This study used monophasic action potentials to investigate the effects of verapamil and propranolol on epinephrineinduced repolarization abnormalities in congenital long QT syndrome.
Early ...afterdepolarizations have been suggested to play a significant role in QT prolongation and ventricular arrhythmias in congenital long QT syndrome. Calcium channel blocking as well as beta-adrenergic blocking agents are reported to be effective in the management of this syndrome.
Monophasic action potentials from 2 to 4 sites were recorded simultaneously in eight patients with the long QT syndrome (22 sites) and in eight control patients (23 sites) and were obtained during constant atrial pacing 1) before epinephrine infusion; 2) during epinephrine infusion (0.1 μg/kg body weight min); 3) after verapamil injection (0.1 mg/kg) during epinephrine infusion; and 4) after both propranolol (0.1 mg/kg) and verapamil injections.
Early afterdepolarizations were recorded in two of the eight patients (2 of 22 sites) during the control state. During epinephrine infusion, early afterdepolarizations were recorded in six patients (six sites), and ventricular premature complexes were induced in three and torsade de pointes in one. Epinephrine prolonged 90% monophasic action potential duration from 348 ± 48 (mean ± SD) to 381 ± 49 ms (22 sites, p < 0.0005) and increased the dispersion of action potential duration (difference between the longest and shortest action potential duration) from 36 ± 20 to 64 ± 34 ms (p < 0.005). Verapamil eliminated (two sites) or reduced (four sites) early afterdepolarizations and abolished ventricular premature complexes in two of the three patients as well as suppressing torsade de pointes. Verapamil shortened the action potential duration to 355 ± 28 ms (p < 0.01 vs. epinephrine) and decreased the dispersion to 44 ± 19 ms (p < 0.05 vs. epinephrine). Propranolol further eliminated (two sites) or reduced (two sites) early afterdepolarizations, abolished ventricular premature complexes in the remaining one patient and further shortened the action potential duration to 337 ± 32 ms (p = 0.09 vs. verapamil). In the control patients, none of the early afterdepolarizations, ventricular arrhythmias or marked prolongations of action potential duration were induced by epinephrine, and neither verapamil nor propranolol changed repolarization variables.
These results indicate that both verapamil and propranolol can improve repolarization abnormalities induced by epinephrine in congenital long QT syndrome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We tested a hypothesis that an enhancement of IKs may play a pivotal role in ventricular proarrhythmia under high sympathetic activity. A 2-dimensional ventricular muscle layer was prepared in rabbit ...hearts, and action potential signals were analyzed by optical mapping. During constant stimulation, isoproterenol (ISP, O.1 μM) significantly shortened action potential duration (APD);chromanol 293B (30 μM), a selective IKs-blocker, reversed the APD shortening. VTs induced in the presence of ISP lasted longer than in the control, and this was reversed by 293B. E-4031 (0.1 μM), a selective IKr-blocker, did not cause such reversal. Spiral-wave (SW) reentry with ISP was characterized by more stable rotation around a shorter functional block line (FBL) than in the control. After application of 293B, SW reentry was destabilized, and rotation around a longer FBL with prominent drift reappeared. The APD abbreviation by ISP close to the rotation center was more pronounced than in the periphery, leading to an opposite APD gradient (center < periphery) compared with controls. This effect was also reversed by 293B. In conclusion, β-adrenergic stimulation stabilizes SW reentry most likely though an enhancement of IKs. Blockade of IKs may be a promising therapeutic modality in prevention of ventricular tachyarrhythmias under high sympathetic activity. Supplementary Figures:available only at http://dx.doi.org/10.1254/jphs.12008FP
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
1 Department of Cardiovascular
Biomechanics and 2 Institute of
Medical Electronics, Faculty of Medicine, University of Tokyo,
Tokyo 113; and
3 Institute for Life
Science Research, Asahi Chemical ...Industry Company, Fuji-City 416, Japan
To explore the mechanism of shear stress-induced downregulation
of vascular cell adhesion molecule 1 (VCAM-1) expression in murine
endothelial cells (ECs), we examined the effect of shear stress on
VCAM-1 gene transcription and assessed the
cis -acting elements involved in this
phenomenon. VCAM-1 mRNA expression was downregulated at the
transcriptional level as defined by nuclear run-on assay and transient
transfection of VCAM-1 promoter-luciferase gene constructs. The
luciferase assay on the VCAM-1 deletion mutants revealed that the
cis -acting element is contained
between 694 and 329 bp upstream from the transcription
initiation site. Gel shift assay using overlapping oligonucleotide
probes of this region showed that oligonucleotides containing a double
AP-1 consensus sequence (TGACTCA) formed distinct complexes with
nuclear proteins extracted from shear-stressed cells. Mutation of
either one or both of two AP-1 consensus sequences completely abolished
the ability of the promoter to respond to shear stress. These results suggest that fluid shear stress downregulates the transcription of the
VCAM-1 gene via an upstream
cis -element, a double AP-1 consensus
sequence, in murine lymph node venule ECs.
vascular endothelial cells; vascular cell adhesion molecule 1; nuclear factor activator protein-1; c- jun
Two isoforms of α-glucosidases (ONG2-I and ONG2-II) were purified from dry rice seeds (
Oryza sativa L., var Nipponbare). Both ONG2-I and ONG2-II were the gene products of ONG2 mRNA expressed in ...ripening seeds. Each enzyme consisted of two components of 6
kDa-peptide and 88
kDa-peptide encoded by this order in ONG2 cDNA (
ong2), and generated by post-translational proteolysis. The 88
kDa-peptide of ONG2-II had 10 additional N-terminal amino acids compared with the 88
kDa-peptide of ONG2-I. The peptides between 6
kDa and 88
kDa components (26 amino acids for ONG2-I and 16 for ONG2-II) were removed by post-translational proteolysis. Proteolysis induced changes in adsorption and degradation of insoluble starch granules. We also obtained three α-glucosidase cDNAs (
ong1,
ong3, and
ong4) from ripening seeds. The ONG1, ONG2, and ONG4 genes were situated in distinct locus of rice genome. The transcripts encoding ONG2 and ONG3 were generated by alternative splicing. Members of α-glucosidase multigene family are differentially expressed during ripening and germinating stages in rice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract The aim of the present study was to investigate the influenza vaccine effectiveness among young children in Japan. Study subjects were recruited from 43 pediatric clinics. Influenza-like ...illness (ILI) was defined as an acute febrile illness with respiratory symptoms; ILI with a fever of ≥39 °C was considered to be severe ILI (SILI). The adjusted OR of vaccination significantly decreased to 0.75 for SILI. Influenza vaccination for young children had a protective effect on the occurrences of SILI. This study also indicated that three key tools (case surveillance with equal scrutiny, confining observation to the peak epidemic period, and adoption of strict criteria for ILI) could minimize outcome misclassification and thus provide adequate methodology for monitoring vaccine effectiveness without laboratory confirmation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Alzheimer's disease (AD) is characterized by amyloid- beta (A beta ) protein and tau deposition in the brain. Numerous studies have reported a central role of A beta in the development of AD, but the ...pathogenesis is not well understood. Collapsin response mediator protein 2 (CRMP2), an intracellular protein mediating a repulsive axon guidance molecule, Semaphorin3A, is also accumulated in neurofibrillary tangles in AD brains. To gain insight into the role of CRMP2 phosphorylation in AD pathogenesis, we investigated the effects of A beta neurotoxicity in CRMP2 phosphorylation-deficient knock-in (crmp2ki/ki) mice, in which the serine residue at 522 was replaced with alanine. Intracerebroventricular (i.c.v.) injection of A beta 25-35 peptide, a neurotoxic fragment of A beta protein, to wild-type (wt) mice increased hippocampal phosphorylation of CRMP2. Behavioral assessment revealed that i.c.v. injection of A beta 25-35 peptide caused impairment of novel object recognition in wt mice, while the same peptide did not in crmp2ki/ki mice. In electrophysiological recording, wt and crmp2ki/ki mice have similar input-output basal synaptic transmission and paired-pulse ratios. However, long-term potentiation was impaired in hippocampal slices of A beta 25-35 peptide-treated wt but not those of crmp2ki/ki. Our findings indicate that CRMP2 phosphorylation is required for A beta -induced impairment of cognitive memory and synaptic plasticity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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