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Notes: Summary The effect of pentoxifylline on the deformability of red cells in sickle cell thalassaemia was investigated. The fluidity of the blood in sickle cell thalassaemia is disturbed and is accompanied by violent pains and irreversible tissue damage caused by capillary occlusions. After treating a 15-years-old female patient with pentoxifylline (2 g orally each day), the fluidity of the blood improved distinctly, and this correlated with a condition free of clinical symptoms. Erythrocyte filtration by Nuclepore filter increased significantly over the 6-month examination period (initial value: $$\dot V_{rel} = 0.068 \pm 0.008$$ ; after 6 months medication: 0.246±0.030). In addition, in the single-pore erythrocyte rigidometer (SER) a significantly improved passage time of individual erythrocytes could be demonstrated (initial value: 62.43±15.72 ms; after 4 weeks medication: 28.13±7.0 ms). The hitherto high number of rheological occlusions in the SER (48±30.9 from 200 individual passages) almost completely disappeared after treatment (1.7±1.2).

Notes: Summary [125Iodo]cyanopindolol [(±)-ICYP], a potent and selective ligand for β-adrenoceptors, exhibited complex biphasic dissociation kinetics. Consequently, in receptor binding studies, the pure (+)- and (-)-enantiomers of ICYP were synthesised and their equilibrium and kinetic binding characteristics were investigated on a membrane preparation of guinea pig left ventricle containing almost only β1-adrenoceptors. All three ligands, i. e. (+)-, (-)- and (±)-ICYP, bind to β-adrenoceptors as assessed by competition experiments with different β-blocking agents; irrespective of the ligand used, the same dissociation constant was found for the competitor. In a first series of saturation binding experiments performed in a low concentration range of free ligand (0–250 pM), ICYP showed the following dissociation constants: K D=93, 9 and 23 pM, and number of binding sites: B max=40,128 and 124 fmoles/mg protein for (+)-, (-)-, and (±)-ICYP, respectively. Asexpected, (±)-ICYP showed the same B max as (-)-ICYP, whereas its K D was approximately two times higher than that of (-)-ICYP. Surprisingly, the B max of (+)-ICYP represented only ∼ 30% of the B max of (-)-ICYP. All three ligands bound apparently to a single class of binding sites. In dissociation experiments, the enantiomers of ICYP showed biphasic dissociation curves as observed for the racemic ligand. (+)-, (-)- and (±)-ICYP showed a rapidly dissociating (k -1=0.488, 0.047 and 0.049 min−1) and a slowly dissociating component (k -2=0.0205, 0.0033 and 0.0025 min−1). The ratio slow dissociating/fast dissociating component represented respectively for (+)-, (-)- and (±)-ICYP 40/60, 90/10 and 90/10. For all three ligands, the association rate constants were of the same order of magnitude (ca. 109 M−1 min−1), typical for a diffusion controlled reaction. In contrast to equilibrium binding studies, the existence of multiple receptor affinity sites was evident from the biphasic dissociation behaviour observed especially with the nonracemic ligands (+)-ICYP and (-)-ICYP. Simulation of theoretical saturation curves performed with the ratios of high versus low affinity sites and the K D-values suggested by kinetic analysis, indicated that the delineation into two affinity states might be visible in saturation experiments, under certain conditions. Therefore, equilibrium binding studies were repeated with an increased number of ligand concentrations covering a large concentration range of 0–800 pM. Simultaneous analysis of saturation curves from the same experiment using three different ligands, provided more accurate estimates of the ratio of high and low affinity sites, as well as the affinity constants of the ligand for each receptor affinity state, in good agreement with the results from kinetic analysis. The contribution of the (+)enantiomer in the binding of the racemic ligand under low receptor concentrations could be neglected since dissociation characteristics of (±)- and (-)-ICYP were identical. A model that explains the biphasic dissociation of (±)-ICYP by differential binding of both enantiomers could be rejected. Kinetic and equilibrium binding characteristics of the three radioligands were not influenced by the guanylnucleotide Gpp(NH)p (10−4 M). The antagonist ICYP binds to β-adrenoceptors in a high and low affinity state which are probably interconvertible.

Notes: Summary The in vitro cardiac effects of DPI 201-106, a novel piperazinyl-indole, were investigated. DPI 201-106 produced concentration-dependent positive inotropic effects in guinea-pig and rat left atria, kitten, rabbit and guinea-pig papillary muscles and Langendorff perfused hearts of rabbits between 10−7 and 3×10−6 mol/l. During isometric twitches, contraction and relaxation phases were prolonged in guinea-pig left atria and right ventricular papillary muscles from kitten and guinea-pigs. Spontaneous sinus rate was decreased in right atria of guinea-pigs and rats. Coronary flow increased in rabbit isolated hearts. Functional refractory period was increased in left atria from guinea-pigs and rats with EC50 values of 1.7 and 0.24 μmol/l respectively. In electrophysiological measurements, DPI 201-106 prolonged the action potential duration (APD70) in guinea-pig papillary muscles up to 70% and in rabbit atria up to 120% at 3 μmol/l. Other action potential characteristics were not changed in guinea-pig papillary muscles but V max was decreased in rabbit left atria. The electrophysiological as well as the positive inotropic effects were stereoselective with the activity residing in the S-enantiomer. DPI 201-106 increased the Ca2+-sensitivity of skinned fibres from porcine trabecular septomarginalis with an EC50 of 0.2 nmol/l. DPI 201-106 did not change cAMP levels in guinea-pig atria and rabbit papillary muscles. Slow action potentials were not induced by DPI 201-106 in partially depolarized guinea-pig papillary muscles. Phosphodiesterase activity of rat hearts was not inhibited by DPI 201-106 at pharmacologically relevant concentrations. The presence of propranolol did not influence the inotropic potency of DPI 201-106 in guinea-pig atria. In conclusion, DPI 201-106 represents a novel type of positive inotropic agents with a synergistic sarcolemmal and intracellular mechanism of action.

Notes: Summary In order to elucidate the regulatory parameters which determine multiple opine formation in marine invertebrates, anaerobiosis was induced in 25 species from several phyla by stimulating the animals to vigorous muscular activity or by subjecting them to environmental hypoxia. The quantity of glycolytic end products and the corresponding amino acids were measured. In a second set of experiments the amounts of substrates and products of the opine dehydrogenase reactions in the isolated introvert retractor muscle (IRM) ofSipunculus nudus were determined in both situations. During environmental hypoxia opines accumulated according to the contents of the corresponding amino acids. Mass action ratios (MAR) of the opine dehydrogenase reactions in the isolated IRM were in the range of control values (octopine dehydrogenase 1.9·1011 mol−2·l2, strombine dehydrogenase 2.2·1010 mol−2·l2). During muscular activity those opines accumulated preferentially which corresponded to the highest opine dehydrogenase activities. In the isolated IRM only octopine accumulated during contractile activity; the MAR of the octopine dehydrogenase reaction was near the control value while the MAR of the strombine dehydrogenase reaction deviated by a factor of 9. The results indicate that during environmental hypoxia the opine dehydrogenases present in a tissue catalyze near equilibrium and the relative amount of opines accumulated is dictated by the concentration of the corresponding amino acids. During muscular activity only those opine dehydrogenases catalyze near equilibrium which are present in sufficiently high activities to keep pace with an increased glycolytic flux. Therefore, different opines may accumulate in the same animal during muscular activity and during environmental hypoxia.

Notes: Die Schwächung von β-Strahlen ist abhängig vom Flächengewicht und vom Verhältnis Ordnungszahl Z/Atomgewicht A des durchstrahlten Mediums. Dies ermöglicht die Messung des Flächengewichts bei konstantem Z/A-Verhältnis, bzw. des Z/A-Verhältnisses bei konstantem Flächengewicht. Die zweite Möglichkeit ist die Grundlage der C/H-Messung in aromatischen Kohlenwasserstoffen; dabei wird der Strahler fest mit einem Schwimmer verbunden, dessen Auftrieb in Abhängigkeit von der Dichte des flüssigen Mediums automatisch ein konstantes Flächengewicht über dem Strahler herstellt, so daß das Meßergebnis nur vom C/H-Verhältnis abhängig ist. In flüssigen Kohlenwasserstoffen wird auf diese Weise ein kontinuierlich arbeitender Nachweis des Wasserstoff-Gewichtanteils auf ± 0,16% erreicht.