Biomedical subjects

Ming-Jai Su

Publications and source records attributed to Ming-Jai Su.

At least 19 recordsLinked to original sources

PubMed2006

In vitro electrophysiological mechanisms for antiarrhythmic efficacy of resveratrol, a red wine antioxidant.

Resveratrol (trans-3, 4', 5-trihydroxystilbene), a natural antioxidant derived from grapes, has beneficial effects against coronary heart disease. Its electrophysiological characteristics for antiarrhythmic efficacy are largely unknown; thus, this study aims to explore the resveratrol's antiarrhythmic effects and conduction system in isolated hearts as well as its electrophysiological effects on cardiac myocytes. In the experiment, resveratrol suppressed the ischemia/reperfusion-induced ventricular arrhythmias in Langendorff-perfused rat hearts. In the current clamp study of the experiment, resveratrol prolonged the action potential duration (APD(50) and APD(90)) and suppressed the upstroke velocity of the action potential (V(max)). In the voltage clamp study, resveratrol inhibited sodium inward current (I(Na)) in a concentration-dependent manner and negative-shifted the voltage-dependent inactivation curve. Resveratrol also reduced the calcium inward current (I(Ca), 51.2+/-13.3% at 100 microM). Furthermore, the transient (I(to)) and sustained (I(ss)) outward potassium currents were decreased 60.2+/-5.7% and 42.3+/-5.2% after exposure to resveratrol (100 microM), respectively. The inward rectifier potassium current (I(K1)) was also reduced 24.2+/-7.0% in the presence of resveratrol (100 microM). In the isolated heart perfusion model, resveratrol (100 microM) prolonged AV nodal refractory period, the Wenckebach cycle length and the conduction through AV node and His-Purkinje system. In conclusion, resveratrol increased the cardiac effective refractory period mainly through inhibiting the ionic channels including I(Na), I(to) and I(ss) which could contribute to the conversion of ischemia/reperfusion-induced lethal arrhythmias.

Action Potentials↗

PubMed2006

Antihyperglycemic effect of aporphines and their derivatives in normal and diabetic rats.

The antihyperglycemic actions of some aporphines and their derivatives in normal Wistar, streptozotocin (STZ)-induced diabetic (IDDM) and nicotinamide-STZ induced diabetic (NIDDM) rats were investigated in this study. These compounds included thaliporphine, glaucine, boldine, N-methyllaurotetanine, and predicentrine and the derivatives, N-[2-(2-methoxyphenoxy)ethyl]norglaucine and diacetyl- N-allylsecoboldine. Bolus intravenous injection of these compounds decreased the plasma glucose levels in a dose-dependent manner in both normal and diabetic rats. Among them, thaliporphine was found to have the most potent antihyperglycemic effect in both NIDDM and IDDM diabetic rats. It was found that thaliporphine could stimulate the release of insulin in both normal and diabetic rats, and a dose of 1 mg per kg thaliporphine could significantly attenuate the increase of plasma glucose induced by an intravenous glucose challenge test in normal rats. Similar treatment with thaliporphine significantly increased the skeletal muscle glycogen synthesis in both normal and diabetic rats. Hence, the hypoglycemic effect of thaliporphine in diabetic rats could be attributed to the stimulation of insulin release and the increase of glucose utilization.

Animals↗

PubMed2006

N-Allylsecoboldine as a novel agent prevents acute renal failure during endotoxemia.

Blockades of cytokine and oxygen radicals release are considered to be beneficial in reducing multiple organ injury and increasing the survival rate in sepsis/septic shock. Thus, we examined the protective efficacy of N-allylsecoboldine, a secoaporphine derivative with antioxidant and alpha1-adrenoceptor blocking activities, in rats treated with endotoxin (E. coli lipopolysaccharide, LPS). Pretreatment of LPS-treated rats with N-allylsecoboldine significantly attenuated the late-phase hypotension, hypoglycemia and incremental plasma tumor necrosis factor (TNF)-alpha. Overproduction of plasma nitrate in endotoxemia was not changed but the continuous decrease of urinary nitrate appeared to be partially ameliorated by N-allylsecoboldine. However, N-allylsecoboldine inhibited the inducible nitric oxide synthase (iNOS) protein expression in the renal cortex of endotoxemic rats. N-allylsecoboldine also improved the endotoxemia-induced organ injury as demonstrated from the conspicuous recovery of marker enzymes in the LPS-treated rats. Endotoxemia was associated with renal dysfunctions as indicated by decreases in renal blood flow, urinary potassium excretion, and renal nitrate clearance. However, pretreatment with N-allylsecoboldine showed significant alleviation of these renal dysfunctions. In addition, a lower dose of N-allylsecoboldine ameliorated the mortality of LPS-treated mice. This study demonstrates N-allylsecoboldine's ability to avail against acute renal failure and increase survival rate during endotoxemia. These beneficial effects may be attributed to the inhibition of iNOS expression, TNF-alpha production, and free radical scavenging activities. However, the role of alpha1-adrenoceptor antagonism for N-allylsecoboldine in sepsis remains unclear.

Acute Kidney Injury↗

PubMed2006

Change of potassium current density in rabbit corneal epithelial cells during maturation and cellular senescence.

BACKGROUND: Voltage-gated potassium (K+) channels may participate in cellular developmental regulation, including cell differentiation, proliferation and apoptosis. This study investigated the change of K + current densities in corneal epithelial cells during maturation and cellular senescence. METHODS: New Zealand white rabbits were divided into three age groups: newborn ( 10.0 pF. Using a whole-cell clamp technique, K+ current was recorded and current densities were calculated. Differences in K+ current densities among newborn, young and adult rabbits, as well as differences among small, medium and large cells, were analyzed. RESULTS: We delineated two types of cells manifesting different amplitudes of depolarization-activated K+ outward currents. The averaged current density of type 1 response cells was significantly larger than that of type 2 cells in newborn, young, and adult groups. For newborn epithelial cells, the depolarization-gated outward K+ current density decreased from small to medium to large cells (p = 0.049, at a membrane potential of 140 mV). A similar pattern of change in current density was also delineated for these cell sizes in young and adult rabbit corneal cells (p < 0.001 for both young and adult rabbits). An increase in depolarization-gated outward K+ current density was also delineated from newborn to young to adult rabbits (p < 0.001, p < 0.001 and p < 0.006 for small, medium and large cells, respectively, at a membrane potential of 140 mV). CONCLUSIONS: Corneal epithelial cells expressed K+ channel densities that were distinct from basal to superficial cells and from newborn to adult rabbits.

Animals↗

PubMed2005

Attenuation of post-ischemia reperfusion injury by thaliporphine and morphine in rat hearts.

Pretreatment with thaliporphine before ischemia affords cardioprotective effects against reperfusion injury via antioxidant activity. This study evaluated whether thaliporphine administered at a certain period after myocardial ischemia conferred the same cardioprotection and assessed its possible new mechanism. The left main coronary artery of anaesthetized rats was occluded for 1 h and then reperfused for 2 h. Thaliporphine was administered at 10 min before reperfusion. Controls received saline only. Morphine, a nonselective opioid receptor agonist, was used as reference compound at 0.3 mg/kg. Thaliporphine at 0.05 and 0.5 mg/kg were found to reduce the infarct size. Recovery of cardiac function was higher in thaliporphine (0.5 mg/kg) group, as assessed by a significant improvement in the rates of pressure development (+dp/dt (max)). This compound also reduced plasma creatine kinase and cardiac MPO activity. These protective effects afforded by thaliporphine were diminished by the opioid receptor antagonists (naloxone or naltrexone) and by the mitochondrial K(ATP) blocker 5HD. In comparison, morphine reduced infarct size and MPO activity in the myocardium but produced slightly improvement in cardiac function after ischemia-reperfusion. These results demonstrate that reperfusion therapy with thaliporphine protect cardiac injury through further mechanism via activation of opioid receptor and opening of mitochondrial K(ATP) channels as morphine but with stronger activity.

Adenosine Triphosphate↗

PubMed2005

Multiple cellular electrophysiological effects of a novel antiarrhythmic furoquinoline derivative HA-7 [N-benzyl-7-methoxy-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione] in guinea pig cardiac preparations.

We studied the electrophysiological and antiarrhythmic actions of HA-7 [N-benzyl-7-methoxy-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione], a furoquinoline alkaloid derivative, in guinea pig heart preparations. In the perfused whole heart model, HA-7 caused a prolongation in the basic cycle length, ventricular repolarization time, and the atrioventricular (AV) nodal Wenckebach cycle length and prolonged the refractory period of the atrium, AV node, and His-Purkinje system. The atrioventricular conduction interval was also prolonged in a frequency-dependent manner. In isolated hearts, HA-7 significantly raised the threshold for experimental atrial fibrillation and reduced the occurrence of reperfusion-induced ventricular fibrillation. Conventional microelectrode-recording study shows that HA-7, but not d-sotalol, prolonged the action potential duration (APD) and decreased the maximum rate of depolarization in isolated atrial strips. In ventricular papillary muscles, higher concentrations of HA-7 caused a prolongation of APD(90) in a frequency-independent manner, whereas d-sotalol exerted a reverse frequency-dependent action on this parameter. Whole-cell patch clamp results on ventricular myocytes indicate that HA-7 decreased both the slow (I(Ks)) (IC(50) = 4.8 muM) and fast component (I(Kr)) (IC(50) = 1.1 muM) of the delayed rectifier K(+) currents. Similar results could also be observed in atrial myocytes. The inward rectifier K(+) current (I(K1)) was also reduced somewhat by HA-7. HA-7 also suppressed the Na(+) inward current (I(Na)) (IC(50) = 2.9 muM) and inhibited the L-type Ca(2+) current (I(Ca)) (IC(50) = 4.0 muM, maximal inhibition = 69%) to a lesser extent. We conclude that HA-7 blocks multiple ionic currents and that these changes affect the electrophysiological properties of the conduction system as well as the myocardial tissues and may contribute to its antiarrhythmic efficacy.

Action Potentials↗

PubMed2005

Arachidonic acid inhibits capacitative Ca2+ entry and activates non-capacitative Ca2+ entry in cultured astrocytes.

Arachidonic acid (AA) plays important physiological or pathophysiological roles. Here, we show in cultured rat astrocytes that: (i) endothelin-1 or thapsigargin (Tg) induces store-depleted activated Ca(2+) entry (CCE), which is inhibited by 2-aminoethoxydiphenyl borane (2-APB) or La(3+); (ii) AA (10 microM) and other unsaturated fatty acids (8,11,14-eicosatrienoic acid and gamma-linoleic acid) have an initial inhibitory effect on the CCE, due to AA- or fatty acid-induced internal acid load; (iii) after full activation of CCE, AA induces a further Ca(2+) influx, which is not inhibited by 2-APB or La(3+), indicating that AA activates a second Ca(2+) entry pathway, which coexists with CCE; and (iv) Tg or AA activates two independent and co-existing non-selective cation channels and the Tg-induced currents are initially inhibited by addition of AA or weak acids. A possible pathophysiological effect of the AA-induced [Ca](i) overload is to cause delayed cell death in astrocytes.

Animals↗

PubMed2005

Thaliporphine increases survival rate and attenuates multiple organ injury in LPS-induced endotoxaemia.

This study addressed the question of whether thaliporphine, a phenolic aporphine alkaloid obtained from Chinese herbs and possessing antioxidant and alpha-1 adrenoceptor antagonistic activity, has protective effects in endotoxaemic rats and we attempted to elucidate the mechanisms contributing to such protective effects. Injection of rats with endotoxin (E. coli lipopolysaccharide, LPS) induced severe hypotension and tachycardia as well as vascular hyporeactivity to noradrenaline. Pretreatment of LPS-treated rats with thaliporphine attenuated the delayed hypotension significantly whilst only a higher dose (1 mg/kg) of thaliporphine decreased LPS-induced tachycardia. LPS significantly increased nitric oxide (NO.) and superoxide anion (O(2).(-)) levels, a response that was reduced by pretreatment with 1 mg/kg thaliporphine. Endotoxaemia for 240 min resulted in a bell-shaped time course for the change of serum tumour necrosis factor-alpha (TNF-alpha) level with a peak at 60 min. Pretreatment of LPS-treated rats with 1 mg/kg thaliporphine significantly reduced the serum TNF-alpha level at 60 min. In addition, LPS caused a biphasic change in blood glucose and thaliporphine attenuated the late-phase decrease in blood glucose. Endotoxaemia induced multiple organ injury in the liver, kidney and heart, as indicated by increases of aspartate aminotransferase (GOT), alanine aminotransferase (GPT), creatinine (CRE), lactate dehydrogenase (LDH) and creatine phosphate kinase muscle-brain (CKMB) levels in serum. These increases of biochemical markers and inflammatory cell infiltration into injured tissues were reduced significantly by treatment with thaliporphine. In addition, thaliporphine increased the survival rate of LPS-treated mice dose-dependently. In conclusion, our results suggest that thaliporphine could be a novel agent for attenuating endotoxin-induced circulatory failure and multiple organ injury and may increase the survival rate. These beneficial effects of thaliporphine may be attributed to the suppression of TNF-alpha, NO. and O(2).(-) production.

Animals↗

PubMed2004

Resveratrol protects myocardial ischemia-reperfusion injury through both NO-dependent and NO-independent mechanisms.

We previously showed that resveratrol (3,4',5-trihydroxystilbene) stimulates NO production and is cardioprotective in rat heart subjected to ischemia-reperfusion (I/R rat heart). We now show that in I/R rat heart, inducible nitric oxide synthase (iNOS) expression is markedly induced, while expression of endothelial nitric oxide synthase (eNOS) and nueronal nitric oxide synthase (nNOS) is unchanged. In animals preconditioned with resveratrol (0.5 to 1 mg/kg body wt), I/R-induced iNOS induction is abrogated; however, expression of eNOS and nNOS is greatly upregulated. The protective effects of resveratrol on I/R rat heart include reduced rhythm disturbances, reduced cardiac infarct size, and decreased plasma levels of lactate dehydrogenase (LDH) and creatine kinase (CK). Among these, the reductions in LDH/CK levels and infarct size are NO-dependent as the coadministration of N(omega)-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg body wt) with resveratrol abolishes the resveratrol effect. In contrast, the reductions in the severity of ventricular arrhythmia and mortality rate are not affected by L-NAME coadministration, suggesting that a NO-independent mechanism is involved.

Animals↗

PubMed2004

Calcium-antagonizing activity of S-petasin, a hypotensive sesquiterpene from Petasites formosanus, on inotropic and chronotropic responses in isolated rat atria and cardiac myocytes.

Petasites formosanus, an indigenous species of Petasites, has been used to treat cardiovascular diseases such as hypertension for years. We have suggested recently that S-petasin, a major sesquiterpene from P. formosanus, inhibits vascular smooth muscle contraction through inhibition of voltage-dependent Ca(2+) channels, a phenomenon possibly responsible for the hypotensive effect of P. formosanus. This study was designed to examine the chronotropic and inotropic actions of S-petasin in the heart in vivo and in vitro. Administration of S-petasin (0.1-1.5 mg/kg i.v.) in anesthetized rats reduced heart rate dose-dependently. This response was consistent with significant suppression of both contractile amplitude and spontaneous firing rate of isolated atria, responses that were not antagonized by atropine (1 microM). Mechanical evaluation in isolated ventricular myocytes showed that S-petasin (0.1 to 100 microM) depressed peak myocyte contraction and intracellular Ca(2+) transients concentration-dependently. The duration of myocyte contraction was not affected. Whole-cell voltage clamp analysis revealed that S-petasin inhibited the L-type Ca(2+) current ( I(Ca,L)) concentration-dependently and shifted the steady-state inactivation curve of I(Ca,L) to more negative potentials. However, a receptor-binding assay failed to identify any significant interaction between S-petasin (0.1-300 microM) and the dihydropyridine binding sites of L-type voltage-dependent Ca(2+) channels. Taken together, these data show that the negative chronotropic and inotropic properties of S-petasin that can be ascribed mainly to I(Ca,L) inhibition, but not to blockade of dihydropyridine binding sites of L-type Ca(2+) channel or to muscarinic receptor activation.

Animals↗

PubMed2004

Morphine inhibits glutamate exocytosis from rat cerebral cortex nerve terminals (synaptosomes) by reducing Ca2+ influx.

Morphine, a mu-opioid agonist, suppressed the Ca(2+)-dependent release of glutamate that was evoked by exposing cerebrocortical synaptosomes to the potassium channel blocker 4-aminopyridine. The presynaptic inhibition produced by morphine was concentration-dependent and blocked by the nonselective opioid receptor antagonist naloxone. As determined by examining the mechanism of mu-opioid receptor-mediated inhibition of glutamate release, morphine caused a significant reduction in 4-aminopyridine-evoked increase in the cytoplasmic free Ca(2+) concentration ([Ca(2+)](c)), but failed to alter both 4-aminopyridine-evoked depolarization of the synaptosomal plasma membrane potential and Ca(2+) ionophore (ionomycin)-induced glutamate release. In addition, morphine was not capable of producing further inhibition on 4AP-evoked glutamate release in synaptosomes pretreated with the cannabinoid CB(1) receptor agonist WIN 55212-2, which has been shown to depress glutamate release through a suppression of presynaptic voltage-dependent Ca(2+) channel activity. These data suggest that morphine exerts its inhibitory effect presynaptically, likely through the reduction of Ca(2+) influx into nerve terminals, and thereby inhibits the release of glutamate in the cerebral cortex. This may therefore indicate that mu-opioid receptor agonists have neuroprotective properties, especially in the excessive glutamate release that occurs under certain pathological conditions.

4-Aminopyridine↗

PubMed2004

The vascular and cardioprotective effects of liriodenine in ischemia-reperfusion injury via NO-dependent pathway.

Liriodenine is an aporphine derivative isolated from the plant Fissistigma glaucescens. Electrophysiological action, particularly the blockage of Na+ and K+ channels, contributes to the drug's well-known anti-arrhythmic action. However, liriodenine's cardioprotective efficacy and the relation of the channel blockages to the efficacy are poorly known, as is the drug's effect on coronary flow and endothelial function. The present study evaluated the protection conveyed by liriodenine to myocardium and coronary endothelial cells under conditions of ischemia-reperfusion and to assess the involvement of a nitric oxide (NO)-dependent mechanism. In the Langendorff model utilizing Sprague-Dawley rat hearts, the left main coronary artery was occluded for 30 min and reperfusion for 120 min. Liriodenine (1 microM) significantly promoted the recovery of coronary flow and decreased myocardial infarction compared with vehicle-treated hearts. The drug attenuated the reduction of endothelial reactivity and NO release. To simulate the condition that occurs in the ischemic stage, human umbilical vein endothelial cells (HUVEC) were cultured in serum free conditions. Liriodenine showed concentration-dependent effects on cell viability associated with anti-apoptosis under serum-deprivation. Liriodenine prevented eNOS reduction in serum-deprived HUVEC and ischemia-reperfusion hearts. The vascular and cardioprotective effects were reversed by N(G)-nitro-L-arginine methyl ester. Another Na+ and K+ channel blocker with similar activities as liriodenine (quinidine) failed to protect endothelial cells and myocytes. These results demonstrate that liriodenine reduces the extent of cardiovascular injuries under ischemia-reperfusion conditions mainly by preserving the eNOS and the NO production.

Animals↗

PubMed2004

Preparation and biodistribution of rhenium-188 ECD/Lipiodol in rats following hepatic arterial injection.

Radiolabeled Lipiodol has routinely been used in hepatoma therapy. In this article an attempt to develop a new (188)Re-ECD/Lipiodol radiopharmaceutical, in which the chelating agent ECD (ethyl cyteinate dimer), is the constituent of the known brain perfusion agent (99m)Tc-ECD, and an evaluation of its stability and biodistribution in rats with hepatic tumors is presented. First, (188)Re-ECD was prepared in a vial, followed by extraction with Lipiodol to get the final product, (188)Re-ECD/Lipiodol. The optimal labeling conditions for (188)Re-ECD were: (1) tartaric acid which is better than EDTA as a weak chelating agent; and (2) 15 mg of SnCl(2), as the reducing agent, and 5-10 mg of tartaric acid in each vial had a better labeling yield. The radiochemical purity of (188)Re-ECD/Lipiodol was more than 94%. Twenty-four male Sprague-Dawley rats with liver tumors were sacrificed at 1, 24, and 48 h (eight rats each time) after an injection of approximately 7.4 MBq of (188)Re-ECD/Lipiodol via the hepatic artery. The radioactivity in the liver tumor is significantly high following therapeutic arterial injection, and relatively low in other organs including the bone, spleen, brain, thyroid, stomach, muscle, blood, and testis throughout this study. In conclusion, the new preparation of (188)Re-ECD/Lipiodol is a candidate agent for the treatment of liver cancer.

Animals↗

PubMed2004

Functional genomic study on atrial fibrillation using cDNA microarray and two-dimensional protein electrophoresis techniques and identification of the myosin regulatory light chain isoform reprogramming in atrial fibrillation.

INTRODUCTION: Functional and structural changes of atrial tissue occur during the natural course of atrial fibrillation (AF), and these changes may contribute to further AF. We investigated the changes in AF tissue using cDNA microarray and two-dimensional protein electrophoresis techniques. METHODS AND RESULTS: We established a porcine model of AF by rapid right atrial appendage pacing at a rate of 600/min. Atrial tissue was obtained after rapid atrial depolarization for 6 weeks. Microarrays containing 6,035 cDNA clones were used to evaluate the alterations of mRNA. Two-dimensional protein electrophoresis was performed to compare protein patterns. In cDNA microarray studies, we identified 387 genes with significant change in the left atrium and 81 genes in the right atrium. Among the genes, the ventricular isoform of the myosin regulatory light chain (MLC-2V) showed the greatest fold of change (9.4 and 7.3 in the left and right atrium, respectively). In protein electrophoresis, the expression levels of three protein spots spanning from 18 to 20 kDa in the acidic region (PI 4.5-5.0) were specifically elevated in the AF group. Interestingly, through tandem mass spectrometric analysis, these three spots were identified as MLC-2V. Thus, MLC-2V expression at the mRNA and protein levels corresponded well, and both indicated a significant increase in AF. CONCLUSION: Both cDNA microarray and two-dimensional polyacrylamide protein electrophoresis studies revealed characteristic changes in AF tissue. We demonstrated the reprogramming of myosin regulatory light chain isoform composition, with a significant increase of its ventricular isoform (MLC-2V).

Animals↗

PubMed2004

Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation.

STUDY OBJECTIVES: The calcineurin-nuclear factor of activated T-cell (NFAT) signal transduction pathway regulates the expression of a plethora of genes in the myocardium. Cytosolic calcium overloading occurs in atrial fibrillation (AF), and this fulfills the condition needed for activation of this pathway. We therefore investigated the NFAT pathway in atrial tissue in a porcine model of AF. METHODS AND RESULTS: AF was induced in eight adult pigs by rapid atrial pacing. Investigations on the calcineurin and NFAT pathway were performed on transmural left atrial tissue obtained 6 weeks after implantation of the pacemaker (pacing for 4 weeks, and AF without pacing for 2 weeks). In the AF group, the left atrial dimension increased significantly (26 +/- 4 mm vs 31 +/- 4 mm, respectively, p < 0.05 [mean +/- SD]). Calcineurin enzyme activity increased significantly in pigs with AF (n = 8) when compared to control pigs (n = 6) [0.143 +/- 0.034 vs 0.038 +/- 0.063 mmol PO(4)(-) released, p < 0.01]. We found that both NFAT-c3 and NFAT-c4, the downstream effectors of calcineurin, increased significantly in the nuclei in AF tissue using immunoblotting. Translocation of NFAT-c3 and NFAT-c4 into the nuclei was also demonstrated in AF tissue microsections using immunohistochemistry. The electrophoresis mobility shift assay further demonstrated that nuclear extracts from AF tissue had a significantly larger binding capacity for NFAT-specific oligonucleotide probes. CONCLUSIONS: Our results demonstrate that calcineurin activity was increased in AF with subsequent NFAT-c3 and NFAT-c4 translocation into the nucleus. Activation of this signal transduction pathway may play an important role in the pathogenesis of AF.

Animals↗

PubMed2003

Direct cardiac effects of As2O3 in rabbits: evidence of reversible chronic toxicity and tissue accumulation of arsenicals after parenteral administration.

Although parenteral administration of As(2)O(3) is highly effective in the treatment of acute promyelocytic leukemia, cardiac toxicity has been reported. This study employed Langendorff perfusion to determine the direct effects of As(2)O(3) in the electrophysiological properties of rabbit hearts after acute or chronic As(2)O(3) treatment (0.2 mg/kg/day iv for 30 days). Tissue accumulations of arsenicals and pathological changes as well as the reversibility of chronic As(2)O(3) effects were assessed. We found that cardiac conduction and repolarization were not altered whatsoever after acute As(2)O(3) treatment at clinically relevant (1, 3, and 10 microM) and higher (30 microM) doses. Nevertheless, an extremely high concentration of As(2)O(3) (300 microM) prolonged the corrected QT interval. Subsequent to chronic As(2)O(3) administration and with 30 microM As(2)O(3) via Langendorff perfusion, polymorphic ventricular tachycardia was observed (1/7, 14%). Corrected QT interval was prolonged, while basic cycle length was shortened. Significant accumulation of arsenicals in the cardiac tissue was found, but without any pathological changes. After As(2)O(3) was discontinued for 30 days, the chronic As(2)O(3) -induced electrophysiological changes improved, no ventricular arrhythmia was noted, and the tissue concentration of arsenicals decreased considerably. We therefore conclude that, although no immediate cardiac effects were discemable at clinically relevant doses, an extremely high concentration of As(2)O(3) could prolong ventricular repolarization. Chronic As(2)O(3) treatment resulted in a prolonged ventricular repolarization, in association with arsenicals accumulation and with risk of ventricular tachycardia. These chronic cardiac toxicities and the tissue accumulation of arsenicals were, however, partially reversible after cessation of As(2)O(3).

Animals↗

PubMed2003

Sympathetic nerve sprouting, electrical remodeling, and increased vulnerability to ventricular fibrillation in hypercholesterolemic rabbits.

Whether hypercholesterolemia (HC) can induce proarrhythmic neural and electrophysiological remodeling is unclear. We fed rabbits with either high cholesterol (HC, n=10) or standard (S, n=10) chows for 12 weeks (protocol 1), and with HC (n=12) or S (n=10) chows for 8 weeks (protocol 2). In protocol 3, 10 rabbits were fed with various protocols to observe the effects of different serum cholesterol levels. Results showed that the serum cholesterol levels were 2097+/-288 mg/dL in HC group and 59+/-9 mg/dL in S group for protocol 1 and were 1889+/-577 mg/dL in HC group and 50+/-21 mg/dL in S group for protocol 2. Density of growth-associated protein 43- (GAP43) and tyrosine hydroxylase- (TH) positive nerves in the heart was significantly higher in HC than S in protocol 1. Compared with S, HC rabbits had longer QTc intervals, more QTc dispersion, longer action potential duration, increased heterogeneity of repolarization and higher peak calcium current (ICa) density (14.0+/-3.1 versus 9.1+/-3.4 pA/pF; P<0.01) in protocol 1 and 2. Ventricular fibrillation was either induced or occurred spontaneously in 9/12 of hearts of HC group and 2/10 of hearts in S group in protocol 2. Protocol 3 showed a strong correlation between serum cholesterol level and nerve density for GAP43 (R2=0.94; P<0.001) and TH (R2=0.91; P<0.001). We conclude that HC resulted in nerve sprouting, sympathetic hyperinnervation, and increased ICa. The neural and electrophysiological remodeling was associated with prolonged action potential duration, longer QTc intervals, increased repolarization dispersion, and increased ventricular vulnerability to fibrillation.

Action Potentials↗

PubMed2003

Age-related differences in the direct cardiac effects of cisapride: narrower safety range in the hearts of young rabbits.

Although cisapride is widely used to treat gastrointestinal motility disorders, it has been associated with QT prolongation, torsades de pointes, and cardiac arrest. Only in children, however, has atrioventricular (AV) block after cisapride been reported. This study used Langendorff perfusion to determine the direct effects of cisapride (0.03, 0.1, 0.3, and 1 microM) on the conduction properties of neonatal (<7 d) and adult (>3 mo) rabbit hearts. At a clinically relevant dose (0.03 microM), cisapride slowed the recovery of the His-Purkinje system. At 0.1 microM, the refractoriness of the His-Purkinje system and conduction through this system were prolonged. Corrected QT intervals and the ventricular refractory period were also lengthened. These parameters were significantly more prolonged in neonates than in adults. The level of AV block at rapid atrial pacing shifted from the AV node to the His-Purkinje system, with an ED(50) of 0.06 and 0.52 microM in the neonate and the adult, respectively. In the neonate, cisapride even resulted in infranodal AV block rhythm (ED50 = 0.12 microM), but this was not the case in the adult. Polymorphic ventricular tachycardia after cisapride was induced in one in seven neonates (14%;, 0.1 microM) and in one in seven adults (14%; 0.03 microM). It is concluded that cisapride may affect the refractoriness of cardiac tissue and that the His-Purkinje system seems to be the most sensitive. In neonatal hearts, this modification may, in fact, progress to infranodal AV block. Such susceptibility to cisapride strongly indicates that the therapeutic safety range used for the young heart should be narrowed.

Age Factors↗