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Biomedical subjects

W Klaus

Publications and source records attributed to W Klaus.

162 records · Page 9Linked to original sources
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Nitric oxide (EDRF) enhances the vasorelaxing effect of nitrendipine in various isolated arteries.

Recent studies suggest endothelium to be involved in the vasorelaxation of calcium antagonists of the 1,4-dihydropyridine type, which may at least in part be mediated by endothelium-derived relaxing factor (EDRF = NO). To study this effect further, the influence of L-NG-nitro arginine (L-NNA), a specific inhibitor of EDRF-synthesis, on nitrendipine-induced vasorelaxation was examined in different isolated porcine arteries. Coronary, basilary, and tail arteries were bathed in Krebs-Henseleit solution and endothelial function was verified by means of substance P, an EDRF releasing neuropeptide. Vasorelaxation of nitrendipine in PGF2 alpha-precontracted arteries was studied in the presence and absence of L-NNA. Nitrendipine-induced vasorelaxation was markedly reduced by the addition of L-NNA in all vessels studied. Tachyphylactic effects of nitrendipine could be excluded. The obtained results may be explained by an enhancement of nitrendipine action by basally released EDRF, alternatively, by an increased EDRF-release induced by this calcium antagonist. Therefore, in a second series of experiments the release of EDRF was studied in isolated coronary arteries under cumulative application of nitrendipine. Using the nitric oxide scavenging properties of oxyhemoglobin, EDRF release was measured spectrophotometrically by means of methemoglobin formation. The application of nitrendipine resulted in a concentration-dependent increase in the extinction rate, indicating an increased release of NO which could be inhibited by preincubation with L-NNA. It may be concluded that, in functionally intact vessels, vasorelaxation induced by nitrendipine may additionally be mediated by an increased release of EDRF.

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Heat production and oxygen consumption of the isolated rabbit heart: their relation to mechanical function.

A method is described for simultaneous determination of the heat production and the oxygen consumption of the isolated, isovolumetrically beating rabbit heart. The perfusion of the heart was performed via the aorta at a constant flow rate with carbogen saturated Tyrode's solution at a temperature of 37.0 degrees C. Heart function was varied by stepwise augmentation of the left intraventricular volume (LVV) by means of a balloon catheter. The following mechanical parameter of heart function were determined: enddiastolic pressure (EDP), peak pressure (PP), developed pressure (DP), max. contraction and relaxation velocity (dP/dt-A and dP/dt-B), enddiastolic tension (Tens-EDP), peak tension (Tens-PP), developed tension (Tens-DP), and circumferential tension (Tens-Cir). DP, dP/dt-A and dP/dt-R showed a maximum response to changes of the LVV at 2.0 ml LVV and 19.3 mm Hg EDP. Heat production (H) and oxygen consumption (Q) were correlated closely to mechanical function and to each other (r = 0.89, n = 8). The ratio H/Q was 4.9 cal/ml O2 and remained constant during the experiment. The myocardial energy consumption was significantly correlated toall contraction parameters with the best fit to DP and Tens-Cir (r = 0.934 and 0.933 resp.). On the basis of the calculated mean regression lines, the function-independent and the function-dependent energy consumption were calculated.

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PubMedDate not supplied

Prearrhythmia: changes preceding arrhythmia, new aspects by epicardial mapping.

The aim of our studies was to examine the electrophysiological conditions prior to the onset of arrhythmia in order to analyze in more detail whether arrhythmia is a sudden event or whether there are early signs preceding arrhythmia. For this purpose a computer-assisted mapping system equipped with 256 AgCl-electrodes for unipolar epicardial multichannel-recording was constructed that provided high temporal and spatial resolution (4 kHz/channel; 1 mm interelectrode distance). The electrodes were fixed to the surface of an isolated rabbit heart (prepared according to the Langendorff-technique; constant perfusion pressure 70 cm H2O; Tyrode solution equilibrated with 95% O2 and 5% CO2 at 37 degrees C) covering nearly the whole heart's surface. The activation times at each electrode were determined as the timepoints of the fastest negative deflection of the epicardial potentials. From these data the origins of epicardial activation were determined ("breakthrough points", BTP), and for each electrode a vector was constructed giving direction and velocity of the epicardial activation. This analysis was carried out for single heart beats under control conditions, under arrhythmogenic conditions (induced either by lowering the K+ concentration from initially 5.4 to finally 2.0 mmol/l or by application of ouabain 0.1, 0.2 or 0.3 mumol/l) or during manifest arrhythmia. By comparison of heart beats under these various conditions with control conditions we determined the percentage of identical BTP (deviating less than 1 mm) and of similar vectors (deviating less than 5 degrees). Under control conditions 80% BTP remained unchanged over a period of 60 min and about 30% of the vectors were similar. Reduction of the extracellular K(+)-concentration or treatment with ouabain resulted in a progressive, concentration-dependent decline in BTP- or vector-similarity (in still rhythmically beating hearts). In some cases these treatments finally lead to variant forms of arrhythmia. Critical values for the onset of arrhythmia were a reduction to 45% BTP-similarity and 18% vector-field-similarity. From these results it is concluded that arrhythmia is preceded by a state characterized by a derangement of the typical activation pattern which may be called prearrhythmia.

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PubMedDate not supplied

The influence of reduced serum potassium level on the toxicity of some cardenolides in guinea pigs.

Recent experiments on the pharmacological properties of the semisynthetic cardiotonic steroid strophanthidin-3-bromoacetate (SBA) have challenged the well-known potassium digitalis antagonism in isolated heart muscle preparations. In order to establish these results in vivo, the minimum lethal doses (LDmin) of ouabain (OUA), digoxin (DO), digotoxin (DT), k-strophanthidin (STR) and SBA were determined by the infusion toxicity method in guinea pigs at normokalemia and hypokalemia. The experimentally induced decrease of the serum potassium concentration (5.0 mmoles/l vs. 3.3 mmoles/l) significantly reduced the LDmin of DO (1.42 vs. 1.05 mumoles/kg), DT (1.78 vs. 1.24 mumoles/kg) and STR (20.16 vs. 15.98 mumoles/kg), whereas the LDmin of OUA (0.37 vs. 0.34 mumoles/kg) was not altered. Contrary, the LDmin of SBA was even slightly, but not significantly increased during hypokalemia (16.77 vs. 19.04 mumoles/kg). In addition, from the experimental data an optimum time of infusion (Topt), corresponding to the LDmin, can be derived, which is equivalent to the time for optimum "utilization" of the drug. The obtained sequence: STR less than OUA less than DO less than DT less than SBA represents the well-known differences in the onset of the pharmacological action in man resp. animal. Hypokalemia in general resulted in a shortening of the Topt, thus indicating a more rapid "utilization" of the drug tested. The above differences of the cardenolide action at reduced serum potassium concentration may be dependent on the recently reported divergent influence of potassium on the association- resp. dissociation rate constants for the interaction of these drugs with their binding site at the Na+-K+-ATPase.

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Vasoconstrictions mediated by an endothelium-derived vasoconstricting factor (EDCF).

To enlighten the role of endothelium in the generation of vasospasms we examined vascular tone after reduction of oxygen supply in dependence on endothelial function in isolated vessels (rabbit aorta abdominalis, pig coronary, and pulmonary artery). Therefore, after ligation of all side branches, vessel segments, prepared either with or without endothelium, were cannulated and arranged in two systems (with two segments each) in a serial manner (system I: endothelium-denuded vessel followed by an endothelium-denuded segment) and perfused with Tyrode's solution (constant flow 20 ml/min). Pressure gradient over each segment was continuously measured. Endothelial function was checked by perfusion with 1 mumol/l actetylholine after precontraction with 0.1 mumol/l norepinephrine, thereby inducing an EDRF mediated vasodilation (greater than 70%) indicating normal endothelial function. After 2 h equilibration with Tyrode's solution the preparations of rabbit aorta abdominalis were perfused for 30 min with oxygen-deprived medium (reduction from 95% O2 and 5% CO2 to 95% N2 and 5% CO2) and a marked long lasting (60 min) increase in pressure gradient (indicating vasoconstriction) was observed in those endothelium-denuded vessel segments which were mounted distal to a normal vessel with an intact endothelium. This contraction could be inhibited by pretreatment with either 1 mumol/l dexamethasone. 1 mumol/l indomethacine or 10 mumol/l methylene blue or attenuated by the TXA2-antagonist BM 17133 (5 mumol/l) but not by radical scavengers as superoxid dismutase or by inhibition of the lipoxygenase by nordihydroguaretic acid. From these results it is concluded that endothelium releases a vasoconstricting factor (EDCF) at pO2 values beneath 550 mm Hg. This EDCF seems to depend on phospholipase A2 and cyclooxygenase, but because of the long-lasting effect it is probably no prostanoid itself, especially not TXA2.

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PubMedDate not supplied

Reduced responses of nitrendipine in PGF2 alpha-precontracted porcine isolated arteries after pretreatment with methylene blue.

Vascular activity of nitrendipine (NTD) in different depolarized and prostaglandin F2 alpha (PGF2 alpha)-precontracted isolated porcine arteries was examined in the presence and absence of methylene blue (MB). Presence of MB potentiated the PGF2 alpha-induced contractions in all vessels studied and reduced the response of NTD in coronary and basilar arteries seven- to 23-fold. Only in ulnar arteries was the affinity of NTD slightly increased. In contrast, MB did not modify the affinity of papaverine under these conditions. Furthermore, MB had no influence on KCl-induced contractions and subsequent vasorelaxation by NTD. It is proposed that MB impaired endothelium derived relaxing factor, thereby stimulating and/or increasing the calcium influx through receptor-operated calcium channels.

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Local myocardial perfusion and epicardial NADH-fluorescence after coronary artery ligation in the isolated guinea pig heart.

In Langendorff-perfused guinea pig hearts, local myocardial perfusion was evaluated by analysis of FITC-dextran-150 elution kinetics after bolus injection. Locally estimated half-times of the monoexponential elution curves showed good correlation with global undisturbed coronary flow. After ligation of the left anterior descending coronary artery indicator transit kinetics in the ischemic area were only slightly affected (increase of t/2 by 30 +/- 19%), indicating a residual flow of 80% to the ligated area. The moderate increase (40 +/- 20%) of NADH-surface fluorescence in the same area confirms a high degree of residual flow. Indicator partition volume (signal peak height after bolus injections) was additionally enhanced. Moreover, indicator transit kinetics changed from monoexponential to composed kinetics. On reperfusion these effects were partially reversible. Ligation of the left coronary artery at its aortic root produced only moderate ischemia, indicating very effective mechanisms in the isolated guinea pig heart from the right coronary artery to support the left ventricle. Severe ischemia as evidenced from NADH-surface fluorescence could be observed only after "stopped flow" ischemia.

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PubMedDate not supplied

The influence of endothelium on the action of PGF2 alpha and some dihydropyridine-type calcium antagonists in porcine basilar arteries.

Vascular endothelium modulates the effect of various vasoconstricting mediators as well as the affinity of dihydropyridine-type calcium entry blockers. To further investigate this influence, vasoconstriction by PGF2 alpha as opposed to KCl and the affinity of nitrendipine and some related 3-ester side-chain derivatives were determined in isolated porcine basilar arteries in the presence and in the absence of intact endothelium, as well as in the presence of methylene blue. Treatment with methylene blue or mechanical endothelial damage increased the contractile work of basilar arteries stimulated by PGF2 alpha and reduced the affinity of the dihydropyridines in such precontracted vessels. Both experimental conditions resulted in nearly the same effect. In addition, the degree of intact endothelium, as determined by substance-P-induced vasodilation, significantly correlated with the corresponding efficacy of all dihydropyridines examined. In contrast, KCl-mediated contractions remained unchanged. It is suggested that the endothelium (probably due to the production and release of endothelium-derived vasorelaxing factors, such as EDRF and/or prostacyclin) may attenuate PGF2 alpha-induced transmembrane calcium influx through receptor operated calcium channels, whereas potential operated calcium channels seems to be unaffected.

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PubMedDate not supplied

Functional and antiischaemic effects of the phosphodiesterase inhibitor levosimendan in isolated rabbit hearts.

UNLABELLED: Several phosphodiesterase inhibitors have been reported to possess antiischaemic properties by improving myocardial oxygen demand/supply balance. Levosimendan is a new phosphodiesterase inhibitor with calcium-sensitizing properties. We investigated the functional and antiischaemic properties of levosimendan in isolated electrically-driven rabbit hearts (Langendorff, constant perfusion pressure: 70 cm H2O, Tyrode solution, Ca++ 1.8 mmol/l, 37 degrees, 200 beats/min.). Acute regional myocardial ischaemia was induced by ligature of a circumflex artery branch and quantified from epicardial NADH-fluorescence photography. RESULTS: The left ventricular pressure was similarly enhanced by levosimendan 10(-7) M or 5 x 10(-6) M (+15%) (P < 0.05). The global coronary flow was increased more markedly by levosimendan 5 x 10(-6) M (+35-50%) compared to 10(-7) M (+25%) (P < 0.05). The relative coronary flow (= global coronary flow/pressure-rate-product) was significantly enhanced only by levosimendan 5 x 10(-6) M (+20-35%) (P < 0.05), but not by levosimendan 10(-7) M (+10-15%) (P > 0.05). Epicardial NADH-fluorescence area and intensity were significantly diminished by levosimendan (-20%) (P < 0.05), and there was no significant difference between myocardial ischaemia reduction by levosimendan 10(-7) M and 5 x 10(-6) M (P > 0.05). CONCLUSION: Levosimendan is an inotrope with coronary dilator activity, showing antiischaemic effects in isolated rabbit hearts. These may be caused by (1) phosphodiesterase-inhibition and improvement of myocardial perfusion and/or (2) by oxygen-sparing effects, related to calcium sensitization of myofilaments, particularly at lower concentrations associated with a lower coronary dilator activity.

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Dissociation of antiplatelet effects from myocardial cytoprotective activity during acute myocardial ischemia in cats by a new carbacyclin derivative (ZK 36 375).

We studied the potential therapeutic value of the chemically stable carbacyclin analogue ZK 36 375 during acute myocardial ischemia and compared the cardiovascular and anti- and disaggregatory effects of the compound in vitro and ex vivo. In anesthetized cats the left anterior descending coronary artery was ligated, and 30 min later an intravenous infusion of ZK 36 375 (3.6 micrograms/kg X min) or vehicle was initiated and continued for 4.5 h. ZK 36 375 reduced the ST-segment elevation at 2-5 h (p less than 0.01) when compared to vehicle-treated cats. ZK 36 375 significantly inhibited both the loss of creatine phosphokinase--specific activity and the decrease in the percentage of bound cathepsin D in the infarcted area of the myocardium (p less than 0.05). ZK 36 375 did not reverse ischemia-induced formation of platelet aggregates in vivo and was found ex vivo to be two to three orders of magnitude less active in preventing platelet aggregation, redispersing platelet aggregates, and relaxing bovine coronary arteries than prostacyclin (PGI2) or its (5E) stereoisomer ZK 36 374. It is concluded that ZK 36 375 has a significant cardioprotective activity in acute myocardial ischemia of the cat that can be dissociated from antiplatelet effects in vivo.

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The effects of molsidomine and its metabolite SIN-1 on coronary vessel tone, platelet aggregation, and eicosanoid formation in vitro--inhibition of 12-HPETE biosynthesis.

We studied the action of the biologically active metabolite of molsidomine, N-morpholino-N-nitrosoamino-acetonitrile (SIN), on eicosanoid formation and functional behavior of bovine coronary arteries and human platelets in vitro. Glyceryltrinitrate (GTN) and prostaglandin (PG) I2 were used as reference compounds. SIN dose-dependently inhibited the thrombin-, collagen-, and primary ADP-induced platelet aggregation. The IC50 was in the range of 0.1-0.8 mumol/L. At these concentrations SIN also inhibited thromboxane formation, but did not influence the PGI2 biosynthesis of coronary vessels. Molsidomine itself was inactive. GTN stimulated vascular PGI2 formation, but did not modify the platelet aggregation at comparable concentrations. A particularly interesting finding was the dose-dependent and apparently complete inhibition of formation of the hydroperoxide of 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) in human platelets by SIN. The IC50 amounted to 1.7 +/- 0.4 mumol/L and was in the same range as with 5,8,11,14-eicosatetraynoic acid (2.0 +/- 0.3 mumol/L). Although the results may not suggest a common mechanism of the antiaggregatory action of GTN and SIN, they provide no evidence of a similar or dissimilar mechanism of action in vascular smooth muscle.

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