. In guinea pig ventricular myocytes only, blockade of I(Ks) causes APD prolongation in a frequency-independent manner, whereas blockade of I(Ks) in rabbit ventricular myocytes shows reverse frequency dependence, as does blockade of I(Kr) in both species. This result can be explained primarily by the higher density of I(Ks) in guinea pig ventricle and by its slow deactivation kinetics, which allows I(Ks) to accumulate at high heart rate because little time is available for complete deactivation of it during diastole. CONCLUSIONS: Density and kinetics of components of I(K) explain why blockade of I(Ks) is more effective at high heart rate in the guinea pig ventricle than in the rabbit ventricle, without adverse effects at low heart rate.

Action Potentials↗

PubMed2001

Phenotype of apolipoprotein E influences the lipid metabolic response of postmenopausal women to hormone replacement therapy.

OBJECTIVES: We investigated whether the phenotype of apolipoprotein E (apo E) would influence the response of postmenopausal Japanese women to hormone replacement therapy (HRT). METHODS: We measured the plasma levels of lipoprotein and apolipoprotein in 242 postmenopausal women at baseline and again after 12 months of HRT. Patients were divided into three groups according to apo E phenotype: E2+ (E2/2 and E2/3, n=21), E3/3 (n=176), E4+ (E3/4 and E4/4, n=45). RESULTS: We found that the E4+ group had the highest levels of total and low density lipoprotein (LDL) cholesterol and apolipoprotein B, being significantly higher than in the E2+ group at baseline. The plasma levels of total and LDL cholesterol showed a significant decrease only in the E2+ and E3/3 groups after 12 months of HRT (E2+ group, total cholesterol -8.9% and LDL cholesterol -21.5%; E3/3 group, total cholesterol -2.9% and LDL cholesterol -9.5%). No significant difference in the reduction of total and LDL cholesterol was found in the E4+ group. Other lipid parameters did not differ in the three groups. CONCLUSIONS: These data show that the apo E phenotype influenced the response of lipid metabolism in postmenopausal women to HRT, especially in the reduction of LDL cholesterol. Therefore, apo E phenotyping may be important in predicting the cholesterol-lowering effect of HRT.

Adult↗

PubMed2001

I(f) current and spontaneous activity in mouse embryonic ventricular myocytes.

Knowledge of the initiation of electrical and contractile activity in the embryonic heart relies to a large extent on data obtained in chicken. In recent years, molecular biological techniques have raised an interest in mouse physiology, including early embryonic development. We studied action potentials and the occurrence of one of the pacemaker currents, I(f), by the whole-cell voltage and current-clamp technique at the earliest stage at which a regular heartbeat is established (9.5 days postcoitum) and at 1 day before birth. We show, first, that at the early stage there is a prominent I(f) in mouse embryonic ventricles, which decreases by 82% before birth in concert with the loss of regular spontaneous activity of ventricular cells. Second, the decrease in I(f) current is associated with a slight change in channel gating kinetics and a decrease in total mRNA expression of the genes encoding for I(f) current. Third, the most prevalent mRNA subtype is switched from HCN4 to HCN2 during the second half of embryonic development. Fourth, the I(f) current may be modulated by the beta-adrenergic cascade, although the coupling to the beta-adrenoceptor in the sarcolemma itself is not yet mature. We conclude that I(f) current of the sinus node type is present in early embryonic mouse ventricular cells. In association with a loss of I(f) current, the ventricle tends to lose pacemaker potency during the second half of embryonic development.

Action Potentials↗

PubMed2001

Short- and long-term effects of amiodarone on the two components of cardiac delayed rectifier K(+) current.

BACKGROUND: Amiodarone is the most promising drug for the treatment of life-threatening tachyarrhythmias in patients with structural heart disease. The pharmacological effects of amiodarone on cardiac ion channels are complex and may differ for short-term and long-term administration. METHODS AND RESULTS: The delayed rectifier K(+) current (I(K)) of ventricular myocytes isolated from rabbit hearts was recorded with the whole-cell voltage-clamp technique. I(K) was separated into 2 components by use of specific blockers for either I(Ks) (chromanol 293B, 30 micromol/L) or I(Kr) (E-4031, 10 micromol/L). Short-term application of amiodarone caused a concentration-dependent decrease in I(Kr) with an IC(50) of 2.8 micromol/L (n=8) but only a minimal reduction in I(Ks). The short-term effects of amiodarone were also determined in Xenopus oocytes expressing the cloned human channels that conduct I(Kr) and I(Ks) (HERG and KvLQT1/minK). HERG current in oocytes was reduced by amiodarone (IC(50)=38 micromol/L), whereas KvLQT1/minK current was unaffected by 300 micromol/L amiodarone. To study the effects of long-term drug administration, rabbits were treated for 4 weeks with oral amiodarone (100 mg. kg(-1). d(-1)) before cell isolation. Long-term administration of amiodarone decreased I(K) to 55% (n=10) in control rabbits and altered the relative density of I(Kr) and I(Ks). The majority (92%) of current was I(Kr). mRNA levels of rabbit ERG,KVLQT1, and minK in left ventricular myocardium did not differ between control and long-term amiodarone. CONCLUSIONS: Amiodarone has differential effects on the 2 components of I(K), depending on the application period; short-term treatment inhibits primarily I(Kr), whereas long-term treatment reduces I(Ks).

Amiodarone↗

PubMed2001

Gap junction remodeling in hypertrophied left ventricles of aortic-banded rats: prevention by angiotensin II type 1 receptor blockade.

Remodeling of gap-junctional organization in hypertrophied left ventricle (LV) in response to pressure overload in rats induced by abdominal aorta banding was investigated by immunoconfocal and electron microscopy. Eight to 12 weeks after banding, rats developed significant LV hypertrophy. In contrast to control LV myocytes, which showed connexin43 (Cx43) labeling largely confined to the intercalated disks, LV myocytes from aortic-banded rats showed dispersion of punctate Cx43 labeling over the entire cell surface. In LV tissues sectioned longitudinally, the proportion of Cx43 label at the intercalated disk decreased significantly (control, 0.87 v aortic-banded, 0.62). En-face views of intercalated disks of hypertrophied myocardium revealed a reduction of Cx43 gap junctions in the disk center, giving rise to a significant decrease in the proportion of the disk occupied by gap-junctional membrane (control, 0.32 v aortic-banded, 0.24). Electron microscopy of hypertrophied LV tissue revealed that Cx43-containing gap junctions were frequently displaced from their usual locations to form side-to-side contacts distant from the disk, and also appeared as annular profiles. In aortic-banded rats treated with the angiotensin II (AII) type 1 receptor (AT1) antagonist, losartan (10 mg/kg/day, 11 weeks) not only LV hypertrophy, but also the gap junction disorganization was markedly reduced. These results suggest that LV hypertrophy induced by pressure overload is associated with Cx43 gap junction disorganization and that AII may play an important role either directly or indirectly in gap-junctional remodeling.

Angiotensin Receptor Antagonists↗

PubMed2001

Early and late elevation of plasma atrial and brain natriuretic peptides in patients after bone marrow transplantation.

Clinical usefulness of bone marrow transplantation (BMT) remains limited by myocardial damage during the post-transplantation period. Measurements of plasma atrial and brain natriuretic peptides (ANP, BNP) during the acute post-transplantation period could serve to monitor cardiac complications since these peptides are known to increase in heart failure depending on its severity. We prospectively analyzed ANP and BNP levels from 14 days before to 100 days after BMT in 46 consecutive patients undergoing allogeneic (n=42) and autologous (n=4) transplantation. Cardiac performance was assessed by echocardiography and radionuclide ventriculography. BNP and ANP levels of the patients on admission (baseline: day-14) were 16.3+/-13.3 pg/ml and 14.4+/-8.8 pg/ml, respectively. There were two different types of changes in the BNP and ANP levels. The 21 patients in group I showed dual peaks of elevation on day 1 (BNP=164.4+/-136.0 pg/ml, P<0.01; ANP=44.5+/-35.4 pg/ml, NS) and day 14 (BNP=233.9+/-106.2 pg/ml, P<0.01; ANP=142.7+/-154.6 pg/ml, P<0.05), whereas the remaining 25 patients in group II had a single peak on day 1 (BNP=124.5+/-124.9 pg/ml, P<0.05; ANP=45.2+/-42.4 pg/ml, NS). The left ventricular ejection fraction on day 63 was unchanged in both groups of patients from the baselines. The time to peak filling rate, a parameter of diastolic function in the radionuclide ventriculography, was significantly prolonged in group I patients (by 30+/-53%), whereas unaffected in group II patients. These results suggest that plasma BNP monitoring for 2 weeks after BMT may be useful for early detection of patients at high risk for cardiac dysfunction in the post-transplantation period.

Adult↗

PubMed2001

Estrogen replacement therapy in postmenopausal women augments reactive hyperemia in the forearm by reducing angiotensin converting enzyme activity.

The precise mechanism of the vasoprotective effect of estrogen replacement therapy in postmenopausal women is not fully understood. The present study sought to determine the role of nitric oxide (NO) and angiotensin-converting enzyme (ACE) in the vasodilator response of the forearm vessels induced by estrogen administration to postmenopausal women. Subjects were divided into two groups. One group received conjugated equine estrogen (0.625 mg daily) orally for 3 months (n=26), while the other received no treatment (control group, n=10). Forearm blood flow was measured by strain-gauge plethysmography. The concentrations of nitrite/nitrate (metabolites of NO), ACE activity, and lipid parameters were measured. Basal forearm blood flow, body weight, blood pressure, and heart rate were similar at baseline in both groups. After 3 months of estrogen administration, the maximal forearm blood flow response during reactive hyperemia and the serum level of nitrite/nitrate each showed a significant increase over baseline values: from 23.6+/-2.0 to 36.5+/-3.1 ml/min per 100 ml tissue (P<0.01), and from 24.8+/-2.3 to 38.6+/-3.6 micromol/l (P<0.01), respectively. Plasma levels of ACE activity were significantly reduced from baseline after 3 months of estrogen treatment (from 12.2+/-0.6 to 10.9+/-0.6 IU/l, P<0.01). No changes were seen in controls. The change in forearm blood flow after sublingual nitroglycerin was similar at baseline versus after 3 months of estrogen administration. The increase in the serum level of nitrite/nitrate after 3 months of estrogen therapy showed a significant inverse correlation (r=0.52, P<0.01) with the reduction in the plasma level of ACE activity. There was no significant correlation between the increase in serum nitrite/nitrate and any change in serum lipids, blood pressure, or other parameters. The administration of oral estrogen to postmenopausal women for 3 months increased the NO-mediated forearm endothelium-dependent vasodilatation. This was likely due, at least in part, to ACE inhibition. The latter may be one mechanism by which ERT provides its well-known cardiovascular benefit.

Blood Flow Velocity↗

PubMed2001

Relationship between the angiotensin-converting enzyme genotype and the forearm vasodilator response to estrogen replacement therapy in postmenopausal women.

OBJECTIVES: We sought to evaluate the relationship between the angiotensin-converting enzyme (ACE) genotype and the change in forearm vasoreactivity in response to a three-month course of oral estrogen in postmenopausal women. BACKGROUND: The ACE genotype is a known predictor of the response to an ACE inhibitor drug; however, it is not clear whether it can modify the effect of estrogen replacement therapy (ERT) on endothelial function in postmenopausal women. METHODS: Fifty-five postmenopausal women received 0.625 mg of conjugated equine estrogen daily for three months. Forearm blood flow (FBF) was measured by strain-gauge plethysmography. RESULTS: Twenty-one, 25 and 9 patients had the insertion/deletion (ID), II and DD genotypes, respectively. Plasma ACE activity was significantly higher at baseline in patients with either the DD or ID genotype than in those with the II genotype (p < 0.05). A significant decrease in plasma ACE activity with ERT was seen in the ID and II genotypes (p < 0.05), but not in the DD genotype. There were no significant differences in the FBF responses to reactive hyperemia at baseline between the three groups. Estrogen replacement therapy did not alter the FBF response to reactive hyperemia in the DD genotype (4.0 +/- 1.3%), although ERT significantly increased the FBF response in the ID and II genotypes (32.6 +/- 7.5% and 30.6 +/- 6.5%, respectively; p < 0.05). Forearm blood flow after administration of sublingual nitroglycerin did not change over three months in any of the three groups. CONCLUSIONS: These findings suggest that the effect of ERT in postmenopausal women on forearm endothelial function may be determined in part by the genotype of the ACE gene.

Administration, Oral↗

PubMed2001

Carvedilol: molecular and cellular basis for its multifaceted therapeutic potential.

Carvedilol is a unique cardiovascular drug of multifaceted therapeutic potential. Its major molecular targets recognized to date are membrane adrenoceptors (beta 1, beta 2, and alpha 1), reactive oxygen species, and ion channels (K+ and Ca2+). Carvedilol provides prominent hemodynamic benefits mainly through a balanced adrenoceptor blockade, which causes a reduction in cardiac work in association with peripheral vasodilation. This drug assures remarkable cardiovascular protection through its antiproliferative/atherogenic, antiischemic, antihypertrophic, and antiarrhythmic actions. These actions are a consequence of its potent antioxidant effects, amelioration of glucose/lipid metabolism, modulation of neurohumoral factors, and modulation of cardiac electrophysiologic properties. The usefulness of carvedilol in the treatment of hypertension, ischemic heart disease, and congestive heart failure is based on a combination of hemodynamic benefits and cardiovascular protection.

Adrenergic alpha-Antagonists↗

PubMed2001

Pacemaker shift in the rabbit sinoatrial node in response to vagal nerve stimulation.

Effects of brief postganglionic vagal nerve stimulation on the activation sequence of the rabbit sinoatrial (SA) node were investigated. Activation sequences in a small area (7 mm x 7 mm) on the epicardial surface were measured in a beat-to-beat manner using an extracellular potential mapping system composed of 64 modified bipolar electrodes with high-gain and low-frequency band-pass filtering. The leading pacemaker site was recognised clearly from both the activation sequence and the characteristic morphology of the potentials. Vagal stimulation resulted in a short-lasting initial slowing of spontaneous rate followed by a long-lasting secondary slowing; a brief period of relative or absolute acceleration was interposed between the two slowing phases. During these changes of spontaneous rate, the leading pacemaker site shifted in a complex beat-to-beat manner by 1-6 mm alongside the crista terminalis in the superior or inferior direction. For the first spontaneous excitation following stimulation, the greater the slowing, the larger the distance of the pacemaker shift. There was no such linear relationship between the extent of slowing and the distance of pacemaker shift for the subsequent beats. These changes in the leading pacemaker site in response to vagal stimulation may be the result of the functional and morphological heterogeneity of the mammalian SA node in terms of innervation, receptor distribution and ion channel densities. Experimental Physiology (2001) 86.2, 177-184.

Animals↗

PubMed2001

Open channel block of HERG K(+) channels by vesnarinone.

Vesnarinone, a cardiotonic agent, blocks I(Kr) and, unlike other I(Kr) blockers, produces a frequency-dependent prolongation of action potential duration (APD). To elucidate the mechanisms, we studied the effects of vesnarinone on HERG, the cloned human I(Kr) channel, heterologously expressed in Xenopus laevis oocytes. Vesnarinone caused a concentration-dependent inhibition of HERG currents with an IC(50) value of 17.7 +/- 2.5 microM at 0 mV (n = 6). When HERG was coexpressed with the beta-subunit MiRP1, a similar potency for block was measured (IC(50): 15.0 +/- 3.0 microM at 0 mV, n = 5). Tonic block of the HERG channel current was minimal (<5% at 30 microM, n = 5). The rate of onset of block and the steady-state value for block of current were not significantly different for test potentials ranging from -40 to +40 mV [time constant (tau) = 372 +/- 76 ms at +40 mV, n = 4]. Recovery from block at -60, -90, and -120 mV was not significantly different (tau = 8.5 +/- 1.5 s at -90 mV, n = 4). Vesnarinone produced similar effects on inactivation-removed mutant (G628C/S631C) HERG channels. The IC(50) value was 10.7 +/- 3.7 microM at 0 mV (n = 5), and the onset and recovery from block of current findings were similar to those of wild-type HERG. Amino acids important for the binding of vesnarinone were identified using alanine-scanning mutagenesis of residues believed to line the inner cavity of the HERG channel. Six important residues were identified, including G648, F656, and V659 located in the S6 domain and T623, S624, and V625 located at the base of the pore helix. These residues are similar but not identical to those determined previously for MK-499, an antiarrhythmic drug. In conclusion, vesnarinone preferentially blocks open HERG channels, with little effect on channels in the rested or inactivated state. These actions may contribute to the favorable frequency-dependent prolongation in APD.

Alanine↗

PubMed2001

Possible involvement of Rho kinase in Ca2+ sensitization and mobilization by MCh in tracheal smooth muscle.

We examined the effects of Rho kinase on contraction and intracellular Ca2+ concentration ([Ca2+](i)) in guinea pig trachealis by measuring isometric force and the fura 2 signal [340- to 380-nm fluorescence ratio (F340/F380)]. A Rho kinase inhibitor, Y-27632 (1-1,000 microM), inhibited methacholine (MCh)-induced contraction, with a reduction in F340/F380 in a concentration-dependent manner. The values of EC(50) for contraction and F340/F380 induced by 1 microM MCh with Y-27632 were 27.3 +/- 5.1 and 524.1 +/- 31.0 microM, respectively. With 0.1 microM MCh, the values for these parameters were decreased to 1.0 +/- 0.1 and 98.2 +/- 6.2 microM, respectively. Tension-F340/F380 curves for MCh indicated that Y-27632 caused an ~50% inhibition of MCh-induced contraction, without a reduction in F340/F380. These effects of Y-27632 were not inhibited by a protein kinase C inhibitor, GF-109203X. Our results indicate that inhibition of Rho kinase attenuates both Ca2+ sensitization and [Ca2+](i).

Amides↗

PubMed2001

Distribution of the muscarinic K+ channel proteins Kir3.1 and Kir3.4 in the ventricle, atrium, and sinoatrial node of heart.

The functionally important effects on the heart of ACh released from vagal nerves are principally mediated by the muscarinic K+ channel. The aim of this study was to determine the abundance and cellular location of the muscarinic K+ channel subunits Kir3.1 and Kir3.4 in different regions of heart. Western blotting showed a very low abundance of Kir3.1 in rat ventricle, although Kir3.1 was undetectable in guinea pig and ferret ventricle. Although immunofluorescence on tissue sections showed no labeling of Kir3.1 in rat, guinea pig, and ferret ventricle and Kir3.4 in rat ventricle, immunofluorescence on single ventricular cells from rat showed labeling in t-tubules of both Kir3.1 and Kir3.4. Kir3.1 was abundant in the atrium of the three species, as shown by Western blotting and immunofluorescence, and Kir3.4 was abundant in the atrium of rat, as shown by immunofluorescence. Immunofluorescence showed Kir3.1 expression in SA node from the three species and Kir3.4 expression in the SA node from rat. The muscarinic K+ channel is activated by ACh via the m2 muscarinic receptor and, in atrium and SA node from ferret, Kir3.1 labeling was co-localized with m2 muscarinic receptor labeling throughout the outer cell membrane.

Animals↗

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↗