Biomedical subjects

H Osswald

Publications and source records attributed to H Osswald.

At least 91 records · Page 5Linked to original sources

PubMed1989

Synthesis and selective vasodilating properties of esters of 2,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-dihydro-pyridine-3,5-di- carboxylic acid.

This study presents the synthesis of new 1,4-dihydropyridine (DHP) derivatives which are phenoxy- and alkoxyalkyl esters of 2,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-dihydropyridine-3,5-dica rbo xylic acid and reports on the biological activity of the compounds. It was found that the DHP derivatives showed high affinity to the DHP receptor of rat brain membranes and antagonize potently the potassium depolarization-induced vasospasm in a fashion compatible with the assumption of a calcium entry blockade. The higher vasodilating potency of especially compound III for the cerebral vasculature might represent an improved selectivity profile due to specific substitution patterns of the DHP molecule by increasing lipophilicity. Thus, the new DHP derivatives might be useful as therapeutic agents for hypertension and impaired cerebral microcirculation.

Animals↗

PubMed1988

Distribution of [125I]omega-conotoxin GVIA and [3H]isradipine binding sites in the central nervous system of rats of different ages.

Potential age-related changes in L- and N-type voltage-sensitive calcium channels (L- and N-VSCCs) were assessed by the in vitro binding of [3H]isradipine ([3H]ISR, 150 pM) and [125]omega-conotoxin GVIA ([125I]omega-CT, 4 pM) to membranes prepared from discrete central nervous system regions of 0.5-, 2-, and 18-month-old rats. The rank orders of [3H]ISR and [125I]omega-CT binding, although differing, indicated that the highest binding was in neocortex, corpus striatum, and hippocampus; radioligand binding was generally not affected by the variable of age. These results suggest that the nonidentical [3H]ISR and [125I]omega-CT binding sites are concentrated in those regions characterized by high densities of synaptic connections, and that these sites, as presumed components of L- and N-VSCCs, are relatively stable during the aging process.

Aging↗

PubMed1988

Omega-conotoxin GVIA and pharmacological modulation of hippocampal noradrenaline release.

The tritium overflow evoked by electrical stimulation of rabbit hippocampal slices labeled with [3H]noradrenaline was inhibited by omega-conotoxin GVIA, a peptide modulator of the N-type voltage-sensitive calcium channel (N-VSCC). The magnitude of this inhibition was unchanged in the presence of substances which interact with N- and/or L-VSCCs (cadmium, neomycin, (-)- and (+)-202-791), alpha 2-adrenoceptors (idazoxan, UK-14304), protein kinase C (4 beta-phorbol-12,13-dibutyrate) or potassium channels (4-aminopyridine). This finding suggests that the attenuation of calcium-dependent neurotransmitter release by omega-conotoxin GVIA is relatively insensitive to alterations of such release effected by other substances.

Aminopyridines↗

PubMed1988

Stimulus-dependent inhibition of platelet aggregation by the protein kinase C inhibitors polymyxin B, H-7 and staurosporine.

Thrombin, 1-oleoyl-2-acetyl-rac-glycerol (OAG), cis- or trans-octadecadienoic acids (linoleic and linolelaidic acid) and the synergistic combination of octadecadienoic acids plus OAG lead to the activation of gel-filtered human platelets, i.e. aggregation via protein kinase C (PKC). Platelet activation by thrombin was only slightly suppressed by polymyxin B, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) or staurosporine, all being potent inhibitors of PKC in vitro. The OAG-induced aggregation, however, was strongly inhibited by H-7 or staurosporine but not by polymyxin B. In contrast, octadecadienoic acid-induced aggregation was substantially inhibited only by polymyxin B. Synergistic activation by OAG plus octadecadienoic acids was strongly suppressed by all three PKC inhibitors. Our results indicate (1) that the ability of various compounds to inhibit PKC in vitro does not correlate with their inhibitory effects in intact cells and (2) that platelet activation induced by various PKC activators exhibits differential PKC-inhibitor sensitivity.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1988

Folinic acid effect on 5-fluorouracil kinetics in vivo.

Synergy of folinic acid and FU has been shown in several experimental systems. In the present study we examined the kinetics of concurrent administration of folinic acid on the kinetics of FU in an in vivo model. Folinic acid significantly increased the amount of FU bound to the TS complex. In the sequential combination of MTX and FU folinic acid had no additional effect. The amount of FU incorporated into RNA was not affected in any of the treatment groups. The results indicate that folinic acid may improve FU cytotoxicity by increased FU binding to TS but has no additional effect on the synergistic sequential MTX-FU combination.

Animals↗

PubMed1987

The influence of sodium ascorbate, menadione sodium bisulfite or pyridoxal hydrochloride on the toxic and antineoplastic action of N-methylformamide in P 388 leukemia or M 5076 sarcoma in mice.

The toxicity of daily subcutaneously applied 500 mg/kg N-methylformamide (NMF) during a period of 8 days in female CD-mice was ameliorated when 100 mg/kg sodium ascorbate, 60 mg/kg menadione bisulfite or 80 mg/kg pyridoxal hydrochloride were applied simultaneously. The comparison of the daily s.c. application of 360 mg/kg NMF with the intermittent s.c. injection of 720 mg/kg NMF with an interval of 48 h in P 388 leukemia showed that the daily application of NMF induced an increase of life span of 82% whereas the intermittent schedule effected a 142% increase of life span. The simultaneous combination of 360 mg/kg NMF with 60 mg/kg sodium ascorbate applied daily caused a 133% increase of life span and the simultaneous combination of 360 mg/kg NMF with 30 mg/kg menadione sodium bisulfite lead to a 126% increase of life span. The combined daily s.c. application of 360 mg/kg NMF with 30 mg/kg pyridoxal hydrochloride induced only a minimal difference compared to the daily application of 360 mg/kg NMF alone. The combination of 720 mg/kg NMF with 120 mg/kg sodium ascorbate applied in intervals of 48 h showed a 164% increase of life span. In advanced M 5076 sarcoma the daily s.c. application of 360 mg/kg NMF effected a 82% increase of life span and the combination of 360 mg/kg NMF with 60 mg/kg sodium ascorbate effected a 135% increase of life span.

Animals↗

PubMed1987

Characterization of the dihydropyridine binding sites of rat neocortical synaptosomes and microvessels.

The dihydropyridine binding sites associated with rat neocortical synaptosomes and microvessels were compared using an in vitro [3H]PN 200-110 [(+)-[methyl-3H]-isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5- methoxycarbonylpyridine-3-carboxylate] binding assay. Saturation experiments yielded similar KD values (approximately 70 pM) and Bmax values (approximately 400 fmol/mg of protein) for the two membrane preparations. Interaction experiments with [3H]PN 200-110 and various calcium-modulating substances provided further evidence for the practically identical nature of the synaptosomal and microvascular dihydropyridine binding sites. These findings predict that lipophilic dihydropyridines, simultaneously occupying the two central binding sites, have the dual effect of altering neuronal function and local blood flow.

Animals↗

PubMed1986

Interference of phorbolesters with endothelium-dependent vascular smooth muscle relaxation.

Histamine-induced endothelium-dependent relaxation (EDR) in the pulmonary artery was inhibited in a concentration-dependent manner by the phorbolester phorbol 12,13-dibutyrate (PDBu) (IC50: 70 nM) whereas EDR occurring in response to ionophore A 23187 was not affected by PDBu. The phorbolester 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), which does not activate protein kinase C (PKC), was without effect on receptor- or ionophore-induced EDR. The observed inhibition of signal transduction by PKC activation is suggested to reflect phosphorylation of the GTP binding protein Ni.

Animals↗

PubMed1986

Overadditive synergism between the intercalators mitoxantrone and lucanthone in advanced L 12010 and P 388 leukemia.

The combination of mitoxantrone with lucanthone, a schistosomicidal and nonmyelotoxic agent, yielded a therapeutic synergism in L 1210 and P 388 leukemia with no increase in toxicity. In that combination the nonmyelotoxic lucanthone enabled the use of the optimal dose of mitoxantrone. The recent hypothesis that planar polycyclic aromatic compounds, mostly comprised by the term intercalators, intercalate with DNA or bind to DNA may need receiving with respect to membrane target sites.

Animals↗

PubMed1986

Urinary polyamine excretion by tumor-bearing and tumor-free mice exposed to cyclophosphamide, 5-fluorouracil and 6-mercaptopurine.

The effects of cytostatic treatment on urinary polyamine excretion have been investigated in tumor-bearing (either Ehrlich carcinoma of S 180 sarcoma) and in tumor-free mice. The animals were exposed to single or multiple treatment with various doses of cyclophosphamide, 5-fluorouracil, or 6-mercaptopurine. Treatment invariably enhanced polyamine excretion dependent on dose and effectiveness of the cytostatic drug. The most pronounced increases were observed in the excretion of spermine and putrescine, with peak excretion usually occurring after 1-2 and 3-4 days, respectively. The urinary excretion of spermidine was relatively modest in untreated mice, but the increases observed following drug treatment were high in proportion. Significant differences in urinary polyamine excretion were observed between tumor-free and tumor-bearing animals following treatment with all cytostatic agents. Peak values were invariably higher in tumor-bearing mice even in those with small, barely detectable tumors. After discontinuation of treatment polyamine excretion returned to normal values and stabilized in groups in which regression predominated, whereas in those groups of animals which showed little or no tumor regression urinary polyamine levels gradually increased again during a 2-week observation period.

Animals↗

PubMed1986

Inhibition of endothelium-dependent smooth muscle relaxation by calmodulin antagonists.

By using the calmodulin antagonists, calmidazolium and N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), the hypothesis was investigated as to whether calmodulin is involved in the sequence of events leading to the endothelium-dependent vascular smooth muscle relaxation. Endothelium-dependent relaxations were studied on two different preparations, the rabbit aorta and the pulmonary artery of the guinea pig. Relaxations were produced in the precontracted rings (noradrenaline 3 X 10(-6) mol/l) in response to acetylcholine, 10(-8) to 10(-6) mol/l (aorta), histamine, 3 X 10(-8) to 1 X 10(-6) mol/l (pulmonary artery) or the calcium ionophore A 23187, 1 X 10(-8) to 3 X 10(-7) mol/l (aorta and pulmonary artery). In the presence of calmidazolium and W-7 the endothelium-dependent relaxation was inhibited in a dose dependent manner. This inhibition was seen in a concentration range that coincides with calmodulin inhibition. The half maximal concentrations of calmidazolium for the inhibition of the relaxation of the aorta induced by acetylcholine and A 23187 were 3 X 10(-6) mol/l and 1.4 X 10(-6) mol/l and that of W-7 were 3.1 X 10(-5) and 3.6 X 10(-5) mol/l, respectively. Complete inhibition was obtained both for acetylcholine-and for A 23187-induced relaxations by preincubation with 1 X 10(-5) mol/l calmidazolium or 1 X 10(-4) mol/l W-7. The half maximal concentrations of calmidazolium for the inhibition of the relaxation of the pulmonary artery in response to histamine and A 23187 were 2.7 X 10(-6) mol/l and 3 X 10(-6) mol/l and complete inhibition was achieved at 1 X 10(-5) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1986

Stereospecific inhibition of 5-HT-induced increase of intracellular free calcium by (+)- and (-)-desmethoxyverapamil in human platelets.

The concentration of intracellular free calcium [Ca2+]i in human platelets was measured by the quin-2 method. 5-Hydroxytryptamine (5-HT) at 10(-5) M induced a rapid transient increase of [Ca2+]i which was antagonized by 10(-7) M ketanserin or cyproheptadine. The verapamil derivative, desmethoxyverapamil (D888), showed stereospecific inhibition of the 5-HT-induced [Ca2+]i increase. The IC50 for (-)-D888 was approx. 2 X 10(-8) M; (+)-D888 was almost 50 times less potent.

Blood Platelets↗

PubMed1985

Maleate induced fall of glomerular filtration rate. A micropuncture study in the rat.

Maleate causes an enhanced excretion of amino acids, glucose, phosphate and bicarbonate. In addition to this inhibition of fluid and electrolyte reabsorption malate decreases glomerular filtration rate (GFR). The present investigation was designed to study the mechanisms of this fall in GFR. In group I (Sprague-Dawley rats; N = 8) maleate (2 mmol/kg body weight i.v.) increased the hydrostatic pressure in proximal tubule from 12.6 +/- 0.5 to 16.3 +/- 0.8 mm Hg (mean + SEM) and stop flow pressure in the first accessible loop of the proximal tubule was unchanged (33.6 +/- 0.4 vs 33.1 +/- 1.3 mm Hg; n.s.). Directly measured hydrostatic pressure in the glomerular capillaries in Munich-Wistar rats (N = 7), however, was reduced by maleate from 47.6 +/- 1.6 to 42.4 +/- 1.9 mm Hg. In group II (N = 8) we determined single nephron filtration rate (SNGFR) from distal and proximal collection sites in the same nephron in a paired fashion under control conditions and after maleate administration to assess the activity of the tubuloglomerular feedback. In the control periods SNGFR (16 nephrons) from distal collection sites was 26.3 +/- 1.6 nl/min whereas SNGFR from proximal collection sites was 31.8 +/- 2.4 nl/min. Following maleate distal SNGFR (17 nephrons) was 15.2 +/- 1.7 nl/min and proximal SNGFR was 24.3 +/- 2.2 nl/min. The ratio distal/proximal SNGFR was 1.23 +/- 0.07 under control conditions and increased to 1.76 +/- 0.1 following maleate indicating enhanced activity of tubuloglomerular feedback.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

The effect of methotrexate pretreatment on 5-fluorouracil kinetics in sarcoma 180 in vivo.

Synergy of sequential MTX and 5-FU has been shown in several in vitro and in vivo systems. In the present study the influence of time interval between MTX and 5-FU and MTX dose on 5-FU accumulation in tumor cells has been examined in Sarcoma 180 in vivo. There was a clear relationship between MTX dose applied and amount of 5-FU detected in the acid-soluble fraction, the RNA fraction and the thymidylate synthase complex fraction. Also, the MTX-5-FU time interval affected clearly the amount of 5-FU detected in all three fractions, the optimum time interval being 8-12 hr. The results indicate that for sequential application of MTX and 5-FU selection of an adequate MTX dose and a sufficient time interval is crucial to achieve synergistic action.

Animals↗

PubMed1985

Timing- and sequence-dependent synergism between etoposide and methotrexate or etoposide, methotrexate and 5-fluorouracil in advanced leukemia L1210.

The optimal synergism in combination therapy of leukemia L1210 depends on the sequence and the timing of the agents used. Etoposide (20 mg/kg applied intravenously) 3 h before methotrexate (50 mg/kg administered subcutaneously) results in significantly improved therapeutic action. Simultaneous application of these drugs, or an exceeding of that interval, do not entail synergism. Similar to the results obtained with other transplantable murine tumors, the optimal interval between methotrexate and 5-fluorouracil treatments of leukemia L1210 amounts to 6 h. Sequential treatment with etoposide (20 mg/kg given intravenously) significantly improves the efficacy of combined methotrexate (50 mg/kg applied subcutaneously) and 5-fluorouracil (80 mg/kg administered subcutaneously). The optimal synergism combining etoposide, methotrexate and 5-fluorouracil is achieved when the interval between etoposide and methotrexate amounts to 3 h followed 6 h later by 5-fluorouracil.

Animals↗

PubMed1984

The curative action of hexamethylmelamine on intramuscularly or intracerebrally implanted Yoshida sarcoma.

Curative effects of hexamethylmelamine (HMM, NSC 13875) against intramuscularly or intracerebrally implanted Yoshida sarcoma depend on the schedules. A twice daily oral administration over a 2-week period showed a significant chemotherapeutic advantage over a single daily administration. The observed curative effect depends on the tumour site and on its mass. The Yoshida sarcoma seems to be one of the most suitable test models for HMM or related derivatives.

Altretamine↗

PubMed1983

Concentration profiles of calcium and oxalate in urine, tubular fluid and renal tissue--some theoretical considerations.

This paper analyzes some aspects of the pathophysiology of urolithiasis. It is emphasized that a better understanding of factors contributing to stone formation can only be gained when the primary nucleation site is identified. Three compartments are considered in which supersaturation as a precondition for stone formation could be present: urine in the urinary tract, tubular fluid from the glomerulus down to the duct of Bellini, and the interstitium of the medulla. From calculations based on micropuncture data it becomes apparent that the oxalate concentration in the tubular fluid at the bend of Henle's loop is 1 or 2 orders of magnitude lower than in the duct of Bellini and that the oxalate concentration maximum invariably must be located in the final urine. The calculation of a tubular concentration profile of oxalate shows, that the probability of intra luminal crystal formation is even less likely for plasma oxalate values of 2-3 microM as compared to 1.2 microM, which therefore should be the correct value. The time necessary for the growth of crystals up to a critical size which can obstruct tubules or ureter is not available in the urinary tract nor in the tubules. However, in the medullary interstitium, where solute concentration is highest, nearly unlimited time for crystal growth is available due to the fact, that in this compartment convective flow is very low. It is concluded that the interstitium of the inner medulla has the best chances to function as the primary nucleation site where particles can be formed of a size which subsequently can obstruct the urinary tract.

Calcium↗

PubMed1982

Asymmetric release of cyclic AMP from guinea-pig and rabbit gallbladder.

The release of cyclic adenosine 3':5'-monophosphate (cAMP) from guinea-pig and rabbit gallbladder was investigated in vitro. Serosal addition of prostaglandin E1 (PGE1) to luminally perfused guinea-pig gallbladders caused a concentration-dependent efflux of cAMP to the mucosal side, the threshold concentration of PGE1 being 10(-7) M. The efflux of cAMP to the serosal side was 7-fold lower. A mucosal sidedness of cAMP release was also observed in stripped preparations of rabbit gallbladder mucosa mounted between two half chambers. No cAMP was found in the solutions bathing the serosal layers isolated from rabbit gallbladders. Fluid secretion was observed at 10(-7) M PGE1, an effect mimicked by serosal, but not mucosal application of cAMP (3.3 x 10(-3) M). This is taken to indicate that the basolateral membrane is more easily permeated by cAMP than the apical membrane, since cAMP is believed to exerts its physiological effects from inside the cell. It is concluded that preferential release of cAMP to the mucosal side is not due to a higher permeability of the brush border membrane but rather represents an as yet undefined transport process which may be of importance for the regulation of excessive intracellular cAMP levels.

Alprostadil↗