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PubMed1994

Sulindac-induced immune hemolytic anemia.

BACKGROUND: Sulindac, a nonsteroidal, anti-inflammatory, indene-derived drug, caused life-threatening immune hemolytic anemia in an individual with back pain. CASE REPORT: A patient was admitted to the hospital with immune hemolytic anemia and kidney and liver failure after several days ingestion of sulindac. The direct antiglobulin test was positive with polyspecific and monospecific anti-IgG but not with anti-C3. The eluate did not react in routine tests but reacted strongly after the addition of sulindac. The serum contained a sulindac-dependent antibody reacting to a titer of 32. The sulindac-dependent antibody was of both IgG and IgM classes and had no apparent blood group specificity. The antibody agglutinated red cells from humans and chimpanzees but not from chickens, rabbits, or sheep, which implied that a specific component on human and chimpanzee red cells was needed for reactivity. The antibody reacted with red cells treated with trypsin, papain, pronase, dithiothreitol, and sialidase. With aggressive medical care, the patient's condition improved. CONCLUSION: These findings appear compatible with the so-called immune complex mechanism for drug-induced immune hemolytic anemia. Physicians are alerted to the severe nature of this syndrome.

Aged↗
PubMed1973

Molecular orbital calculations of magnetic circular dichroism spectra: a benzene-indole sequence.

The magnetic circular dichroism of benzene and indole derivatives was measured down to 190 nM. The following pairs of molecules have magnetic circular dichroisms of the opposite sign in the B(2u) absorption region: aniline and benzonitrile, indene and indoline, indole and 4-aminoindole, and 4-aminoindole and 5-aminoindole. The sign and magnitude of the magnetic circular dichroisms observed are in good agreement with those calculated by the semiempirical self-consistent field with configuration interaction Pariser-Parr-Pople method with incorporation of variable pi-electronegativity and sigma-polarization. The energy dominator in the magnetic rotational strength expression serves to limit the important contributions to a few terms only.

Aniline Compounds↗
PubMed1984

Characterization of a herpes simplex virus type 1 mutant resistant to benzhydrazone, a selective inhibitor of herpesvirus glycosylation.

Benzhydrazone [BH; 1H-benz[f]indene-1,3(2H) -dionebis(amidinohydrazone)] significantly inhibits glycosylation of proteins, but only in cells infected with herpes simplex virus. We report on a herpes simplex virus type 1 (HSV-1) mutant resistant to BH. A syncytium-inducing mutant designated HSV-1(13)S11 was found to be biochemically resistant to BH in that [14C]glucosamine incorporation was not inhibited in infected HEp-2 cells exposed to the drug. Intertypic recombinants were obtained which showed that BH resistance is encoded in the DNA of the mutant virus and may be transferred into the genome of BH-sensitive HSV. In the recombinants the biochemical resistance marker segregated from the syncytial marker, suggesting that the two markers probably map in different loci. The BH-resistant mutant did not complement wild-type BH-sensitive HSV-1 and -2. Furthermore, resistance was apparent in HEp-2 but not in Vero cells. The paper discusses the hypothesis that inhibition of glycosylation of HSV proteins is the consequence of modification or selective transport of BH involving a HSV gene product.

Carcinoma, Squamous Cell↗
PubMed1995

Stable amplification of the S-adenosylmethionine decarboxylase gene in Chinese hamster ovary cells.

A Chinese hamster ovary cell subline (CHO/664) > 1000-fold resistant to the S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor, CGP-48664 (4-(aminoiminomethyl)-2,3-dihydro-1H-inden-1-one diaminomethylenehydrazone), has been developed and characterized. The cells were also cross-resistant to the highly specific nucleoside analog inhibitor of AdoMetDC, MDL-73811. These unique cells stably overexpress AdoMetDC due to a 10-16-fold amplification of the AdoMetDC gene, which resulted in a similar increase in AdoMetDC transcript levels. In the presence of 100 microM CGP-48664, the CHO/664 cells displayed AdoMetDC activities similar to the parental line. Following removal of the inhibitor, AdoMetDC activity increased steadily over 20 days to 10-12 times that found in parental CHO cells. Decarboxylated (dc) AdoMet pools accumulated rapidly from < 5 pmol/10(6) cells to approximately 1000-1500 pmol/10(6) cells at 3 days due to diffusion away of intracellular inhibitor and to the depletion of putrescine and spermidine as aminopropyl acceptors in dcAdoMet-mediated synthase reactions. Polyamine pools shifted as putrescine, and spermidine pools were processed forward to spermine. During the period from 3 days to 20 days, dcAdoMet pools fell steadily and eventually stabilized at 100-200 pmol/10(6) cells. Providing excess putrescine at this time as an aminopropyl acceptor rapidly lowered dcAdoMet pools and led to a near normalization of polyamine pools, indicating that both dcAdoMet and putrescine are essential in maintaining steady-state polyamine pool profiles. As with cell line variants that overproduce ornithine decarboxylase, polyamine transport was found to be increased in CHO/664 cells due to an apparent inability of the system to down-regulate polyamine transport in response to polyamine excess. Given the unique metabolic disturbances seen in these cells, we anticipate that in addition to providing a useful system for evaluating the specificity of newly developed AdoMetDC inhibitors, they will undoubtedly prove valuable for investigating the various regulatory interrelationships involved in polyamine homeostasis and possibly other aspects of purine metabolism.

Adenosylmethionine Decarboxylase↗
PubMed2002

Identification of the structure and origin of thioacidolysis marker compounds for cinnamyl alcohol dehydrogenase deficiency in angiosperms.

Molecular marker compounds, derived from lignin by the thioacidolysis degradative method, for cinnamyl alcohol dehydrogenase (CAD) deficiency in angiosperms have been structurally identified as indene derivatives. They are shown to derive from hydroxycinnamyl aldehydes that have undergone 8-O-4-cross-coupling during lignification. As such, they are valuable markers for ascertaining plant responses to various levels of CAD down-regulation. Their derivation illustrates that hydroxycinnamyl aldehydes incorporate into angiosperm lignins by endwise coupling reactions in much the same way as normal monolignols do, suggesting that the hydroxycinnamyl aldehydes should be considered authentic lignin precursors.

Alcohol Oxidoreductases↗
PubMed2004

Two new norsesquiterpenes from Ligularia lapathifolia.

Two new norsesquiterpenes were isolated from the extracts of the roots and rhizomes of Ligularia lapathifolia (Franch.) Hand.-Mazz. Their structures were identified as 2-acetyl-3a-methyl-5-(2-methyl-but-2-enoyloxy)-3a,4,5,6,7,7a-hexahydro-H-indene-4-carboxylic acid (1) and 2-acetyl-8a-methyl-2-(2-methyl-but-2-enoyloxy)-6-oxo-1,2,3,4,4a,5,6,8a-octahydro-naphthalene-1-carboxylic acid (2), respectively, on the basis of spectral data and for 1 by single-crystal X-ray analysis.

Asteraceae↗
PubMed1999

Formation of anion-selective channels in the cell plasma membrane by the toxin VacA of Helicobacter pylori is required for its biological activity.

The vacuolating toxin VacA, a major determinant of Helicobacter pylori-associated gastric diseases, forms anion-selective channels in artificial planar lipid bilayers. Here we show that VacA increases the anion permeability of the HeLa cell plasma membrane and determines membrane depolarization. Electrophysiological and pharmacological approaches indicated that this effect is due to the formation of low-conductance VacA pores in the cell plasma membrane and not to the opening of Ca(2+)- or volume-activated chloride channels. VacA-dependent increase of current conduction both in artificial planar lipid bilayers and in the cellular system was effectively inhibited by the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), while2-[(2-cyclopentenyl-6,7dichloro-2, 3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetic acid (IAA-94) was less effective. NPPB inhibited and partially reversed the vacuolation of HeLa cells and the increase of ion conductivity of polarized Madine Darby canine kidney cell monolayers induced by VacA, while IAA-94 had a weaker effect. We conclude that pore formation by VacA accounts for plasma membrane permeabilization and is required for both cell vacuolation and increase of trans-epithelial conductivity.

Animals↗
PubMed2004

Pharmacological characterization of beta-adrenoceptor subtypes mediating relaxation in porcine isolated ureteral smooth muscle.

PURPOSE: We pharmacologically characterized the functional beta-adrenoceptor subtypes mediating porcine ureteral smooth muscle relaxation. MATERIALS AND METHODS: The effects of various beta-adrenoceptor agonists and antagonists on KCl induced tonic contractions in isolated porcine ureteral preparations were evaluated using a functional experimental technique. RESULTS: The rank order of potency for the catecholamines tested was isoprenaline > adrenaline > noradrenaline. All beta2-adrenoceptor agonists tested (salbutamol, procaterol and terbutaline) attenuated the KCl induced contraction. The 2 beta3-adrenoceptor agonists CL-316243 ((R, R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]-1,3-benzodioxole-2,2-dicarboxylate], Kissei, Nagano, Japan) and CGP-12177A ((+/-)[4-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2 H-benzimidazol-2-one hydrochloride], Funakoshi, Tokyo, Japan) also relaxed the ureter. The beta1-adrenoceptor agonist dobutamine had a relaxing effect on the ureter only at high concentrations (over 1 x 10 M). Isoprenaline induced relaxation was antagonized by the beta2-adrenoceptor antagonist ICI-118,551 ((+/-)-1-[(2,3-dihydro-7-methyl-1 H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride, Sigma, St. Louis, Missouri) but not by the beta1-adrenoceptor antagonist CGP 20712A ((+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1 H-imidazol-2-yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulphonate, Funakoshi). In the presence of 1x 10 M CGP 20712A plus 1 x 10 M ICI-118,551 the beta3-adrenoceptor antagonist SR 58894A (3-(2-allylphenoxy)-1-[(1 S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2 S)-2-propanol hydrochloride, Kissei) antagonized isoprenaline induced relaxation. CONCLUSIONS: Our results suggest that porcine ureteral smooth muscle is relaxed by beta2 and beta3-adrenergic stimulation, as in humans.

Adrenergic beta-Agonists↗
PubMed2006

The organic preservation of fossil arthropods: an experimental study.

Modern arthropod cuticles consist of chitin fibres in a protein matrix, but those of fossil arthropods with an organic exoskeleton, particularly older than Tertiary, contain a dominant aliphatic component. This apparent contradiction was examined by subjecting modern cockroach, scorpion and shrimp cuticle to artificial maturation (350 degrees C/700 bars/24 h) following various chemical treatments, and analysing the products with pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS). Analysis of artificially matured untreated cuticle yielded moieties related to phenols and alkylated substituents, pyridines, pyrroles and possibly indenes (derived from chitin). n-Alkyl amides, C16 and C18 fatty acids and alkane/alk-1-ene homologues ranging from C9 to C19 were also generated, the last indicating the presence of an n-alkyl component, similar in composition to that encountered in fossil arthropods. Similar pyrolysates were obtained from matured pure C16 and C18 fatty acids. Py-GC/MS of cuticles matured after lipid extraction and hydrolysis did not yield any aliphatic polymer. This provides direct experimental evidence that lipids incorporated from the cuticle were the source of aliphatic polymer. This process of in situ polymerization appears to account for most of the fossil record of terrestrial arthropods as well as marine arthropods that lacked a biomineralized exoskeleton.

Animals↗
PubMed1990

Feruloylputrescine and Caffeoylputrescine Are Not Involved in Growth and Floral Bud Formation of Stem Explants from Nicotiana tabacum L. var Xanthi nc.

The role of feruloylputrescine (FP) and of caffeoylputrescine (CP) was investigated in an explant system of stem explants from day-neutral Nicotiana tabacum L. var Xanthi nc. Previously, a correlation between cortical callus formation and increase in FP content, as well as between in vitro flower formation and increase in CP content had been shown. During the explant growth in vitro, the increase of both FP and CP was inhibited by 4-fluor-(1-amino-2-phenylethyl)phosphonic acid and 2-amino-indene-2-phosphonic acid, both inhibitors of phenylalanine ammonia-lyase (EC 4.3.1.5). dl-alpha-difluoromethylarginine, an inhibitor of arginine decarboxylase (ADC, EC 4.1.1.19), prevented only the increase in FP, while dl-alpha-difluoromethylornithine, an inhibitor of ornithine decarboxylase (EC 4.1.1.17), reduced only that of CP. Increase in dry weight and the formation of cortical callus and of floral buds of explants were not affected by any of the inhibitors. We conclude, in contrast to earlier hypotheses, that FP and CP do not trigger growth and differentiation in the explants. It seems more likely that FP and CP increase in response to auxin and cytokinin in the media.

Journal Article↗
PubMed2001

Diels-Alder adducts of medium-ring carbocyclic dienes prepared by rearrangement of catalytically generated cyclic oxonium ylides.

The novel bicyclic and tricyclic systems dimethyl (4aS*,6S*)-6-methoxy-7-oxo-4a,5,6,7,8,9-hexahydro-2H-benzocycloheptene-3,4-dicarboxylate, C(16)H(20)O(6), (I), dimethyl (4aS*,6R*)-6-methoxy-7-oxo-4a,5,6,7,8,9-hexahydro-2H-benzocycloheptene-3,4-dicarboxylate, C(16)H(20)O(6), (II), (3aS*,9R*,10aS*,10bR*)-9-methoxy-2-oxa-1,3a,4,6,7,8,9,10,10a,10b-decahydro-3H-cyclohepta[e]indene-1,3,8-trione, C(14)H(16)O(5), (III), and (1S*,2R*,9S*,10aR*)-9-methoxy-8-oxo-1,2,3,5,6,7,8,9,10,10a-decahydrobenzocyclooctene-1,2-dicarboxylic acid, C(15)H(20)O(6), (IV), have been crystallographically characterized, allowing the determination of the relative configuration of the stereogenic centres. The poor quality of the dicarboxylic acid crystals necessitated the use of synchrotron radiation.

Journal Article↗
PubMed2003

A doubly bridged isodicyclopentadienyl zirconium complex: bis[N-(3,5-dimethylphenyl)-N-[(eta5-isodicyclopentadien-2-yl)dimethylsilyl]amido-kappaN]zirconium(II) diethyl ether solvate.

Transmetallation of the dilithium salt of (3,5-dimethyphenylamino)(isodicyclopentadienyl)dimethylsilane by treatment with zirconium tetrachloride in a 2:1 ratio leads to the substitution of all four chloride ligands. With the applied stoichiometry, the title complex, [Zr(C(20)H(25)NSi)(2)].C(4)H(10)O, was obtained and crystallized from diethyl ether. X-ray diffraction characterization showed that both isodicyclopentadienyl ligands (alternatively called 4,5,6,7-tetrahydro-4,7-methano-1H-indene) are complexed to the metal on their exo face in a completely stereoselective manner and that they are eta(5)-bonded to the Zr atom.

Journal Article↗
PubMed2003

ansa-[(tert-Butylamino)(isodicyclopentadienyl)dimethylsilane]Zr(NMe2)2 prepared by an amine-elimination reaction.

An amine-elimination reaction was used to obtain the title compound, i.e. (N-tert-butyl-N-[[(1,2,3,3a,7a-eta)-4,5,6,7-tetrahydro-4,7-methano-1H-inden-2-yl]dimethylsilyl]amido-kappaN)bis(N-methylmethanaminato-kappaN)zirconium(IV) or [isodiCpSiMe(2)N-tert-butyl]Zr(NMe(2))(2) (Cp is cyclopentadienyl), [Zr(C(16)H(25)NSi)(C(2)H(6)N)(2)], in very good yield. Treatment of isodiCpHSiMe(2)NH-tert-butyl with Zr(NMe(2))(4) leads to the formation of a yellow solid that can be purified by sublimation. The single-crystal structure of the product shows the exo complexation of the isodicyclopentadienyl ligand to the Zr atom. The Cp portion of this ligand is bonded to the Zr atom in a eta(5) manner, with a Zr-Cg (Cg is the ring centroid) distance of 2.2352 (10) A. The isodiCpSiMe(2)N-tert-butyl ligand has a constrained geometry, which is exhibited by the small angle of 95.55 (10) degrees for N-Si-C(Cp).

Journal Article↗
PubMed1998

A [[TiCl2(isodiCp)]2(mu-O)] dimer and a twinned cyclic [TiCl(isodiCp)(mu-O)]4 tetramer.

The mu-oxo dimer mu-oxo-bis[dichloro[(1,2,3,3a,7a-eta)- 4,5,6,7-tetrahydro-4,7-methano-1H-indenyl]titanium], [Ti2Cl4(mu-O)(C10H11)2], and the mu-oxo cyclic tetramer, cyclo-tetra-mu-oxo-tetrakis[chloro[(1,2,3,3a,7a-eta)-4,5,6,7-tetrahydro- 4,7-methano-1H-indenyl]titanium], [Ti4Cl4(mu-O)4(C10H11)4], have been synthesized by electrophilic attack of TiCl4 on the exo-trimethylsilyl derivative of isodiCp (isodiCp is the isodicyclopentadienide anion or 4,5,6,7-tetrahydro-4,7-methano-1H-indene) in the presence of trace amounts of moisture. Both structures are endo isomers, with each Ti atom bonded in a eta 5 manner to the Cp ring of the isodiCp ligand. Both display a slight bending of the isodiCp group about the bond common to the Cp ring and the norbornane fragment, such that the norbornane group is displaced in the direction away from the Ti atom. The dihedral angles which describe this bending are 9.0 (3) and 10.2 (3) degrees for the dimer, and 9.2 (2) degrees for the tetramer. The dimer contains a bent Ti-O-Ti angle of 159.5 (2) degrees. The tetramer forms tetragonal crystals, which are twinned by merohedry on the (110) plane. The tetramer molecule contains a crystallographic 4 axis, with the Ti atoms linked by the O atoms in a mu-oxo manner to form an eight-membered ring.

Crystallography, X-Ray↗
PubMed2004

Cl- channels are expressed in human normal monocytes: a functional role in migration, adhesion and volume change.

Increased adhesion and diapedesis of monocytes appear to be primary initiating factors in the pathophysiology of occlusive vascular diseases, including atherosclerosis and restenosis. However, the underlying mechanisms of transendothelial migration and invasion of monocytes into the blood vessels are not known. Alterations in ion channels on the cell membrane are generally involved in induced changes in shape and volume. In the present study, we investigated the expression and functional role of chloride channels in freshly isolated human blood monocytes. The Cl- currents in whole-cells were measured by the patch-clamp technique. We observed whole cell Cl- currents, which were time-independent and outwardly rectifying. The chloride channel blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-oxy]acetic acid 94 (IAA94) attenuated the Cl- currents. NPPB and IAA94 also inhibited chemotaxis of monocytes, as measured in Boyden chemotactic chambers, with the same sensitivity. NPPB but not IAA94, increased the cell volume as measured by shape change, and decreased tumour necrosis factor (TNF)-alpha-induced monocyte adhesion to endothelial cells. These results suggest that monocytes contain Cl- channels which regulate transendothelial migration of monocytes, due presumably to an alteration in cell volume.

Adult↗
PubMed2005

Novel protein kinase C-beta isoform selective inhibitor JTT-010 ameliorates both hyper- and hypoalgesia in streptozotocin- induced diabetic rats.

AIM: Activation of protein kinase C (PKC) is thought to play an important role in the pathogenesis of diabetic microvascular complications. PKC-beta is elevated in hyperglycaemic conditions, both in vivo and in vitro. In this study, pharmacological effects of a novel PKC-beta isoform selective inhibitor, JTT-010 ((2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate), on diabetic neuropathy were examined. METHODS: PKC inhibitory activity of JTT-010 was evaluated with an enzyme assay. For the in vivo study, streptozotocin (STZ)-induced diabetic rats were treated with JTT-010 for 12 weeks and tail/sciatic nerve conduction velocity (NCV) evaluated. Hyper/hypoalgesia was evaluated using tail-flick and formalin tests. RESULTS: JTT-010 inhibited PKC-betaI and -betaII with IC50 values of 4.0 and 2.3 nm respectively. For other PKC isoforms, IC50 values were 54 nm or greater. In STZ-induced diabetic rats showing a reduction in tail/sciatic nerve conduction velocities, JTT-010 (0.3-3 mg/kg) ameliorated the reduction of these velocities. In a formalin test, STZ-induced diabetic rats had hyperalgesia in the first phase. JTT-010 reduced nociceptive response at doses of 0.1 mg/kg or higher. Furthermore, STZ-induced diabetic rats showed hypoalgesia in the second phase of the formalin test and tail-flick test. JTT-010 also ameliorates these symptoms at doses of 0.1 mg/kg or higher. CONCLUSIONS: These observations suggest that PKC-beta contributes not only to diabetic hyperalgesia, but also to hypoalgesia and also contributes to defects in NCV. PKC-beta inhibitor, JTT-010, may be beneficial in suppressing the development of diabetic nerve dysfunction, including hyperalgesia and hypoalgesia.

Animals↗
PubMed1994

Pharmacologic properties of the swelling-induced chloride current of dog atrial myocytes.

INTRODUCTION: Swelling-induced chloride currents may contribute to cardiac electrical activity and cell volume regulation. Identification of selective blockers would aid in understanding the functional contribution(s) of this current. METHODS AND RESULTS: Dog atrial cells were used to investigate the pharmacologic properties of the swelling-induced chloride current. Whole cell patch clamp was used. Swelling-induced chloride current was activated by osmotic stress. Initially, the chloride selectivity and calcium independence of the swelling-induced current in dog atrial cells was demonstrated. Subsequently, a number of putative chloride channel blockers were examined. Anthracene-9-carboxylic acid (1 mM) and dideoxyforskolin (100 microM) and extracellular cAMP (5 mM) were found to partially inhibit the swelling-induced chloride current (approximately 50%, 80%, and 10% inhibition, respectively). Niflumic acid (100 microM), nitrophenylpropylamino benzoate (NPPB; 10 to 40 microM), and (+) 2-[(2-cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxy-1H-inden -5-yl)oxy d acetic acid (indanyloxyacetic acid; IAA-94; 100 microM) could fully inhibit the swelling-induced chloride current without decreasing cell size. DIDS (100 microM) and dinitrostilbene disulfonic acid (DNDS; 5 mM) fully inhibited outward currents but only partially inhibited inward current. CONCLUSIONS: Niflumic acid, IAA-94, and NPPB were identified as full blockers of cardiac swelling-induced chloride current. Nonspecific effects were identified for each of the full blockers. Experiments that use these agents as functional antagonists should be carefully designed and interpreted with caution.

Animals↗
PubMed2005

Effect of beta-adrenoceptor blockers on human ether-a-go-go-related gene (HERG) potassium channels.

Patients with congenital long QT syndrome may develop arrhythmias under conditions of increased sympathetic tone. We have addressed whether some of the beta-adrenoceptor blockers commonly used to prevent the development of these arrhythmias could per se block the cardiac HERG (Human Ether-a-go-go-Related Gene) potassium channels, which would be a most unwanted side effect. HERG potassium channels were heterologously expressed in Xenopus oocytes and the currents measured by two-electrode-voltage-clamp technique. Propranolol caused a concentration-dependent inhibition of HERG current with an IC50 value of 81 microM at -10 mV. When HERG was co-expressed with the accessory subunit KCNE2, an IC50 value of 52 microM was determined. The block by propranolol was voltage-dependent, but it did not change the HERG channel deactivation kinetics. The propranolol analogue ICI118551 ((+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) blocked the HERG channel with similar affinity, whereas the beta1-receptor antagonists metoprolol and atenolol showed weak effects. Further, the four compounds blocked HERG channels expressed in a mammalian HEK293 cell line. These data showed that HERG blockade by beta-adrenoceptor blockers occurred only at high micromolar concentrations, which are significantly above the recently established safe margin of 100 (Redfern et al., 2003).

Action Potentials↗