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A randomized, double-blind, placebo-controlled, dose-ranging study of dofetilide in patients with inducible sustained ventricular tachyarrhythmias.
Echt DS, Lee JT, Murray KT, Vorperian V, Borganelli SM, Crawford DM, Friedrich T, Roden DM
(1995) J Cardiovasc Electrophysiol 6: 687-99
MeSH Terms: Adolescent, Adult, Aged, Anti-Arrhythmia Agents, Double-Blind Method, Electrocardiography, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Phenethylamines, Sulfonamides, Tachycardia, Ventricular
Show Abstract · Added January 20, 2015
INTRODUCTION - Dofetilide is a new antiarrhythmic agent with potent IK blocking properties in vitro. We developed a dose-ranging, placebo-controlled study design to define the range of effective doses and to evaluate the clinical electrophysiology of intravenous dofetilide in patients in whom sustained ventricular tachycardia or fibrillation was reproducibly inducible at baseline electrophysiologic testing.
METHODS AND RESULTS - The initial four patients received low doses that were increased in subsequent groups of four if adverse effects were absent. In each group of four patients, one patient was randomly assigned to placebo (double blind). Twenty-four patients were studied at six incremental loading and maintenance infusion regimens. Dofetilide (0.1 to 8.0 ng/mL) produced concentration-related increases in the % delta of QT (r = 0.79, P < 0.001), QTc (r = 0.60, P = 0.02), RR (r = 0.62, P < 0.02), and right ventricular effective refractory period (cycle length 600 msec; r = 0.68, P = 0.04). Placebo produced no changes in any of these measurements. Sustained ventricular tachycardia or ventricular fibrillation was no longer inducible in 1 of 6 patients receiving placebo and 8 of 18 receiving dofetilide (4 to 13 sec nonsustained ventricular tachycardia was induced in 4 of these 8). One patient developed torsades de pointes at a high concentration (5.3 ng/mL).
CONCLUSIONS - We conclude that: (1) dofetilide produces concentration-related IK blocking effects in patients; (2) an incremental dose-ranging study design aids in identifying the range of doses demonstrating electrophysiologic effects and efficacy; (3) a concomitant placebo group provides important data to assess reproducibility of results over time; and (4) further studies of dofetilide's efficacy and toxicity should be conducted.
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14 MeSH Terms
nMDA receptor activation increases cyclic AMP in area CA1 of the hippocampus via calcium/calmodulin stimulation of adenylyl cyclase.
Chetkovich DM, Sweatt JD
(1993) J Neurochem 61: 1933-42
MeSH Terms: 2-Amino-5-phosphonovalerate, 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone, 6-Cyano-7-nitroquinoxaline-2,3-dione, Adenylyl Cyclases, Animals, Ascorbic Acid, Calcium, Calmodulin, Cell Membrane, Colforsin, Cyclic AMP, Deoxyadenosines, Dopamine, Enzyme Activation, Evoked Potentials, Glycine, Hippocampus, In Vitro Techniques, Isoproterenol, Kinetics, Models, Neurological, N-Methylaspartate, Pyramidal Tracts, Quinoxalines, Rats, Receptors, N-Methyl-D-Aspartate, Sulfonamides, Theophylline, Trifluoperazine
Show Abstract · Added April 2, 2019
We observed previously that activation of N-methyl-D-aspartate (NMDA) receptors in area CA1 of the hippocampus, through either NMDA application or long-term potentiation (LTP)-inducing high-frequency stimulation (HFS), results in an increase in cyclic AMP. In the present study, we performed experiments to determine the mechanism by which NMDA receptor activation causes this increase in cyclic AMP. As the NMDA receptor-mediated increase in cyclic AMP is dependent upon extracellular calcium, we hypothesized that NMDA receptors are coupled to adenylyl cyclase (AC) via calcium/calmodulin. In membranes prepared from area CA1, AC was stimulated by calcium in the presence of calmodulin, and the effect of calcium/calmodulin on AC in membranes was blocked by the calmodulin antagonists N-(6-aminohexyl)-5-chloro-1- naphthalenesulfonamide (W-7) and trifluoperazine (TFP). In intact hippocampal slices, W-7 and TFP blocked the increase in cyclic AMP levels caused by both NMDA application and HFS of Schaffer collateral fibers. Exposure of hippocampal slices to elevated extracellular potassium to induce calcium influx also caused increased cyclic AMP levels; the increase in cyclic AMP caused by high potassium was also blocked by W-7 and TFP. These data support the hypothesis that NMDA receptor activation is positively coupled to AC via calcium/calmodulin and are consistent with a role for cyclic AMP metabolism in the induction of NMDA receptor-dependent LTP in area CA1 of the hippocampus.
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MeSH Terms
Agonist stimulation of Na+/K+/Cl- cotransport in rat glomerular mesangial cells. Evidence for protein kinase C-dependent and Ca2+/calmodulin-dependent pathways.
Homma T, Burns KD, Harris RC
(1990) J Biol Chem 265: 17613-20
MeSH Terms: Alkaloids, Amino Acid Sequence, Angiotensin II, Animals, Calcimycin, Calcium-Calmodulin-Dependent Protein Kinases, Carrier Proteins, Cells, Cultured, Chlorides, Epidermal Growth Factor, Glomerular Mesangium, Kinetics, Molecular Sequence Data, Oligopeptides, Pertussis Toxin, Potassium, Protein Kinase C, Protein Kinase Inhibitors, Protein Kinases, Rats, Sodium, Sodium-Potassium-Chloride Symporters, Staurosporine, Substrate Specificity, Sulfonamides, Thrombin, Virulence Factors, Bordetella
Show Abstract · Added January 28, 2014
Studies were performed to investigate regulatory pathways of loop diuretic-sensitive Na+/K+/Cl- cotransport in cultured rat glomerular mesangial cells. Angiotensin II, alpha-thrombin, and epidermal growth factor (EGF) all stimulated Na+/K+/Cl- cotransport in a concentration-dependent manner. Pertussis toxin pretreatment reduced the effects of angiotensin II and alpha-thrombin but not that of EGF. Addition of the protein kinase C inhibitor staurosporine or down-regulation of protein kinase C by prolonged incubation with phorbol 12-myristate 13-acetate partially reduced the effects of angiotensin II and alpha-thrombin and completely blunted the phorbol 12-myristate 13-acetate-induced stimulation of Na+/K+/Cl- cotransport but did not affect EGF-induced stimulation. Exposure of cells to a calcium ionophore, A23187, resulted in a concentration-dependent stimulation of Na+/K+/Cl- cotransport, which was not significantly inhibited by down-regulation of protein kinase C but was completely inhibited by the calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7). Stimulation of the cotransport by angiotensin II or alpha-thrombin was also partially inhibited by W-7. Inhibitory effects of protein kinase C down-regulation and W-7 were additive and, when combined, produced a complete inhibition of angiotensin II-induced stimulation of Na+/K+/Cl- cotransport. In saponin-permeabilized mesangial cells, phosphorylation of a synthetic decapeptide substrate for Ca2+/calmodulin-dependent kinase II, Pro-Leu-Ser-Arg-Thr-Leu-Ser-Val-Ser-Ser-NH3, was demonstrated. Maximal activation of the decapeptide substrate phosphorylation required the presence of Ca2+ and calmodulin and was dependent on Ca2+ concentration. These findings indicate that stimulation of Na+/K+/Cl- cotransport by angiotensin II and alpha-thrombin is mediated by protein kinase C and Ca2+/calmodulin-dependent kinases whereas the action of EGF is mediated by other pathways.
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27 MeSH Terms
Effects of calmodulin antagonists on hydrogen-translocating shuttles in perfused rat liver.
Hamatani Y, Inoue M, Kimura K, Shiota M, Ohta M, Sugano T
(1991) Am J Physiol 261: E325-31
MeSH Terms: Adrenalectomy, Alanine, Aminooxyacetic Acid, Animals, Asparagine, Calcium, Calmodulin, Chlorpromazine, Glycerolphosphate Dehydrogenase, Hyperthyroidism, Hypothyroidism, Liver, Male, Mitochondria, Liver, NAD, Oxidation-Reduction, Perfusion, Propylthiouracil, Rats, Rats, Inbred Strains, Reference Values, Sorbitol, Sulfonamides, Thyroxine, Trifluoperazine, Triiodothyronine, Vasopressins
Show Abstract · Added December 10, 2013
The effects of calmodulin antagonists on the capacity of hydrogen-translocating shuttles were studied in the perfused rat liver. The capacity was estimated by measuring the changes in the rate of production of glucose from sorbitol during the oxidation of ethanol [T. Sugano, T. Ohta, A. Tarui, and Y. Miyamae. Am. J. Physiol. 251 (Endocrinol. Metab. 14): E385-E392, 1986]. Thyroxine given to intact rats increased the activity of alpha-glycerophosphate dehydrogenase (alpha-GPD). Glucocorticoid replacement in adrenalectomized rats decreased the activity of the alpha-GPD to values obtained after treatment with PTU. In either thyroxine-treated or steroid-replaced rats, the capacity of hydrogen-translocating shuttles increased markedly. However, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), trifluoperazine, and chlorpromazine inhibited the increased capacity in steroid-replaced rats and had no effect on the increased capacity in thyroxine-treated rats. W-7 inhibited the stimulatory effects of norepinephrine on the capacity of the malate-aspartate shuttle without inhibition of efflux of intracellular Ca2+. The stimulatory effects of vasopressin on the malate-aspartate shuttle were also inhibited by W-7, trifluoperazine, and chlorpromazine. The results suggest that the malate-aspartate shuttle may be regulated by Ca(2+)-calmodulin.
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27 MeSH Terms
Regulation of Na(+)-H+ exchange by ATP depletion and calmodulin antagonism in renal epithelial cells.
Burns KD, Homma T, Harris RC
(1991) Am J Physiol 261: F607-16
MeSH Terms: Adenosine Triphosphate, Amiloride, Animals, Calmodulin, Carrier Proteins, Cell Membrane, Cells, Cultured, Cytosol, Epithelial Cells, Epithelium, Hydrogen-Ion Concentration, Kidney, Protein Kinase C, Sodium-Hydrogen Exchangers, Sulfonamides
Show Abstract · Added January 28, 2014
The present studies examined effects of ATP depletion and calmodulin antagonism on stimulation of Na(+)-H+ exchange by cytosolic acidification in renal epithelial cells (LLC-PK1). ATP depletion significantly inhibited both amiloride-sensitive 22Na+ uptake (P less than 0.001; n = 12) and Na(+)-dependent intracellular pH (pHi) recovery in 2',7'-bis (carboxyethyl)-5(6)-carboxyfluorescein acetoxymethylester (BCECF/AM)-loaded cells. Calmodulin antagonists, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7) and calmidazolium, both caused a concentration-dependent inhibition of Na(+)-H+ exchange activity. The W-7-induced inhibition of Na(+)-H+ exchange occurred in cells incubated for 24 h with phorbol 12-myristate 13-acetate, indicating that the effect of W-7 was not mediated by protein kinase C inhibition. Both W-7 and ATP depletion shifted the pHi dependence of the antiporter, and ATP depletion also reduced the maximal activity. In LLC-PK1/CL4 cells grown on permeable filters, W-7 inhibited the cytosolic acidification-stimulated basolateral exchanger by 54 +/- 5% (P less than 0.005; n = 7) and, in contrast, stimulated the apical exchanger by 28 +/- 13% (P less than 0.05; n = 6). ATP depletion significantly inhibited apical Na(+)-H+ exchange. These results suggest that an ATP-Ca(2+)-calmodulin-dependent process is involved in regulation of Na(+)-H+ exchange in LLC-PK1 cells. A Ca(2+)-calmodulin-dependent process activated the amiloride-sensitive basolateral Na(+)-H+ exchanger and inhibited the amiloride-resistant apical antiporter. Phosphorylation of these two Na(+)-H+ exchangers or regulatory proteins by a Ca(2+)-calmodulin-dependent protein kinase may mediate this differential regulation.
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15 MeSH Terms
Transforming growth factor (TGF)-beta stimulates hepatic jun-B and fos-B proto-oncogenes and decreases albumin mRNA.
Beauchamp RD, Sheng HM, Ishizuka J, Townsend CM, Thompson JC
(1992) Ann Surg 216: 300-7; discussion 307-8
MeSH Terms: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Albumins, Animals, Cells, Cultured, Down-Regulation, Gene Expression Regulation, Genes, fos, Genes, jun, Isoquinolines, Liver, Mice, Piperazines, Protein Kinase Inhibitors, RNA, Messenger, Sulfonamides, Tetradecanoylphorbol Acetate, Transforming Growth Factor beta
Show Abstract · Added May 3, 2013
Transforming growth factor-beta (TGF-beta) modulates some components of the acute phase response in hepatic cells. The mechanisms for these actions of TGF-beta are largely unknown. The authors recently found that the decrease in albumin mRNA after TGF-beta 1 treatment required de novo RNA and protein synthesis, suggesting that TGF-beta acts through induction of another gene. The purpose of the current study was to determine whether TGF-beta 1 could regulate the expression of both the jun and fos genes that encode transcriptional regulatory proteins that constitute the AP-1 complex, and to determine whether expression of these genes may be coordinated with the decrease in albumin mRNA. Northern blot hybridization was used to determine levels of specific mRNAs. Transforming growth factor-beta 1 increased the levels of both jun-B and fos-B mRNA by 60 minutes after treatment of mouse hepatoma (BWTG3) cells. When TGF-beta 1 was removed from the media after 4 hours, there was a sustained effect of increased jun-B and decreased albumin mRNA (greater than 48 hours), and the subsequent decrease in jun-B levels coincided with the increase in albumin mRNA. The tumor-promoting phorbol ester (phorbol 12-myristate 13-acetate [PMA]), known to induce jun and fos gene expression, caused increases in jun-B and fos-B that preceded the decrease in albumin mRNA levels at 24 hours. These observations are consistent with our hypothesis that jun-B and fos-B induction may participate in downregulation of albumin synthesis as well as other hepatic responses to TGF-beta.
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17 MeSH Terms