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J Brendel

Publications and source records attributed to J Brendel.

11 recordsLinked to original sources
PubMed2004

Effects of the atrial antiarrhythmic drug AVE0118 on cardiac ion channels.

Previous studies in pigs and goats have demonstrated that AVE0118 prolongs atrial refractoriness without any effect on the QT-interval. The purpose of the present study was to investigate the effect of the compound on various cardiac ion channels. AVE0118 blocked the pig Kv1.5 and the human Kv1.5 expressed in Xenopus oocytes with IC(50) values of 5.4+/-0.7 microM and 6.2+/-0.4 microM respectively. In Chinese hamster ovary (CHO) cells, AVE0118 decreased the steady-state hKv1.5 current with an IC(50) of 1.1+/-0.2 microM. The hKv4.3/KChIP2.2 current in CHO cells was blocked by AVE0118 by accelerating the apparent time-constant of inactivation ( tau(inact)), and the integral current was inhibited with an IC(50) of 3.4+/-0.5 microM. At 10 microM AVE0118 tau(inact) decreased from 9.3+/-0.6 ms ( n=8, control) to 3.0+/-0.3 ms ( n=8). The K(ACh) current was investigated in isolated pig atrial myocytes by application of 10 microM carbachol. At a clamp potential of -100 mV the I(KACh) was half-maximally blocked by 4.5+/-1.6 microM AVE0118. In the absence of carbachol, AVE0118 had no effect on the inward current recorded at -100 mV. Effects on the I(Kr) current were investigated on HERG channels expressed in CHO cells. AVE0118 blocked this current half-maximally at approximately 10 microM. Comparable results were obtained in isolated guinea pig ventricular myocytes, where half-maximal inhibition of the I(Kr) tail current occurred at a similar concentration of AVE0118. Other ionic currents, like the I(Ks), I(KATP) (recorded in guinea pig ventricular myocytes), and L-type Ca(2+) (recorded in pig atrial myocytes) were blocked by 10 microM AVE0118 by 10+/-3% ( n=6), 28+/-7% ( n=4), and 22+/-13% ( n=5) respectively. In summary, AVE0118 preferentially inhibits the atrial K(+) channels I(Kur), I(to) and I(KACH). This profile may explain the selective prolongation of atrial refractoriness described previously in pigs and goats.

Animals↗
PubMed2001

Synthesis and activity of novel and selective I(Ks)-channel blockers.

Since the discovery of the I(Ks)-potassium channel as the slowly activating component of the delayed rectifier current (I(k)) in cardiac tissue, the search for blockers of this current has been intense. During the screening of K(ATP)-channel openers of the chromanol type we found that chromanol 293B was able to block I(Ks). Chromanol 293B is a sulfonamide analogue of the K(ATP)-channel openers but had no activity on this target. Experiments were initiated to improve the activity and properties based on this lead compound. As a screening model we used Xenopus oocytes injected with human minK (KCNE1). Variations of the aromatic substituent and the sulfonamide group were prepared, and their activity was evaluated. We found that the greatest influence on activity was found in the aromatic substituents. The most active compounds were alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfonamide) 10a for development as an antiarrhythmic drug. The absolute configuration, resulting from an X-ray single-crystal structure analysis, was determined.

Animals↗
PubMed2001

Characterization of a novel Kv1.5 channel blocker in Xenopus oocytes, CHO cells, human and rat cardiomyocytes.

The inhibitory effects of the novel Kv1.5 channel blocker, S9947 (2'-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide), on cloned human Kv1.5 (hKv1.5), expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells, and on native cardiac ultrarapid delayed rectifier potassium currents (IKur) in rat (ventricle myocytes) and human (atrial myocytes) were investigated. The influence of S9947 on the action potential was examined in rat ventricular myocytes. Using the two-electrode voltage-clamp technique in Xenopus oocytes and the patch-clamp technique (whole cell configuration) in CHO cells, hKv1.5 was inhibited by S9947 with IC50 values of 0.65 microM and 0.42 microM, respectively. In addition, inhibition of human Kv4.3 (hKv4.3) and HERG by 10 microM S9947 was low (approximately 20%) and absent, respectively. Using the patch-clamp technique in the whole cell configuration, IKur currents in rat ventricular (rIKur) cardiomyocytes and human atrial (hIKur) cardiomyocytes were inhibited by S9947 with IC50 values of 0.96 microM and 0.07 microM, respectively. In contrast, rat cardiac inward rectifier current (rIK1) and rat (rIto) and human (hIto) cardiac transient outward currents were only inhibited by approximately 20% with 10 microM S9947. In rat cardiomyocytes, using the patch-clamp technique, action potential duration was increased by S9947 in a concentration-dependent (0.3-10 microM) and rate-independent manner. The data show that S9947 suppresses both cloned (Kv1.5) and native (IKur) cardiac potassium currents. Furthermore, S9947 prolongs rat action potential in a rate-independent manner.

Action Potentials↗
PubMed2000

Quantum cryptography using entangled photons in energy-time bell states

We present a setup for quantum cryptography based on photon pairs in energy-time Bell states and show its feasibility in a laboratory experiment. Our scheme combines the advantages of using photon pairs instead of faint laser pulses and the possibility to preserve energy-time entanglement over long distances. Moreover, using four-dimensional energy-time states, no fast random change of bases is required in our setup: Nature itself decides whether to measure in the energy or in the time base, thus rendering eavesdropper attacks based on "photon number splitting" less efficient.

Journal Article↗
PubMed2000

Inhibition of IKs channels by HMR 1556.

Chromanol HMR 1556 [(3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methylmethanesulfonamide], a novel inhibitor of the slow component of the delayed outward current in heart muscle cells (IKs), has been characterized in several in-vitro systems. mRNA encoding for the human protein minK was injected into Xenopus oocytes, leading to the expression of IKs channels. HMR 1556 inhibited this current half-maximally at a concentration of 120 nmol/l (IC50). Expression of the K+ channels Herg, Kv 1.5, Kv 1.3 and Kir2.1, and also the cationic current HCN2, were blocked little or not at all by 10 micromol/l HMR 1556. In isolated ventricular myocytes from the guinea pig the whole-cell patch-clamp method revealed inhibition of the IKs current with an IC50, of 34 nmol/l. Other current components, like IKr and IK1. were only slightly blocked at an HMR 1556 concentration of 10 micromol/l, whereas 10 micromol/l HMR 1556 inhibited the transient outward current I(to) and the sustained outward current I(sus) in rat ventricular myocytes by 25% and 36%, respectively. The L-type Ca2+ channel in guinea pig cardiomyocytes was blocked by 10 micromol/l HMR 1556 by 31%. Guinea pig right papillary muscles were investigated by the micropuncture technique at various pacing rates. In the frequency range of 0.5-7 Hz HMR 1556 (1 micromol/l) caused a prolongation of the action potential duration at 90% repolarization (APD90) by 19%-27%. In the presence of isoproterenol (10 micromol/l) the prolongation of the APD90 was more pronounced at low pacing rates (47% at 0.5 Hz and 35% at 1 Hz, compared with 25% at 7 Hz). The monophasic action potential was recorded in Langendorff-perfused guinea pig hearts. In spontaneously beating preparations, HMR 1556, at 0.1 micromol/l and 1 micromol/l, prolonged the MAPD90 by 3% and 10%, respectively, with no further prolongation at 10 micromol/l. The prolongation was much greater at low pacing rates [25% at 100 beats per min (bpm) and 13% at 150 bpm] than at fast pacing rates (9% at 350 bpm). The left ventricular pressure LVPmax was not affected at 1 micromol/l HMR 1556, but it decreased by 15% at 10 micromol/l. Other parameters, like the heart rate and coronary flow, were only slightly decreased at 1 micromol/l HMR 1556. In conclusion, HMR 1556 is a potent and selective inhibitor of the IKs current in guinea pig ventricular myocytes. The prolongation of the action potential duration is maintained at fast pacing rates.

Animals↗
PubMed2000

Molecular impact of MinK on the enantiospecific block of I(Ks) by chromanols.

Slowly activating I:(Ks) (KCNQ1/MinK) channels were expressed in Xenopous: oocytes and their sensitivity to chromanols was compared to homomeric KCNQ1 channels. To elucidate the contribution of the ss-subunit MinK on chromanol block, a formerly described chromanol HMR 1556 and its enantiomer S5557 were tested for enantio-specificity in blocking I:(Ks) and KCNQ1 as shown for the single enantiomers of chromanol 293B. Both enantiomers blocked homomeric KCNQ1 channels to a lesser extent than heteromeric I:(Ks) channels. Furthermore, we expressed both WT and mutant MinK subunits to examine the involvement of particular MinK protein regions in channel block by chromanols. Through a broad variety of MinK deletion and point mutants, we could not identify amino acids or regions where sensitivity was abolished or strikingly diminished (>2.5 fold). This could indicate that MinK does not directly take part in chromanol binding but acts allosterically to facilitate drug binding to the principal subunit KCNQ1.

Animals↗
PubMed1995

Cardiovascular actions of the furoxan CAS 1609, a novel nitric oxide donor.

1. This study examines the cardiovascular effects of CAS 1609 (4-hydroxymethyl-furoxan-3-carboxamide) in vitro as well as in vivo in various animal models. 2. CAS 1609 relaxed guinea-pig pulmonary artery strips without endothelium with IC50-values of 0.9 microM (phenylephrine contracted) and 15 microM (KCl-depolarized). This effect was inhibited by oxyhaemoglobin. In these arteries CAS 1609 significantly increased (+192%) guanosine 3':5'-cyclic monophosphate levels, which indicates that the compound acts as a donor of nitric oxide (NO). 3. In the anaesthetized pig, CAS 1609 (0.3-1.0 mg kg-1, i.d.) significantly lowered blood pressure and left ventricular end-diastolic pressure. Left ventricular contractility was slightly reduced and heart rate remained almost unchanged. 4. In anaesthetized dogs, i.v. or i.d. administration of CAS 1609 (0.3-3.0 mg kg-1) decreased, in a dose-related fashion, preload and afterload of the heart, cardiac output, left ventricular work and myocardial oxygen consumption. This haemodynamic profile is similar to that of known NO-donors. 5. In anaesthetized dogs with acute heart failure due to intracoronary injection of microspheres, CAS 1609 (0.3 mg kg-1, i.v.) improved the haemodynamic condition and reduced mortality by 80%. 6. In conscious dogs, oral treatment with a dose of 0.5 mg kg-1 given twice daily at 07 h 00 min and 19 h 00 min (each dose had a duration of action > or = 12 h) for 5 days showed no signs of tolerance to the haemodynamic effects of the drug. 7. All these data indicate that CAS 1609 is a potent, long-lasting orally active donor of NO, devoid of tolerance development.

Administration, Oral↗
PubMed1991

Studies of desensitization and cross-desensitization to immunologic and nonimmunologic stimuli that evoke contraction and histamine release in superfused guinea pig trachea.

This study examined the possibility that there is cross-desensitization between immunologic and nonimmunologic stimuli that evoke contraction and histamine release (HR) in the isolated guinea pig trachea. Compound 48/80 and D-tubocurarine were found to cause homologous and heterologous desensitization for both contraction and HR from superfused trachea. Specific antigen challenge of trachea obtained from animals sensitized with either IgG1 (ovalbumin [OA]) or IgE (oxazalone-human serum albumin [OX-HSA]) also resulted in homologous desensitization for both contraction and HR. However, in experiments with animals sensitized with both IgG1 and IgE antibodies, prechallenge with OA resulted in cross-desensitization to OX-HSA, whereas the reverse sequence was ineffective in eliciting this phenomenon. This may be related to the type of desensitization produced by each antigen (specific versus nonspecific) or to heterogeneity of mast cells in the tissue. Prechallenge of the trachea with compound 48/80 or D-tubocurarine failed to alter subsequent effects of antigen after active sensitization with OA or passive sensitization with either IgG1 or IgE antibodies. Small but statistically significant decreases in tracheal responses to D-tubocurarine were observed after antigen prechallenge to active both IgG1 and IgE antibodies. This is the first study to demonstrate a cross-desensitization between compound 48/80 and D-tubocurarine and the first to examine cross-desensitization with IgG1 and IgE antibodies in the guinea pig trachea. The overall conclusion is that there is no major overlap in the desensitization mechanisms between immunologic and nonimmunologic stimuli in the guinea pig trachea.

Animals↗
PubMed1984

Isolation of guinea pig basophils using anti-leukocyte antibody and density gradient centrifugation on Percoll.

Peripheral blood basophils were isolated from guinea pigs using a 2-step procedure. Initial enrichment of basophils was achieved by treating leukocyte preparations obtained from whole blood with antibody to contaminating granulocytes and mononuclear cells. Basophil populations of 82% purity (mean; range 65-99%) were obtained by subsequent application of the antibody treated preparation to discontinuous Percoll gradients. The isolated basophils were viable and shown to be functional by histamine release upon stimulation with various secretogogues.

Animals↗