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W Klaus

Publications and source records attributed to W Klaus.

At least 19 recordsLinked to original sources
PubMed2002

Pharmacokinetics of intra-arterial mitomycin C in the chemoembolization treatment of liver metastases with polyvinylalcohol or degradable starch microspheres.

OBJECTIVES: In cancer treatment, arterial blood flow reduction by embolization combined with intra-arterial chemotherapy may be advantageous by achieving high and prolonged drug concentrations in the tumor, and lower systemic drug exposure. The pharmacokinetics of intra-arterial mitomycin C (MMC) was investigated in patients with liver metastases undergoing chemoembolization treatment. METHODS: The chemoembolization treatment consisted of the use of polyvinylalcohol microspheres (ITC-Contour, diameter 150-250 micro m, irreversible vessel occlusion, 20 mg MMC, 15 patients) followed by sealing of the supplying artery with Ethibloc. Alternatively, starch microspheres (Spherex, diameter 45 micro m, biologically degradable, 10 ml of suspension containing 60 mg starch/ml, 20 mg MMC in 7 patients, 15 mg/m2 body surface in 3 patients) were used. MMC was infused over 6 min into the artery supplying the tumor. Serum MMC concentrations were determined from peripheral venous blood samples [protein precipitation with acetonitrile, reverse-phase HPLC with ultraviolet detection (C18 column, elution with 0.01 M, pH 6.5 phosphate buffer/methanol, v/v 70:30, 365 nm)]. The pharmacokinetic parameters were computed assuming an open two-compartment model and linear kinetics. RESULTS: The disposition parameters for MMC in patients treated with polyvinylalcohol microspheres were comparable to data from the literature (C(max)=913+/-98 ng/ml, T(max)=7.7+/-0.3 min, V(c)=0.27+/-0.03 l/kg, V(ss)=0.59+/-0.07 l/kg, Cl=757+/-67 ml/min, T(1/2 alpha)=5.8+/-0.8 min, T(1/2 beta)=50.4+/-4.1 min). There was no significant difference in the disposition parameters for MMC between patients treated with polyvinylalcohol microspheres and those treated with starch microspheres ( P>0.05). In particular, there was no significant difference in the standardized AUC between the groups; this implies that the systemic toxicity of MMC is comparable when polyvinylalcohol microspheres and ethibloc (AUC 1472+/-123 microg min/l per 1 mg MMC) or starch microspheres (AUC: 1448+/-172 microg min/l per 1 mg MMC) are used. CONCLUSION: The AUC values found in this study do not indicate a reduction in the systemic toxicity of MMC if applied intra-arterially in combination with embolizing microspheres, when compared to the AUC values in the literature for intra-arterial application without embolization, or intravenous MMC application. The amount of starch microspheres may have been too small to cause marked effects. On the other hand, there is a very wide range of AUC values reported in the literature for different application modes, and the use of such historical controls is not adequate for detecting more subtle advantages of the chemoembolization procedure, which may, however, exist.

Aged↗
PubMed2001

Nisoldipine increases the bioavailability of endothelial NO.

Different observations suggest that dihydropyridine calcium antagonists alter endothelial NO release. Therefore, in a first step we investigated whether part of the nisoldipine (a dihydropyridine calcium antagonist with a possible selectivity for coronaries)-induced vasorelaxation was due to an NO release from the endothelium in porcine coronary arteries. Secondly, we directly measured whether nisoldipine increased NO release from rabbit aorta or the nisoldipine enantiomers (Bay R 1223, Bay R 1224) from rat aorta. Thirdly, we determined whether nisoldipine exerted antioxidative properties in segments of porcine aorta with intact endothelium. Blocking endothelial NO synthase with N-nitro-L-arginine resulted in a significant shift of the relaxation curve to higher concentrations. Accordingly, nisoldipine induced a concentration-dependent release of NO (direct electrochemical detection) from native endothelium which already started at a therapeutical level (1 nmol/l nisoldipine/6.5 +/- 1.2 nmol/l NO). To evaluate whether this effect was due to an antioxidative protection of NO, we examined the influence of nisoldipine on a hyperglycemia (30 mmol/l, 20 min)-induced reactive oxygen species release of vascular endothelium from porcine coronary arteries. Nisoldipine concentration-dependently reduced the reactive oxygen species release (>50%; 10 micromol/l). Moreover, a carbachol-induced NO release (rabbit aorta) which was significantly diminished by hyperglycemia was completely restored in the presence of nisoldipine (3 micromol/l). We conclude that nisoldipine increases the NO bioavailability which may result in an ameliorated endothelial function.

Animals↗
PubMed2001

Protein-bound conformation of a specific inhibitor against Candida albicans myristoyl-CoA:protein N-myristoyltransferase in the ternary complex with CaNmt and myristoyl-CoA by transferred NOE measurements.

UNLABELLED: Transferred nuclear Overhauser enhancement (trNOE) experiments have been performed to study the bioactive conformation(s) of Ro09-3472/000 derivatives in the ternary complex with Candida albicans myristoyl-CoA: protein N-myristoyltransferase (CaNmt) and myristoylCoA (MyrCoA). A critical step in the trNOE study is to identify 'true' trNOEs in the spectra. Nonspecific binding of ligands to target proteins and/or spin diffusion effects can give rise to 'false' trNOEs, which may lead to an incorrect conclusion if used to derive bound conformations. In this study for all ligands the observed trNOEs arose from specific binding interactions with the active site of CaNmt. This was shown by displacing the ligand with the known tightly binding active-site inhibitor 1 [Devadas, B., Zupec, M.E., Freeman, S.K., Brown, D.L., Nagarajan, S., Sikorski, J.A., McWherter, C.A., Getman, D. P. & Gordon, J.I. (1995) J. Med. Chem. 38, 1837-1840] and measuring the resonance linewidths in the NMR spectrum before and after addition of the competitive inhibitor. The compounds were also tested for nonspecific protein binding with bovine serum albumin (BSA) using the same METHOD: Of the six compounds tested, Ro09-3700/001 (racemate) and its optically pure enantiomers, Ro09-4764/001(S) and Ro09-4765/001(R), showed both specific binding to CaNmt and no interaction with BSA. The NMR data of these molecules in the ternary complex with CaNmt/MyrCoA could thus be used for a detailed structural analysis. Thereby, the conformation of the bound ligand was obtained from a conformational search using the observed trNOEs as a selection filter. The NMR-determined conformations are in good agreement with the recently solved CaNmt-bound X-ray structures of two similar Ro09-3472/000 derivatives.

Acyltransferases↗
PubMed2001

Studies of the toxic effects of norepinephrine on isolated cardiomyocytes of guinea-pigs.

Catecholamines have been demonstrated to possess direct cardiotoxic effects mediated by oxygen free radicals in isolated organ preparations. In order to assess direct cytotoxic properties, the influence of exogenous noradrenaline (norepinephrine, CAS 51-41-2) (10(-6) mol/l) on isolated guinea-pigs cardiomyocytes was examined, in the presence of propranolol (10(-6) mol/l) and phentolamine (10(-6) mol/l) to inhibit adrenoceptor-mediated effects. Cell viability was assessed by morphologic examination (% of striated, rod-shaped cells), before and after a treatment period of 15 and 60 min by the measurement of intracellular enzyme activities in the supernatant of the suspension (lactate dehydrogenase, creatine kinase, aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase). The proportion of viable, rod-shaped cardiomyocytes (21.6% +/- 7.6% after preparation, before starting the treatments) significantly decreased over the experimental time (p < 0.05) and, concomitantly, the activity of intracellular enzymes in the supernatant increased. There was no difference between controls and treated suspensions. Thus, there is no evidence for direct toxic effects of norepinephrine in micromolar concentration on isolated cardiomyocytes of guinea-pigs. However, cytoprotective effects by propranolol and/or phentolamine cannot be excluded in this model.

Adrenergic alpha-Antagonists↗
PubMed2001

Modulation of human platelet aggregation by the phosphodiesterase type 5 inhibitor sildenafil.

The aim of this study was to investigate if the phospodiesterase type 5 inhibitor sildenafil inhibits collagen- or ADP-induced human platelet aggregation and bleeding time. To investigate this, two studies were designed. In the first, a single oral dose of sildenafil, 100 mg, was administered to healthy men. Bleeding time was determined and agonist (ADP and collagen)-induced platelet aggregation (ex vivo in platelet rich plasma) was measured 0, 1, and 4 h after application. In the second, a single oral dose of sildenafil, 50 mg, was administered and, in addition to the parameters in the first study, we also determined the platelet aggregation after 24 h and measured the effect of a nitric oxide donor (S-nitroso-N-acetylpenicillamine [SNAP]) in combination to mimic a physiologic nitric oxide release from the endothelium. The bleeding time of 1 h after sildenafil medication (100 mg) was significantly prolonged but recovered toward control values after 4 h, whereas application of sildenafil at a lower dose (50 mg) did not alter the bleeding time. Sildenafil (100 and 50 mg) did not inhibit the ADP-induced aggregation, whereas the collagen-induced aggregation (100 mg) was markedly reduced after 1 h and significantly inhibited 4 h after application. This inhibitory effect was overcome by higher concentrations of collagen. SNAP (0.5 microM) induced an inhibition of platelet aggregation that was potentiated after taking sildenafil (50 mg, 1 and 4 h afterward) and abrogated after 24 h. These data indicates that sildenafil may inhibit collagen-induced platelet aggregation ex vivo. After co-administration of nitric oxide, collagen- and ADP-induced platelet aggregation was significantly inhibited, which may reflect physiologic conditions of an in vivo system.

Adenosine Diphosphate↗
PubMed2001

Nifedipine increases endothelial nitric oxide bioavailability by antioxidative mechanisms.

Short-term treatment of the endothelium with dihydropyridine calcium antagonists resulted in an increased release in NO that is not due to a modulation of L-type calcium channels, because macrovascular endothelial cells do not express this channel. We investigated whether long-term (48 hours) treatment of porcine endothelial cell cultures with the dihydropyridine calcium antagonist nifedipine resulted in a similar enhanced NO liberation. Regarding to the underlying mechanism, we examined whether (1) nifedipine changed the mRNA and protein levels of the constitutive endothelial NO synthase (NOS) in endothelial cell cultures or (2) nifedipine exerts an NO protective effect via its antioxidative properties, as revealed in a cell culture model and with native endothelium from porcine coronary arteries. Nifedipine induced a significant time- and concentration-dependent increase (132+/-47%, 1 micromol/L, 40 minutes' incubation) in the basal NO liberation (oxyhemoglobin assay). This increased NO release was not due to elevated NOS (type III) mRNA (Northern blot analysis) and protein (Western blot analysis) levels. However, nifedipine (both short- and long-term treatment) significantly reduced the basal and glucose (20 and 30 mmol/L)-stimulated formation of reactive oxygen species (lucigenin assay) of endothelial cell cultures and native cells. We conclude that the calcium antagonist nifedipine enhances the bioavailability of endothelial NO without significantly altering the NOS (type III) mRNA and protein expression, possibly via an antioxidative protection. This increased NO availability may cause part of the vasodilation and might contribute to the antithrombotic, antiproliferative, and antiatherosclerotic effects of dihydropyridine calcium antagonists.

Animals↗
PubMed2001

Studies on the role of superoxide anion radicals for the cardiotoxicity of adrenochrome.

Adrenochrome is an oxidative product of adrenaline and possesses cardiotoxic properties. As oxygen free radicals play a role in the cytotoxic effects of catecholamines, the role of superoxide anion radicals, as mediators of adrenochrome toxicity, was investigated using electrically-driven Langendorff rabbit hearts with depleted catecholamine stores. Repetitive regional myocardial ischemia (MI) was induced by coronary artery branch ligature, and MI was quantitated from epicardial NADH-fluorescence photography. Adrenochrome (10(-6) mol/l) was added to the perfusion solution after a reperfusion period of 20 min, 30 min before the 2nd coronary occlusion, with or without the additional application of SOD (30 U/ml). Left ventricular pressure was significantly enhanced by adrenochrome (p < 0.05), but it fell rapidly down below its initial value (p < 0.05). Coronary flow was significantly decreased by adrenochrome (p < 0.05). Whereas epicardial NADH-fluorescence was similar after repetitive coronary occlusions in untreated controls, it was significantly enhanced by adrenochrome (p < 0.05). The deleterious effects of adrenochrome on MI were not inhibited by SOD. Thus, there is no evidence for superoxide anion radicals as mediators of the deleterious effects of adrenochrome on MI in isolated rabbit hearts. The deleterious effects of adrenochrome on MI in isolated rabbit hearts might be caused by functional effects, impairing the oxygen consumption/oxygen supply balance.

Adrenochrome↗
PubMed2000

Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening.

Random screening provided no suitable lead structures in a search for novel inhibitors of the bacterial enzyme DNA gyrase. Therefore, an alternative approach had to be developed. Relying on the detailed 3D structural information of the targeted ATP binding site, our approach combines as key techniques (1) an in silico screening for potential low molecular weight inhibitors, (2) a biased high throughput DNA gyrase screen, (3) validation of the screening hits by biophysical methods, and (4) a 3D guided optimization process. When the in silico screening was performed, the initial data set containing 350 000 compounds could be reduced to 3000 molecules. Testing these 3000 selected compounds in the DNA gyrase assay provided 150 hits clustered in 14 classes. Seven classes could be validated as true, novel DNA gyrase inhibitors that act by binding to the ATP binding site located on subunit B: phenols, 2-amino-triazines, 4-amino-pyrimidines, 2-amino-pyrimidines, pyrrolopyrimidines, indazoles, and 2-hydroxymethyl-indoles. The 3D guided optimization provided highly potent DNA gyrase inhibitors, e. g., the 3,4-disubstituted indazole 23 being a 10 times more potent DNA gyrase inhibitor than novobiocin (3).

Anti-Infective Agents↗
PubMed2000

Nitric oxide causes a cGMP-independent intracellular calcium rise in porcine endothelial cells-a paradox?

This study was undertaken to investigate the influence of exogenous NO on intracellular calcium levels of porcine aortic endothelial cell culture monolayers. Spontaneous NO liberating substances with different half-life periods (NOC-9 [10 micromol/L] approximately 1 min, SNAP [10 micromol/L] approximately 4 h), and an aqueous NO gas solution [130 nmol/L] were added onto the monolayers. All three solutions induced a rapid and similar calcium rise in the endothelial cells. NOC-9 as a rapidly NO releasing compound was selected to be investigated more thoroughly. The NOC-9 calcium rise is not dependent on the activation of the guanylate cyclase since preincubation with a specific guanylate cyclase inhibitor [ODQ, 10 micromol/L] did not alter the effect and a cGMP analogue [8-bromo-cGMP 10 micromol/L] did not significantly elevate calcium levels. The NOC-9 induced calcium rise could be completely blocked by removal of extracellular calcium and partly blocked by SKF 96365 [10 micromol/L], an unspecific inhibitor of the receptor operated calcium channels. Incubation with N-nitroarginine [100 micromol/L] slightly but significantly reduced basal calcium levels in the cell cultures. Therefore, we conclude that exogenous NO elevates [Ca(2+)](i) in cultured porcine aortic endothelial cells. This effect is not dependent on cGMP, and a calcium influx is involved. Moreover, constitutively formed endogenous NO seems to be necessary to maintain basal calcium levels.

Animals↗
PubMed2000

The calcium antagonist nifedipine inhibits the uptake of acetylated LDL into endothelial cells.

The uptake of LDL and modified LDL into macrophages via specific receptors is one of the crucial steps during atherogenesis. Recently, similar receptors for acetylated and oxidized LDL were characterized in endothelial cells. It is known that dihydropyridine calcium antagonists may attenuate the formation of atherosclerotic plaques presumably by an increased nitric oxide (NO) release from endothelial cells. Therefore, we investigated whether the uptake of acetylated LDL into endothelial cells may be altered by the calcium antagonist nifedipine with special emphasis on the NO metabolism. Treatment of porcine endothelial cell cultures with nifedipine induced a significant concentration-dependent inhibition of the uptake of acetylated LDL. This effect could be completely prevented by coincubation with L-nitro-N-arginine, a competitive NO synthase inhibitor. Treatment with the NO donor SNAP resulted in a similar significantly reduced uptake of acetylated LDL. To test whether this effect is due to an NO-mediated cGMP mechanism, we incubated cells with 8-bromo-cGMP and coincubated cells with nifedipine and the soluble guanylyl cyclase inhibitor ODQ. 8-bromo-cGMP partly mimicked the nifedipine effect and ODQ partly reversed the nifedipine effect but not to a significant extent. Therefore, we conclude that the calcium antagonist nifedipine inhibits the uptake of acetylated LDL into endothelial cells via an NO- but presumably not by a cGMP-mediated process, which may possibly contribute to the antiatherogenic action of this drug.

Acetylation↗
PubMed2000

Automation of NMR measurements and data evaluation for systematically screening interactions of small molecules with target proteins.

In this technical note we describe the setup and application of automated sample preparation and usage of flow-through NMR equipment for the characterization of ligand binding on proteins. In addition, we focus on the perspectives of automated analysis of 2D HSQC spectra to identify changes in patterns indicative for ligand binding or changes of sample conditions. In this context we discuss a combination of statistical and non-statistical data analysis.

Amines↗
PubMed2000

Simultaneous measurement of intracellular Ca(2+) and nitric oxide: a new method.

Different methods to measure the unstable radical nitric oxide (NO) have been established. We are going to present a new method to measure intracellular calcium and NO simultaneously in endothelial cells. A new fluorescent dye (DAF-2) has been developed recently which binds NO resulting in an enhanced fluorescence. We loaded porcine aortic endothelial cells with Fura-2, a fluorescent dye commonly used to measure intracellular calcium, and DAF-2 simultaneously (cell permeable dyes). Using excitation wavelengths of lambda 340 nm (Fura-2) and lambda 485 nm (DAF-2) we could show that thrombin induces an intracellular calcium increase and simultaneously a NO formation in endothelial cells which could be blocked by a NO synthase inhibitor. This new method of a simultaneous measurement of intracellular calcium and NO provides the possibility to follow intracellular calcium and NO distributions online, and is sensitive enough to monitor changes of NO formed by the constitutive endothelial NO-synthase.

Animals↗
PubMed1999

Characterization of the binding interface between ubiquitin and class I human ubiquitin-conjugating enzyme 2b by multidimensional heteronuclear NMR spectroscopy in solution.

Ubiquitin-conjugating enzymes (Ubc) are involved in ubiquitination of proteins in the protein degradation pathway of eukaryotic cells. Ubc transfers the ubiquitin (Ub) molecules to target proteins by forming a thioester bond between their active site cysteine residue and the C-terminal glycine residue of ubiquitin. Here, we report on the NMR assignment and secondary structure of class I human ubiquitin-conjugating enzyme 2b (HsUbc2b). Chemical shift perturbation studies allowed us to map the contact area and binding interface between ubiquitin and HsUbc2b by1H-15N HSQC NMR spectroscopy. The serine mutant of the active site Cys88 of HsUbc2b was employed to obtain a relatively stable covalent ubiquitin complex of HsUbc2b(C88S). Changes in chemical shifts of amide protons and nitrogen atoms induced by the formation of the covalent complex were measured by preparing two segmentally labeled complexes with either ubiquitin or HsUbc2b(C88S)15N-labeled. In ubiquitin, the interaction is primarily sensed by the C-terminal segment Val70 - Gly76, and residues Lys48 and Gln49. The surface area on ubiquitin, as defined by these residues, overlaps partially with the presumed binding site with ubiquitin-activating enzyme (E1). In HsUbc2b, most of the affected residues cluster in the vicinity of the active site, namely, around the active site Cys88 itself, the second alpha-helix, and the flexible loop which connects helices alpha2 and alpha3 and which is adjacent to the active site. An additional site on HsUbc2b for a weak interaction with ubiquitin could be detected in a titration study where the two proteins were not covalently linked. This site is located on the backside of HsUbc2b opposite to the active site and is part of the beta-sheet. The covalent and non-covalent interaction sites are clearly separated on the HsUbc2b surface, while no such clear-cut segregation of the interaction area was observed on ubiquitin.

Amino Acid Sequence↗
PubMed1999

Pseudocholinesterase-activity reduction during cardiopulmonary bypass: the role of dilutional processes and pharmacological agents.

UNLABELLED: 1. Pseudocholinesterase (ChE) activity is a determinant of the elimination kinetics of several drugs used in anesthesia. The time course of ChE activity was investigated in 16 patients undergoing cardiosurgery for a cardiopulmonary bypass (CPB) in normothermia or hypothermia. 2. The onset of the CPB was accompanied by a decrease in ChE activity (-37%) (P<0.05) and protein concentration (-24%) (P<0.05). The quotient ChE activity/protein concentration was numerically reduced to a smaller extent (-15%) (P>0.05). After the CPB was finished, ChE activity and the protein concentration remained low for the remaining operation time. 3. There was no difference in ChE activity, measured in vitro at 37 degrees C, between the normothermic and hypothermic group (P>0.05). 4. There was no correlation between heparin concentration in serum and reduction of ChE activity in vitro (P>0.05). In vitro, the ChE activity was not affected by either heparin in doses as high as 10,000 U/ml or aprotinin in doses as high as 10,000 U/ml (P>0.05). 5. CONCLUSIONS: (1) ChE activity is reduced by CPB mainly by hemodilution and (2) the pharmacological agents used in the present anesthetic technique (heparin, aprotinin, midazolam, fentanyl, propofol and mivacurium) do not inhibit ChE activity at therapeutic serum concentrations.

Aged↗
PubMed1999

NMR investigation and secondary structure of domains I and II of rat brain calbindin D28k (1-93).

Calbindin D28k, a member of the troponin C superfamily of calcium-binding proteins, contains six putative EF hand domains but binds only four calcium-atoms: one at a binding site of very high affinity and three calcium-atoms at binding sites of lower affinity. The high-affinity site could be located within domain I while domains III, IV, and V bind calcium less tightly. The recombinant protein construct calb I-II (residues 1-93) comprising the first two EF hands affords a unique opportunity to study a pair of EF hands with one site binding calcium tightly and the second site empty. A series of heteronuclear 2D, 3D and 4D high-resolution NMR experiments were applied to calb I-II, and led to the complete assignment of the 1H, 13C and 15N resonances. The secondary structure of the protein was deduced from the size of the 3JHN-Halpha coupling constants, the chemical shift indices of 1Etaalpha, 13Calpha, 13C' and 13Cbeta nuclei and from an analysis of backbone NOEs observed in 3D and 4D NOESY spectra. Four major alpha-helices are identified: Ala13-Phe23, Gly33-Ala50, Leu54-Asp63, Val76-Leu90, while residues Ala2-Leu6 form a fifth, flexible helical segment. Two short beta-strands (Tyr30-Glu32, Lys72-Gly74) are found preceding helices B and D and are arranged in an anti-parallel interaction. Based on these data a structural model of calb I-II was constructed that shows that the construct adopts a tertiary structure related to other well-described calcium-binding proteins of the EF-hand family. Surprisingly, the protein forms a homodimer in solution, as was shown by its NMR characterization, size-exclusion chromatography and analytical ultra-centrifugation studies.

Amino Acid Sequence↗
PubMed1999

Crataegus extract blocks potassium currents in guinea pig ventricular cardiac myocytes.

Crataegus extract is used in cardiology for the treatment of mild to moderate heart failure (NYHA II) in Germany. However, little is known about the electrophysiological actions of Crataegus extract in the heart. Recently, it was shown that Crataegus extract prolongs the refractory period in isolated perfused hearts and increases action potential duration in guinea pig papillary muscle. It was the aim of this study to find out the mechanism of the increase in action potential duration caused by Crataegus extract. Using the patch-clamp technique, we measured the effects of Crataegus extract (10 mg/l; flavonoid content: 2.25%, total procyanidin content: 11.3 +/- 0.4%) on the inward rectifier and the delayed rectifier potassium current in isolated guinea pig ventricular myocytes. To get some insight into the mechanism underlying the positive inotropic effect of Crataegus extract, we also looked for effects on the L-type calcium current. Crataegus extract slightly blocked both the delayed and the inward rectifier potassium current. The inhibition amounted to 25% and about 15%, respectively. This amount of inhibition of these repolarising currents is sufficient to explain the prolongation of action potential duration caused by Crataegus extract. To our surprise we could not detect any influence of Crataegus extract on the L-type calcium current. In summary, our results show that Crataegus extract blocks repolarising potassium currents in ventricular myocytes. This effect is similar to the action of class III antiarrhythmic drugs and might be the basis of the antiarrhythmic effects described for Crataegus extract. Our measurements of the L-type calcium current indicate that Crataegus extract's positive inotropic effect is not caused by phosphodiesterase inhibition or a beta-sympathomimetic effect.

Animals↗