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Biomedical subjects

W Klaus

Publications and source records attributed to W Klaus.

At least 91 records · Page 5Linked to original sources
PubMed1991

Investigation of the solution structure of the human parathyroid hormone fragment (1-34) by 1H NMR spectroscopy, distance geometry, and molecular dynamics calculations.

The structure of human parathyroid hormone fragment (1-34) in a solvent mixture of water and trifluoroethanol has been determined by 1H nuclear magnetic resonance spectroscopy and a combination of distance geometry and molecular dynamic simulations. After complete assignment of the 1H signals, the nuclear Overhauser enhancement data imply the existence of two alpha-helices, comprising residues 3-9 and 17-28, joined by a nonstructured region. The absence of any long-range NOEs and the relative magnitudes of the sequential NOEs and the 3J(HNH alpha) values reflect an inherent flexibility within the entire fragment. The final structures refined by molecular dynamics further support the above results and allow discussion of structural-activity relationships.

Amino Acid Sequence↗
PubMed1991

The influence of 3-ester side chain variation on the cardiovascular profile of nitrendipine in porcine isolated trabeculae and coronary arteries.

It has been reported that the lipophilicity of dihydropyridine-type calcium entry blockers may influence both their negative inotropic and their vasodilator activities. The action of nitrendipine and six related 3-ester side-chain derivatives with increasing alkyl and aryl substituents have been investigated in isolated porcine trabecular muscles and coronary artery rings. The lipophilicity of the drugs was determined by high-pressure liquid chromatography. In addition, some sterical parameters of the ester derivatives were considered. For the drugs tested, an increase in 3-ester side chain volume correlated well with increasing lipophilicity. Compared to nitrendipine, vascular selectivity of the ester side-chain derivatives, as expressed by the ratio of their negative inotropic and vasodilator activities, was much reduced. Neither vasodilator nor negative inotropic activity was directly related to the corresponding lipophilicity. Based on these results, earlier suggestions about the influence of the ester side-chain in dihydropyridines on their cardiovascular profile are extended.

Animals↗
PubMed1991

Hydrophobic properties of novel dihydronaphthyridine calcium antagonists and biological activity in porcine isolated cardiac and vascular smooth muscle.

Dihydronaphthyridine calcium antagonists are structurally related to the well known dihydropyridines and act in a similar manner. In order to establish the vascular selectivity of these compounds contractile force was evaluated in porcine isolated ventricular trabeculae and right coronary arteries. The dihydropyridine derivatives nisoldipine and nitrendipine as well as the structurally different compounds gallopamil and flunarizine were included for comparison purpose. All compounds studied exhibited dose-dependent negative inotropic and vasodilator activities. The negative inotropic potency of all dihydronaphthyridines, especially of the highly lipophilic bulky ester-variated derivatives (Goe 5584-A, Goe 5806-A) was comparable to that of flunarizine but was considerably less pronounced than that of nisoldipine, nitrendipine or gallopamil. By contrast, half-maximal vasodilator responses of the dihydronaphthyridines studied in coronary arteries being in the nanomolar concentration range were comparable to the dihydropyridines nisoldipine and nitrendipine, whereas the activity of gallopamil and flunarizine was less marked. On the other side the dihydronaphthyridines, especially the more hydrophilic 3-ethylester-4-(2-cyanophenyl) derivative Goe 5606, exerted an obvious biphasic concentration-response behaviour in coronary arteries leading to a high affinity relaxant process in subnanomolar concentrations, whereas the low affinity response could be observed at rather high concentrations (mostly greater than 1 microM). Mainly due to their relative uneffectiveness in cardiac muscle, vascular selectivity of the dihydronaphthyridines was considerably higher than that of the structurally related dihydropyridines nisoldipine resp. nitrendipine increasing in the following order: nitrendipine less than nisoldipine less than Goe 5606 less than Goe 5438 less than Goe 5584-A less than Goe 5806-A. By contrast, gallopamil exerted a slight cardiac preference, whereas the vascular selectivity of flunarizine was also pronounced.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Endothelial function and contractility of human vena saphena magna prepared for aortocoronary bypass grafting.

The aim of this study was to examine whether contractility and endothelial function of the human saphenous vein prepared for aortocoronary bypass grafting are altered by the surgical technique, e.g. cannulation and gentle distension of the vessel. Two segments (2 cm length each) of native vena saphena magna and 2 segments (2 cm length each) of the same vessel prepared for coronary bypass grafting were taken for further experimentation. After ligation of all side branches the segments were cannulated and arranged in two systems (with two segments each) in a serial manner (system I: prepared vessel followed by a native segment; system II: native vessel followed by a prepared segment) and perfused with Tyrode's solution at a constant flow rate of 20 ml/min (PO2 = 45 mmHg). Pressure gradient was measured continuously over each segment as a function of the vessel's radius according to the Hagen-Poiseuille equation. Endothelial and smooth muscle function was checked by perfusion with increasing concentrations of acetylcholine (ACH) to provoke the release of endothelium-derived relaxing factor (EDRF) (ACH; 0.3, 1, 3, 10, 30 mumol/L) after precontraction of the vessels with 1 mumol/L norepinephrine (NE). This showed normal contractility and ACH-induced relaxation in the native vessels but a reduced contractile response and a total lack of ACH-EDRF-induced relaxation in the prepared vessels. Perfusion with 5-hydroxytrytamine (5-HT) (0.25, 0.5, 1, 10 mumol/L for 10 min each concentration) resulted in marked constriction of all vessels with preserved contractility which could be completely prevented by pretreatment with the 5-HT2-receptor antagonist ketanserine (20 mumol/L).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

[Interaction between thrombocytes and the coronary system in the presence of SIN 1 and nitroglycerin after endothelial damage].

For further examination of the interaction of platelets with coronary endothelium in more detail, porcine platelets were infused into the coronary system of isolated, Langendorff-perfused rabbit hearts. The hearts were preincubated with very low activity of collagenase inducing functional endothelial lesion characterized by 50% reduction of EDRF-dependent dilation. Platelet infusions into those hearts were accompanied by a sudden myocardial failure and a significant retention of the platelets infused. When in addition to platelets the hearts were perfused with SIN 1 or GTN the global coronary flow did not fall below critical values. Moreover, the platelet recovery was not any longer diminished. After heart passage the platelets aggregation was more inhibited with SIN 1 than with GTN. SIN 1 and GTN in concentrations applicated to the heart could not inhibit porcine platelet aggregation, thus the aggregation behaviour reflects the different availability for platelets of the liberated NO during coronary passage.

Animals↗
PubMed1990

Proton nuclear magnetic resonance assignments and secondary structure determination of the ColE1 rop (rom) protein.

The complete resonance assignment of the ColE1 rop (rom) protein at pH 2.3 was obtained by two-dimensional (2D) proton nuclear magnetic resonance spectroscopy (1H NMR) at 500 and 600 MHz using through-bond and through-space connectivities. Sequential assignments and elements of regular secondary structure were deduced by analysis of nuclear Overhauser enhancement spectroscopy (NOESY) experiments and 3JHN alpha coupling constants. One 7.2-kDa monomer of the homodimer consists of two antiparallel helices connected by a hairpin loop at residue 31. The C-terminal peptide consisting of amino acids 59-63 shows no stable conformation. The dimer forms a four-helix bundle with opposite polarization of neighboring elements in agreement with the X-ray structure.

Amino Acid Sequence↗
PubMed1990

Nifedipine antagonizes ouabain-induced ST-segment changes and derangement of epicardial activation pattern in isolated rabbit hearts.

Isolated rabbit hearts, perfused according to the Langendorff technique were treated with 0.2 mumol/l ouabain or with a combination of 0.2 mumol/l ouabain and 3 nmol/l nifedipine. In a second series of experiments, a combination of 0.2 mumol/l ouabain with 0.2 mumol/l nitroglycerin was examined. Under this treatment, coronary flow and left ventricular pressure were continuously measured and, furthermore, the epicardial potential distribution was mapped with high temporal (4 kHz/channel) and spatial resolution (256 electrodes, arranged in 4 plates with 64 electrodes each, 8 x 8 matrix with 1 mm mesh size). Ouabain led to the expected positive inotropy of 10%, but also to a decrease in coronary flow of 15%. Besides these changes a nearly generalized ST-segment elevation could be observed. Moreover, the epicardial activation pattern was disturbed by changes in the location of epicardial breakthrough-points. Concomitantly, the epicardial activation vector field was deranged. Under the additional influence of nifedipine, coronary flow was reduced by only 5%, whereas the positive inotropic effect remained unchanged. The epicardial ST-elevation was diminished significantly and there was no derangement in the process of epicardial activation. Nitroglycerin led to an increase in relative coronary flow comparable to that observed under nifedipine but did not antagonize the disturbances of the process of activation by ouabain and only partially inhibited ST-elevation. Hence, it is concluded that ouabain already provokes coronary vasoconstriction in therapeutic concentrations leading to ST-elevation and prearrhythmic changes in the process of excitation. These changes could be diminished by additional treatment with nifedipine, but not with nitroglycerin.

Animals↗
PubMed1990

Effects of nimodipine on infarct size and cerebral acidosis after middle cerebral artery occlusion in the rat.

The objective of this study was to determine the effect of nimodipine on infarct development and local brain pH after middle cerebral artery occlusion in the rat. Female Fischer-344 rats were subjected to permanent occlusion of the left middle cerebral artery by electrocoagulation. After 6, 12, or 24 hours, brains were frozen, and infarct size, degree of edema formation, and local brain pH were quantified by standard histology or the umbelliferone technique, respectively. In control rats, cortical infarct size was increased from 29.5 microliters at 6 hours to 72.5 microliters at 24 hours after vessel occlusion. In striatum only, an insignificant increase from 15.2 to 24.7 microliters in infarct volume was observed during this period. Edema increased from 7% to 22% in cortical and from 4% to 39% in the striatal infarct areas during this time. Nimodipine (0.1 mg/kg s.c.), given 45 minutes before and again 8 and 16 hours after middle cerebral artery occlusion, did not alter infarct size at 6 hours but considerably improved outcome at later times. Edema formation was lower at 12 hours in the group treated with the calcium antagonist (p less than 0.05). By contrast, effects on local brain pH were seen as early as 6 hours after the vessel occlusion. Nimodipine greatly reduced the areas exhibiting the lowest pH values beyond pH 6.0 (p less than 0.05). Similar effects by nimodipine on brain pH were observed in the 12-hour series, whereas at 24 hours after middle cerebral artery occlusion, a shift to more alkalotic values was noted with no overt differences between control and drug-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1989

Nucleotide and AP5A complexes of porcine adenylate kinase: A 1H and 19F NMR study.

Proton and fluorine nuclear magnetic resonance spectroscopies (NMR) were used as methods to investigate binary complexes between porcine adenylate kinase (AK1) and its substrates. We also studied the interaction of fluorinated substrate analogues and the supposed bisubstrate analogue P1,P5-bis(5'-adenosyl) pentaphosphate (AP5A) with AK1 in the presence of Mg2+. The chemical shifts of the C8-H, C2-H, and ribose C1'-H resonances of both adenosine units in stoichiometric complexes of AK1 with AP5A in the presence of Mg2+ could be determined. The C2-H resonance of one of the adenine bases experiences a downfield shift of about 0.8 ppm on binding to the enzyme. The chemical shift of the His36 imidazole C2-H was changed in the downfield direction on ATP-Mg2+ and, to a lesser extent, AMP binding. 19F NMR chemical shifts of 9-(3-fluoro-3-deoxy-beta-D-xylofuranosyl)adenine triphosphate (3'-F-X-ATP)-Mg2+ and 9-(3-fluoro-3-deoxy-beta-D-xylofuranosyl)adenine monophosphate (3'-F-X-AMP) bound to porcine adenylate kinase could be determined. The different chemical shifts of the bound nucleotides suggest that their mode of binding is different. Free and bound 3'-F-X-AMP are in fast exchange with respect to their 19F chemical shifts, whereas free and bound 3'-F-X-ATP are in slow exchange on the NMR time scale in the absence as well as in the presence of Mg2+. This information could be used to determine the apparent dissociation constants of the nucleotides and the 3'-F-X analogues in the binary complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Monophosphate↗
PubMed1989

The potential of epicardial activation mapping in isolated hearts for the assessment of arrhythmogenic and antiarrhythmic drug activity.

In isolated rabbit hearts perfused according to the Langendorff technique, the pathway and time course of the epicardial activation process were studied by means of computer-assisted epicardial potential mapping, using a matrix of 256 unipolar AgCl electrodes (1 mm spatial and 0.25 msec temporal resolution). Activation time of each electrode was calculated (point of time of fastest negative intrinsic deflection). From the activation times of the surrounding electrodes, the direction and velocity of activation for each electrode were calculated, thereby allowing construction of an epicardial vector field. Furthermore, breakthrough points (BTPs) were determined as the earliest activated electrodes in a given region. Vector-field orientation and BTP localization were compared under different conditions during perfusion with Tyrode's solution or during drug treatment. Thereby, we determined the similarity of the vector fields (two vectors were considered to be identical if not differing by more than 5 degrees) and the percentage of BTPs with changed localization, referred to the total number of BTPs. For verification of the method we treated the hearts with ouabain (0.2 mumol/l) and observed progressive decline in vector-field similarity from 32% down to 14%, resulting in arrhythmia. Concomitantly, the percentage of BTPs with identical localization decreased from 81% to 50%. These changes could be reversed by additive treatment with 10 nmol/1 verapamil. From these results we conclude that arrhythmia is preceded by a state of deteriorated epicardial activation pattern (prearrhythmia), which can be quantitatively evaluated and used for detection of preventive antiarrhythmic drug action.

Animals↗
PubMed1989

Response to histamine of the intact coronary system in an isolated rabbit heart preparation.

In isolated Langendorff-perfused rabbit hearts concentration-response relations for histamine were analysed with and without H2-receptor blocker cimetidine (10(-5) mol l-1). The diameter of large epicardial coronary arteries was determined by video angiometry. Global coronary flow and left ventricular isovolumetric pressure were continuously registered. Histamine concentration (10(-7)-6 X 10(-6) mol l-1) reduced the diameter of large coronary arteries up to -50%, however, this vasoconstriction was maximal after 1 min and was then attenuated within the following 20 min. Coronary flow and left ventricular pressure were not significantly altered. In the presence of cimetidine the histamine-induced vasoconstriction was stabilized and not reversed with time. Moreover, the extent of vessel wall narrowing was intensified (up to -70%) when compared with histamine alone. Furthermore, severe functional myocardial failure was observed (flow reduction to 40% of control).

Animals↗
PubMed1989

A new endothelium-dependent vasoconstricting factor (EDCF) in pig coronary artery.

In order to investigate the influence of the endothelium on hypoxia-induced vasospasms we examined vascular tone after reduction of the oxygen supply, dependent on endothelial function. Therefore, after ligation of all side branches, vessel segments of porcine or human right coronary arteries or of rabbit abdominal aorta, prepared either with or without endothelium, were cannulated, perfused with Tyrode's solution and arranged in a serial manner (system I: endothelium-denuded vessel followed by a normal segment; system II: normal vessel followed by an endothelium-denuded segment). The pressure gradient over each segment was continuously measured as a function of vessel radius. After 2 h equilibration the oxygen concentration in the perfusion and superfusion solutions was lowered (reduction from 'control' = 95% O2/5% CO2 to 'hypoxia' = 95% N2/5% CO2) leading to a marked long-lasting vasoconstriction in those endothelium-denuded vessel segments which were mounted distal to a normal vessel with an intact endothelium, whereas the other vessels did not change their tone. This hypoxic contraction could be inhibited by pretreatment with either 1 mumol l-1 dexamethasone or quinacrine or indomethacine. From these results it is concluded that endothelium releases a vasoconstricting factor (EDCF) under hypoxic conditions probably dependent on phospholipase A2 and cyclooxygenase. This EDCF may be of pathophysiological importance by inducing or aggravating hypoxic vasospasms.

Animals↗
PubMed1989

The influence of endothelium on glyceryl trinitrate induced relaxation in corresponding arteries and veins of the rabbit.

Glyceryl trinitrate (GTN) induced relaxation was investigated in preparations of corresponding femoral arteries and veins from rabbits containing the intact endothelium in comparison to denuded vessels. Either vascular rings (app. 5 mm segments) or helical cut strips were isotonically mounted in organbaths (37 degrees C, Krebs-Henseleit-buffer). Vessels were precontracted with their specific EC-50 of norepinephrine. Cumulative concentration response curves for GTN were evaluated. Arteries and veins were dilated in a concentration dependent manner in the range of 1 nmol/l to 0.1 mmol/l. V.femoralis was the most sensitive vessel with an EC-50 of 10 nmol/l. There was no significant difference in the sensitivity of veins with or without endothelium. In contrast to this, for half-maximal relaxation of A. femoralis 2-3 orders of magnitude higher concentrations were necessary, depending on the presence of endothelium. The concentration ratio artery/vein (A/V) amounted to 800 in normal vessels, 100 in denuded vessels, resp. indicating that for half-maximal relaxation of endothelium containing arteries significant higher concentrations were needed. By preincubation for 60 min with the EC-90 of GTN in arteries, as well as in veins, tolerance could be induced independently of the presence of endothelium. However, veins were more affected than arteries, but tolerant veins were still more sensitive to GTN than tolerant arteries. This was true both for preparations with and without endothelium (A/V = 70 in normal vessels, 20 in denuded vessels, resp.). Moreover, the endothelial dependence of arterial relaxation was attenuated. Treatment of the tolerant vessels with cystein (1 mmol/l) did abolish the GTN-tolerance in veins but not in arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Two-dimensional NMR studies of the porcine muscle adenylate kinase.

Porcine adenylate kinase was subjected to one- and two-dimensional proton NMR studies in order to identify amino acid spin systems and obtain sequence-specific resonance assignments. With a combination of results from a map of side-chain distances resulting from the refined X-ray crystallographic data and nuclear Overhauser effect spectroscopy (NOESY), assignments are suggested for all the aromatic spin systems.

Adenylate Kinase↗
PubMed1988

Novel halogenated dihydropyridine derivatives with high vascular selectivity.

Calcium channel antagonists of the dihydropyridine type exhibit preferential vasodilator properties. To study whether this vascular selectivity is due to distinct steric modifications or may be influenced by the physicochemical nature of these drugs, contractility in guinea pig heart isolated papillary muscles, vasodilator properties in isolated rabbit femoral arteries and the lipophilicity of some novel halogenated dihydropyridines have been examined. All newly synthesized derivatives exhibited dose-dependent negative inotropic and vasodilator effects. The negative inotropic potency of all the halogenated derivatives was weaker than that of the parent compound nitrendipine. In contrast, compared to nitrendipine the vasodilator potency of the ester substituted derivatives was slightly increased, while halogen substitution in position 2 and 6 of the dihydropyridine nucleus decreased the vasodilator potency. As a result of the different influence on cardiac and vascular smooth muscle an improved vascular selectivity of the drugs was attained. The ester-substituted dihydropyridine derivatives showed a 9 times (3-bromoethyl-nitrendipine) or 11 times (3-chloroethyl-nitrendipine) higher vascular selectivity with respect to nitrendipine. Correlation of the lipophilicity with the physiological properties showed an increase in biological activity with decreasing lipophilicity. Within the ester-halogenated dihydropyridine derivatives an inverse trend was observed (increasing vasodilation with increasing lipophilicity), indicating a different influence of lipophilicity with the ester-substituted compounds on the different tissues examined. The improved vascular selectivity of the novel halogenated dihydropyridines may be at least in part a consequence of the different lipophilicity of the drugs. In addition, differences in the binding affinities of the dihydropyridines subordinate to distinct voltage dependent conformation states of the calcium channel may contribute.

Animals↗
PubMed1988

A new method for analysing the geometry and timecourse of epicardial potential spreading.

A 256 unipolar electrode matrix fixed at the surface of an isolated rabbit heart was connected to a PC system via an amplifying and analog/digital converting frontend computer. This system allows measurement of 256 electrodes within 100 microseconds with a sampling rate of 0.25 ms. The data are displayed on a PC system either on-line as common ECG-recordings or off-line in projection on a two-dimensional model of the heart surface. Thereby, it is possible to visualize the epicardial potential spreading in a slow-motion presentation on a high resolution computer graphic. The samples are displayed sequentially and can be delayed by choice. This method allows the determination of the origin ("break-through-points") of the epicardial excitation and an analysis of the potential spreading. The electrodes are arranged in four grids with 64 electrodes each at an interelectrode distance of 1 mm. Thereby, it is possible to evaluate the direction of the epicardial excitation wave and the local state of epicardial activation. Furthermore, it is possible to demonstrate irregular pacemakers or re-entry circuits. The method seems to be helpful in analysis of cardiac arrhythmogenesis and mode of action of anti-arrhythmic agents.

Analog-Digital Conversion↗
PubMed1987

Platelet induced aggravation of acute ischaemia in an isolated rabbit heart model.

In isolated coronary ligated rabbit hearts the effects of washed human platelets on the size of the epicardial ischaemic area and on recovery from ischaemia during 60 min of reperfusion was evaluated by endogenous NADH-surface-fluorescence photography. Infusion of washed human platelets to non-ischaemic control hearts produced a decrease in left ventricular pressure to 64(3)% of control (n = 4), no change in global coronary flow rate, no retention of platelets (recovery 108(9)%), and no alteration in basal NADH-fluorescence. When platelets were infused into coronary ligated hearts, however, the size of the epicardial ischaemic area was significantly enhanced to 127(8)% (n = 5) of control. Moreover, this increase in size was negatively correlated with the recovery of platelets in the coronary effluent: the lower the recovery rate the larger the ischaemic area (y = 253-1.44x, r = -0.855, n = 15, p less than 0.001). When platelet infusion was stopped after 30 min the enlargement of the ischaemic area seemed to be reversible. When the coronary ligature was released, however, and the ischaemic myocardium reperfused the recovery from ischaemia was retarded in the platelet treated hearts as shown by functional (left ventricular pressure and flow) and metabolic (NADH-fluorescence) indices. Thus it is directly shown for the first time in an isolated in vitro heart preparation that platelets aggravate myocardial ischaemia.

Acute Disease↗