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Biomedical subjects

G Zimmer

Publications and source records attributed to G Zimmer.

At least 127 records · Page 7Linked to original sources
PubMed1989

Avoiding reperfusion injury after limb revascularization: experimental observations and recommendations for clinical application.

This study tests the hypothesis that reperfusion injury is the principal cause of limb loss after acute arterial occlusion and that this injury is avoidable. Of 61 isolated hindlimbs amputated at the level of the hip joint, 17 were controls (group I), 5 were perfused without ischemia to establish the validity of the model (group II), and 15 underwent 4 hours of ischemia at room temperature without reperfusion (group III). Acute embolectomy was simulated in 24 limbs after 4 hours of ischemia; 12 were reperfused with standard Krebs-Henseleit solution at 100 mm Hg (group IV), and 12 were reperfused under controlled conditions (i.e., 37 degrees C, 50 mm Hg) with substrate-enriched modified reperfusate (group V). Leg volume, water content, contractile function, and high-energy phosphate content were assessed and data were expressed as mean +/- SD. Four hours of ischemia caused a profound fall in adenosine triphosphate content (4.0 vs 26.0 mmol/L/gm of protein, p less than or equal to 0.001). Uncontrolled reperfusion resulted in severe reperfusion injury; massive edema developed (83% vs 75%, p less than or equal to 0.01), leg volume increased markedly (21.5% above control, p less than or equal to 0.001), and no contractile function followed electrical stimulation. In contrast, controlled reperfusion resulted in normal water content (76.9% vs 75.0%, NS) and minimal change of leg volume (5.5% +/- 5% of control, NS), replenished adenosine triphosphate completely (24.2 vs 26.4 mmol/L/gm of protein, NS), and restored immediate contractile function in all limbs (24.3% +/- 14% of control). This study shows that 4 hours of room-temperature ischemia (18 degrees C) does not produce irreversible damage of the rat hindlimb because the reperfusion injury that follows uncontrolled reperfusion can be avoided. Immediate recovery of contractile function can be restored if the conditions of reperfusion are controlled by gentle reperfusion pressure (50 mm Hg) at 37 degrees C and if a modified substrate-enriched, hyperosmotic, alkalotic, low-Ca++ reperfusate is administered.

Adenine Nucleotides↗
PubMed1988

Spontaneous sister chromatid exchange in normal bone marrow and Ph-positive chronic myelocytic leukemia.

The frequency of spontaneous sister chromatid exchange was studied in normal marrow derived from 38 healthy donors and 40 untreated patients with chronic phase CML. The sister chromatid exchange frequency was significantly lower in the leukemic cells (range, 2.32 +/- 1.31 to 4.76 +/- 2.37 per metaphase; mean, 3.18 +/- 0.49) than in normal marrow (range, 2.36 +/- 1.44 to 5.54 +/- 2.24 per metaphase; mean, 3.92 +/- 0.72). The contraction status of chromosomes was comparable in normal and Ph-positive metaphases. The reduction of sister chromatid exchange in leukemic cells was seen in all chromosome groups. The analysis of cell cycle specific proliferation according to the typical staining patterns of metaphases due to the number of cell cycles during which bromodesoxyuridine was substituted, revealed longer cell cycle times for the leukemic cells.

Adolescent↗
PubMed1988

Mitochondrial sulfhydryl groups under oligomycin-inhibited, aging, and uncoupling conditions: beneficial influence of cardioprotective drugs.

Uncoupling, oligomycin-inhibited, and aging/swelling conditions comprise three models for mitochondrial dysfunction. In these models, the effects of cardioprotective agents on rat heart mitochondrial membrane -SH reactivity have been studied. For -SH detection two different chromophores were used: dithionitrobenzoate (NbS2) and monobromobimane (MB). The objective of this study is to reveal the influence of three cardioprotective substances against the loss of membrane -SH reactivity: (i) The thiol reagent 2-mercaptopropionylglycine (MPG) prevents the decrease of thiols caused by carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP), aging, and oligomycin measured with MB and NbS2, and the diminution by oleate detected with MB. The small amount of MPG (6 nmol/mg protein), necessary for the protection, agrees with oligomycin sensitivity of the -SH groups concerned. (ii) The active metabolite of molsidomine, 3-morpholinosydnonimine (SIN-1), protects against the decrease of thiols by FCCP, oleate, and aging monitored with MB. In the case of oligomycin -SH groups accessible to NbS2 are protected. (iii) Another antianginal drug, isosorbidedinitrate (ISDN) does not protect membrane thiol groups. In contrast to SIN-1, ISDN probably requires enzymatic activation. It is suggested that MPG as well as SIN-1 may help to restitute the original -SH status of the mitochondrial membrane.

Aging↗
PubMed1988

Reactivity of mitochondrial sulfhydryl groups toward dithionitrobenzoic acid and bromobimanes under oligomycin-inhibited and uncoupling conditions.

Thiol reactivity was determined in rat heart mitochondria using chromophores of differing polarities: monobromobimane (MB), dithionitrobenzoate (NbS2), and bromobimane-q (MQ). The purpose of this study is to correlate reaction rates of protein thiols in the mitochondrial membrane with the oligomycin-inhibited and uncoupled states: In all cases investigated the reactivity of -SH groups toward MB decreases under the above conditions. In parallel with an increase of their uncoupling activities the uncouplers reduce the reaction rate of thiol groups toward NbS2 and, progressively, toward MQ, indicating differences in sensitivity of thiol groups to uncouplers depending on the polarity of the environment. The pattern of -SH reactivity under inhibition by oligomycin resembles that of carbonylcyanide-p-trifluoromethoxyphenylhydrazone. Functional changes of the mitochondrial membrane probably correlate with reactivity/polarity changes of membrane -SH groups. Masking of membrane thiol groups thus is not specific for uncouplers but is also observed under inhibition with oligomycin.

Animals↗
PubMed1987

Prostaglandin E2 directly protects isolated rat gastric surface cell membranes against bile salts.

Rat gastric surface cell membranes were prepared and the effect of taurocholic acid assessed by ESR spectroscopy using the 16-doxylstearic acid spin label. Taurocholic acid increased the polar part of the spectra, indicating an augmented amount of spin label molecules with a polar environment. Concomitantly, mobility of the spin label molecule was augmented. The effect of taurocholic acid was completely prevented by the previous addition of prostaglandin E2. This suggests a direct protective efficiency of prostaglandin E2 on rat gastric surface cell membranes without the metabolic participation of intact cells.

Animals↗
PubMed1987

A multiparameter analysis of the perfused rat heart: responses to ischemia, uncouplers and drugs.

In perfused rat hearts alterations of aortic flow and mitochondrial membrane potential resulting from uncoupling of oxidative phosphorylation, hypoxia and treatment with a cardioprotective drug (2-mercaptopropionylglycine (MPG) have been studied. Mitochondrial membrane potential was followed by surface fluorimetry on DASPMI stained hearts. This fluorochrome specifically stains mitochondria in living cells; fluorescence intensity is related to the electrochemical gradient. Aortic flow turned out to be a much more sensitive indicator of heart function than ventricular pressure or mitochondrial membrane potential. No direct relationship exists between mitochondrial membrane potential and ATP production under the different metabolic conditions. Two phases of hypoxic mitochondrial damage have been deduced: the first results in derangement of ATP synthases while membrane potential is maintained, the second in irreversible damage of mitochondrial membranes with loss of membrane potential.

Adenosine Triphosphate↗
PubMed1987

Free radical scavenging drugs, assessed by ESR studies: influence of hemoglobin.

To monitor free radical scavenging properties of drugs, the 'stable' radical 2,2,6,6-tetramethylpiperidino-1-oxyl (TEMPO) was used. The sydnonimine molsidomine (SIN-1) effectively reduced the ESR signal whereas the nitrate isosorbidemononitrate (ISMN) did not. Thiol reagents like 2-mercaptopropionylglycine (MPG) or glutathione (GSH) only were effective in the presence of Fe2+ or Fe3+. Protein-bound iron in hemoglobin proved about four times more effective in reducing ESR signal height by thiols. It is suggested that the decrease in thiol content adds to the lack in protein bound iron of hemoglobin to induce the burst of free radicals in hypoxia (ischemia) and reperfusion.

Cyclic N-Oxides↗
PubMed1987

Improvement of myocardial function after global hypoxia by protection of the inner mitochondrial membrane.

In the present study the hypothesis is tested that hypoxia causes morphological damage to the inner mitochondrial membrane and that this damage can be reversed by modification of the reoxygenated perfusate. Using the working rat heart model, hearts in group I (n = 40) were subjected to a 30 min normothermic, normoxic phase and a 90 min hypoxic phase, followed by 60 min reoxygenation. Hearts in group II (n = 32) were also subjected to a 30 min normoxic and a 90 min hypoxic phase. However, after 30 min of reoxygenation 1.5 mmol/l 2-mercaptopropionylglycine (MPG) was injected in the reoxygenated solution in order to test its ability to improve mitochondrial function. Mitochondrial function was assessed by measuring oxygen uptake (ST3), ST4, respiratory control index (RCI), ADP/O and oxidative phosphorylation rate (OPR). In addition mechanical function (heart rate, aortic and coronary flow, cardiac output, stroke volume) was monitored along with ultrastructural parameters. 90 min of hypoxia caused a deterioration of all parameters with persistent impairment in hemodynamic, morphologic and biochemical functions after 60 min of reoxygenation (group I). The role of the ATP-synthetases in the pathogenesis of oxygen-paradox is discussed. In contrast, the MPG-enriched reoxygenated solution (group II) improved hemodynamics, ultrastructure and mitochondrial function significantly (alpha = 0.05). It is concluded from these data that the ATP-synthetases are damaged during oxygen-deficiency and that MPG may be a useful drug for protecting the inner mitochondrial membranes during reoxygenation.

Adenosine Diphosphate↗
PubMed1987

A novel cardioprotective regimen for improvement of inner mitochondrial membrane function after ischemic stress.

Treatment of the normoxic working rat heart with 1 mmol/l 2-mercaptopropionylglycine (MPG) results in a significant increase of postischemic aortic flow. Measurement of N,N-dimethylaminostyrylmethylpyridinium iodide (DASPMI) fluorescence on the surface of the heart preparation gives semiquantitative information on mitochondrial energization in situ. No differences in fluorescence have been found between therapy and control groups. This finding is confirmed by fluorescence studies on isolated mitochondria. Investigations on postischemic mitochondrial oxygen consumption and ATPase clearly reveal ameliorated function of oxidative phosphorylation and reduced ATP splitting activity by MPG treatment. Mitochondrial energization (i.e. membrane potential) thus does not run strictly parallel with oxidative and phosphorylative capabilities.

Adenosine Triphosphatases↗
PubMed1986

31P-NMR spectroscopic investigations and mitochondrial studies on the cardioprotective efficiency of 2-mercaptopropionylglycine.

Contents of high energy phosphates in the isolated perfused rat heart were followed during ischemia and reperfusion using 31P NMR spectroscopy. Application of 2-mercaptopropionylglycine resulted in significantly higher content of ATP in the reperfusion phase whereas during ischemia no differences between control and therapy hearts were found. Analysis of postischemic mitochondrial function reveals that improved ATP level is paralleled by an increased respiratory control index and a reduced ATPase activity. It is suggested that 2-mercaptopropionylglycine may cause increase of high energy phosphates during reperfusion by improving mitochondrial oxidative phosphorylation.

Adenosine Triphosphatases↗
PubMed1986

ATP synthase complex from beef heart mitochondria. Separation of protein bands in the region of 28-31 kDa.

ATPase/ATP synthase preparations originally contain protein bands in the 28-31-kDa region. The present study demonstrates separation of the band at 29 kDa (adenine nucleotide translocator) from a band at approximately 31 kDa. In cholate/ammonium sulfate-extracted ATP synthases removal of the 31-kDa band results in decrease of ATP-Pi exchange and oligomycin sensitivity of the ATPase activity. It is suggested that the protein band at 31 kDa is heterogeneous, containing diverse activities, the identities of which are yet to be determined.

Adenosine Triphosphatases↗
PubMed1986

On the interaction between anthralin and mitochondria: a revision.

Anthralin is an inhibitor of oxidative phosphorylation at concentrations found in vivo. ADP-stimulated oxygen consumption is diminished. Consequently, the rate of ATP synthesis is reduced and mitochondrial ATP content declines. Neither the isolated ATPase (F1F0-ATPase), nor the mitochondrial membrane-bound ATPase are influenced by the drug. Respiration under resting conditions is not affected. The experimental data unequivocally indicate that anthralin is not an uncoupler of oxidative phosphorylation, as previously stated. Furthermore, the interpretation that respiratory deficiency induced in yeast strains by anthralin is a consequence of petite mutations has to be reconsidered. Under in vivo conditions, anthralin inhibits respiration per se. Our experiments, including the electron spin resonance spectroscopy, reveal that anthralin alters mitochondrial membrane structure and function simultaneously. A redox or free-radical mediated step may be involved. In consequence, inhibition of ATP production occurs which may become the limiting factor for increased cellular metabolism in psoriasis.

Adenine Nucleotides↗
PubMed1986

Effects of bepridil on heart mitochondrial membrane and the isolated rat heart preparation.

Bepridil (Cordium) was found to activate rat heart mitochondrial membrane-bound ATPase at concentrations of 10 nmol/l-10 mumol/l. By contrast, oligomycin-sensitive ATPase from beef heart mitochondria was inhibited at concentrations of 1-10 mumol/l. In both systems sensitivity toward the inhibitor oligomycin was reduced. Under the influence of the drug, RCR (coupling degree of electron transport to ATP synthesis), ST3 (oxygen uptake in presence of substrate and ADP) and OPR (oxidative phosphorylation rate, amount of ATP synthesized in mitochondrial metabolic state ST3) values are reduced, indicating partial inhibition of oxidative phosphorylation. At 0.25 mumol/l concentration of bepridil, in the isolated normoxic working rat heart preparation aortic flow was reduced to zero. No changes in oxidative phosphorylation parameters were found in mitochondria isolated from these preparations. In the isolated, working rat heart preparation bepridil at a concentration of 0.05 mumol/l reduced aortic flow to about 75% of its original value. In this preparation, no cardioprotective effects (neither on aortic flow nor on mitochondrial function) could be demonstrated during postischemic reperfusion. It is suggested, that in vitro mitochondrial activities of bepridil are not related to in vivo action of the drug.

Adenosine Triphosphatases↗
PubMed1985

2-Mercaptopropionylglycine and related compounds in treatment of mitochondrial dysfunction and postischemic myocardial damage.

Reversal of mitochondrial dysfunction caused by uncouplers of oxidative phosphorylation, diamide, ageing and ischemia was studied using 2-mercaptopropionylglycine (MPG) in reduced and oxidized (ox-MPG) forms and other SH compounds. Rat heart mitochondria and mitochondrial ATPase, OS-ATPase from beef heart and the isolated working rat heart preparation were examined. MPG and ox-MPG partly prevented and reversed mitochondrial uncoupling and improved deteriorated heart function. ATPase activities were decreased by MPG and ox-MPG in both types of preparation. Three mechanisms are probably involved in thiol action. These comprise alternatively and/or additively: a) SH/S-S interchange reactions; b) free radical scavenger function; c) polar-polar (apolar) interactions. This may contribute to improve oxidative phosphorylation which is considered as a result of recoupling damaged mitochondria by MPG.

Adenosine Triphosphatases↗
PubMed1985

Influence of molsidomine on thiol-groups of mitochondrial membranes.

The active metabolite of molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester, Corvaton), SIN-1 (3-morpholinosydnone imine), from 5 nmolar concentration onward, unmasks SH-groups of rat heart mitochondrial membranes. By comparison, the organic nitrate isosorbide dinitrate was found to mask the SH-groups of rat heart mitochondria. In beef heart mitochondria, both antianginal substances decrease SH-group reactivity but to a different extent. Unmasking of mitochondrial SH-groups also did no longer occur in aged rat heart mitochondria. These findings may explain previous observations that for the formation of the guanylcyclase activating metabolite no thiol is necessary in the case of molsidomine, whereas organic nitrates need extra thiol for activation of guanylcyclase.

Adenosine Triphosphatases↗
PubMed1984

An interspecies approach to the investigation of the red cell membrane glucose transporter.

Glucose transport differs in red cells of various species. The following sequence of transport velocities was found: man greater than newborn pig greater than rat, dog greater than cattle greater than pig. No correlation was found between the amount of protein in band 3 and glucose transport activity. By contrast, a very clear peak in the band 4.5 region was found for newborn pigs, whereas adult pigs did not exhibit a corresponding peak in the electrophoresis. Thus further evidence is provided by our investigations in favour of band 4.5 region for glucose transport activity in red cells.

Animals↗