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Biomedical subjects

H Holmsen

Publications and source records attributed to H Holmsen.

At least 163 records · Page 9Linked to original sources
PubMed1979

Myositis ossificans progressiva. Clinical and metabolical observations in a case treated with a diphosphonate (EHDP) and surgical removal of ectopic bone.

A 20-year-old woman with a severely crippling myositis ossificans progressiva was treated with a diphosphonate (EHDP), 10-20 mg/kg/day. While being treated with this drug, surgical removal of ectopic bone was performed. Although ectopic calcification recurred postoperatively, considerable functional improvement was achieved. At the highest dosage of EHDP, hypercalcaemia gradually appeared, but was reversible upon cessation of drug treatment. It is probably related to a direct effect of EHDP on the bone.

Adult↗
PubMed1977

Prostaglandin endoperoxide--thromboxane synthesis and dense granule secretion as positive feedback loops in the propagation of platelet responses during "the basic platelet reaction".

Platelets respond to a great variety of stimuli by a sequential display of shape change, aggregation, prostaglandin/thromboxane synthesis--dense granule secretion and alpha-granule secretion. It is suggested that these responses are independent of each other, and caused by an increase in the concentration of a second messenger, liberated to the cytoplasm through the interaction between an extracellular agonist and the platelet membrane. The extent of the propagation of responses is determined by the strength of the stimulus. Stimuli can be subdivided into 1) original, applied stimuli and 2) platelet-produced stimuli (substances secreted from dense granules, prostaglandins and thromboxanes); these stimuli may act synergistically. In this way the platelet has two apparently independent means of potentiating their response to external stimuli which act as two separate positive feedback loops.

Blood Platelets↗
PubMed1977

Effects of sodium azide on platelet function.

Sodium azide in low concentrations (0.1-10 micrometer) was found to have inhibitory effects on human platelet function. Primary aggregation induced by ADP, epinephrine, thrombin and the ionophore A 23187 was decreased. To evaluate the effect of azide apart from secondary processes, the platelets were treated with indomethacin to prevent prostaglandin/thromboxane synthesis for all inducers; in addition, effects of secreted ADP, in the case of thrombin and A 23187, was prevented by the presence of creatine phosphate plus creatine phosphokinase ADP, epinephrine and A 23187, but not thrombin-induced primary aggregates, dispersed immediately upon addition of azide. Azide powerfully inhibited dense granule secretion induced by collagen, ADP and epinephrine as measured both by 14C-serotonin secretion and as judged by secondary aggregation. Shape change induced by ADP, thrombin or A 23187 was not affected. Azide had no effect on energy metabolism. Since the aggregation experiments were performed in the presence of indomethacin, and malondialdehyde formation from arachidonic acid was not affected by azide, it seemed unlikely that the inhibition by azide of platelet function was related to inhibition of synthesis of prostaglandins and thromboxanes. It is concluded that azide exerts its effects directly on the common pathway for platelet responses.

Azides↗
PubMed1977

Thrombin-stimulated myosin phosphorylation in intact platelets and its possible involvement secretion.

A 20,000 dalton polypeptide, which is phosphorylated in intact platelets pre-incubated with 32P-PO4, has been identified as a platelet myosin light chain. Stimulation of intact platelets with thrombin produced a 5-fold increase in the amount of radioactive phosphate incorporated into the light chain. Myosin phosphorylation preceeded acid hydrolase secretion and occurred concomitantly with adenine nucleotide secretion. These results are suggestive of participation of contractile mechanisms in platelet secretion.

Blood Platelets↗
PubMed1977

Adenine nucleotide metabolism of blood platelets. X. Formaldehyde stops centrifugation-induced secretion after A23187-stimulation and causes breakdown of metabolic ATP.

A23187 induced shape change, aggregation and secretion of platelets in plasma. When rapid cooling was used to stop secretion and centrifugation to separate the cells from the medium, maximal amounts of storage ATP plus ADP and preadsorbed [14C]serotonin were found in the supernatant immediately (less than 5 s) after A23187 addition. These results suggested that A23187 could cause shape change and aggregation through secreted ADP and not directly. When secretion was stopped with chilling and formaldehyde treatment before centrifugation, the secreted substances appeared after a lag of 60-120 s, i.e. after shape change was terminated and aggregation was well on its way. These two platelet responses thus seemed to be independent of secretion and induced directly by A23187. The absence of a lag period when secretion was stopped by chilling alone was thought to be due to centrifugation-induced secretion of platelets conditioned by A23187. Formaldehyde completely inhibited centrifugation-induced secretion. At 37 degrees C, formaldehyde caused rapid breakdown of metabolic ATP in platelets with a pattern dependent on the formaldehyde concentration: Below 50 mM, ATP was converted to inosine plus hypoxanthine via ADP, AMP and IMP and the adenylate energy charge was preserved. Above 100 mM, AMP was the end product with a drastic reduction in the adenylate energy charge. These changes were not due to lysis of the platelets, but were apparently caused by an formaldehyde-induced increase in cellular ATP consumption. Platelet secretion is usually associated with a conversion of metabolic ATP to hypoxanthine. Formaldehyde had to be used to stop secretion and since it caused breakdown of ATP, additional smaples were taken out for nucleotide determination during stirring of platelet-rich plasma with A23187. It was found that metabolic ATP was converted to inosine plus hypoxanthine only during the secretion step.

Adenosine Diphosphate↗
PubMed1977

Hydrogen peroxide lowers ATP levels in platelets without altering adenyalte energy charge and platelet function.

H2O2 irreversibly reduced metabolic platelet ATP levels with a corresponding accumulation of hypoxanthine. This process was enhanced by sodium azide or potassium cyanide and by increasing H2O2 concentrations. The adenylate energy charge was unaltered when less than two thirds of the metabolic ATP had disappeared but decreased markedly when more ATP disappeared. Platelet shape change, primary aggregation, dense granule and alpha-granule secretion were unaffected by H2O2-induced lowering of ATP provided that the adenylate energy charge did not fall by more than 5%; at greater adenylate energy charge reduction, platelet functions were inhibited. These results indicate that cell functions depend more on adenyalte energy charge than on the ATP level and expands the applicability of this view from bacterial systems to a mammalian cell, the human platelet.

Adenosine Diphosphate↗
PubMed1977

Hydrogen peroxide, an inhibitor of platelet function: effect on adenine nucleotide metabolism, and the release reaction.

The in vitro effects of H2O2 on platelet adenine nucleotide metabolism and on the ADP-induced platelet release reaction were examined. All studies were performed on human platelet-rich plasma (PRP) preincubated with (3H)-adenine. Within 3 min of incubation with PRP, H2O2 (100-500 micronM) caused an irreversible reduction in the (3H)-ATP level with a concomitant increase in (3H)-IMP and (3H)-inosine and hypoxanthine levels. The adenylate energy charge (AEC) initially decreased while the ATP level fell. The AEC, however, returned to levels slightly lower than the control during further incubation. No leakage of ATP and ADP to plasma was observed. The fall in the steady-state levels of (3H)-ATP increased with increase of the H2O2 concentration (decrease of 8.7-40% at H2O2 concentrations from 5 to 600 micronM). H2O2 pretreatment of PRP caused absence of ADP-induced biphasic aggregation, partial inhibition of the primary wave, and complete inhibition of release of platelet nonmetabolic ATP and ADP. Our in vitro findings support the view that part of the inhibitory effect of H2O2 may be related to the lowering of metabolic ATP levels in platelets.

Adenine Nucleotides↗
PubMed1977

Abnormal platelet function in Chediak-Higashi syndrome.

Platelets in an infant with Chediak-Higashi (C-H) syndrome without bleeding manifestations and not in the accelerated phase showed abnormal function consistent with storage pool disorder as shown by abnormal aggregation, decreased storage capacity and release of [14C]5-HT, low endogenous 5-HT, reduced ATP and ADP with an increased ATP/ADP ratio, increased specific radioactivity of ADP after [14C]adenine labelling, decreased release of adenine nucleotides after stimulation, impaired secretion of acid hydrolases despite normal stores, and decreased calcium content. Incorporation of [14C]adenine into metabolic pool adenine nucleotides was normal. Nucleotide conversion to hypoxanthine in stimulated platelets was mildly impaired. Platelet cyclic-AMP (c-AMP) was initially elevated, but even when c-AMP returned to normal levels after ascorbate treatment, platelet function was not improved. Elevated intracellular c-AMP was not solely responsible for the abnormal platelet function.

Adenosine Diphosphate↗
PubMed1977

ADP-induced refractory state of platelets in vitro. II. Functional and ultra studies on gel filtered platelets.

Gelfiltered platelets (GFP) in calcium free Tyrode solution containing albumin, glucose and adenosine deaminase were preincubated with 1 micronM 14C-ADP or 0.15 M NaCl (control) at 37 degrees C. The breakdown of extracellular 14C-ADP was markedly inhibited in this medium. No aggregation took place without fibrinogen, but the platelets underwent a disc to sphere transformation with development of refactoriness towards ADP. Presence of 2 mM CaCl2 in the incubation medium did not prevent refractoriness as reported earlier with washed rabbit platelets. When the ADP degrading enzyme, apyrase, was added at 30 min of incubation a partial recovery of the aggregability was observed. Electron microscopic studies showed that the partial restoration of the aggregation response, due to ADP degradation by apyrase, was accompanied by a return of discoidal morphology of the platelets. The ultrastructural studies showed further that spherical form with large number of pseudopods is not by itself a necessary or sufficient indication of platelets in a refractory state. However, the results indicated that spherical platelets are more vulnerable to external factors. It was concluded that refractoriness was mainly caused by a direct effect on the platelets by ADP itself, but the studies also suggested that deteriorating, irreversible, intracellular changes may take place when platelets are in spherical shape. An artificial medium, mechanical stress, incubation at 37 degrees C are factors that probably speed up these changes.

Adenine↗
PubMed1976

Adenine nucleotide metabolism of blood platelets. IX. Time course of secretion and changes in energy metabolism in thrombin-treated platelets.

Changes in the energy metabolism of washed human platelets were compared with the kinetics of secretion induced by thrombin (5 units/ml). A 50% decrease in the level of metabolic ATP (3H-labelled), which was essentially complete in 30s, was matched in rate by adenine nucleotide secretion from storage in dense granules. Incubation of platelets with antimycin before thrombin addition increased the rate of fall in metabolic ATP, but did not affect the rate of adenine nucleotide secretion. beta-N-Acetylglucosaminidase secretion, which was slower than adenine nucleotide secretion in control platelets, was noticeably inhibited by antimycin, confirming previous reports that different regulatory mechanisms exist for dense and alpha-granule secretion. The rates of rephosphorylation of metabolic ADP to ATP via glycolysis and oxidative phosphorylation were estimated by measuring lactate production and O2 consumption in resting and thrombin-stimulated platelets and compared to the level of metabolic ATP (9-10 nmol/mg of platelet protein in the resting state). The rate of ATP production was stimulated at least two fold from 12 nmol to 24 nmol/min/mg within seconds of thrombin addition. This increased rate was maintained over the observed period of 5 min although the level of metabolic ATP had decreased to 4-5 nmol/mg within 30 s; the turnover of the remaining metabolic ATP thus increased four fold over the resting state although the actual stimulation of energy production was only two fold.

Adenosine Diphosphate↗
PubMed1976

Transport and metabolism of adenosine in human blood platelets.

The uptake and metabolism of [14C]- or E[3H] adenosine have been studied in suspensions of washed platelets and in platelet rich plasma. The appearance of radioactivity in the platelets and the formation of radioactive adenosine metabolites have been used to determine the uptake. Adenosine is transported into human blood platelets by two different systems: a low Km system (9.8 muM) which is competitively inhibited by papaverine, and a high Km system (9.4 mM) which is competitively inhibited by adenine. Adenosine transported via the low Km system is probably directly incorporated into adenine nucleotides, while adenosine transported through the high Km system arrives unchanged inside the platelet and is then converted into inosine and hypoxanthine or incorporated into adenine nucleotides.

Adenine↗
PubMed1976

Thrombin-induced oxygen consumption, malonyldialdehyde formation and serotonin secretion in human platelets.

The relationship of a thrombin-induced burst in O2 consumption to lipid peroxidation in washed human platelets was investigated by measuring malonyldialdehyde, a by-product of endoperoxide degradation in platelets. The ratio of O2 consumed by malonyldialdehyde produced was approximately 7:1. Acetylsalicylate blocked the formation of malonyldialdehyde completely and partially inhibited the O2 burst induced by thrombin. 5,8,11,14-Eicosatetraynoic acid inhibited the O2 burst as well as the malonyldialdehyde formation completely. The release of [14C]serotonin was not affected by either inhibitor.

Blood Platelets↗