[Phosphodiesterase inhibition as a new positive-inotropic principle].
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2,2'-Dipyridyl↗
Biomedical subjects
A Hartmann
Publications and source records attributed to A Hartmann.
Hypernatremia inhibits NaHCO3 reabsorption and associated NaCl reabsorption in dogs.
To examine the effect of selective rise of plasma NaCl concentration (hypernatremia) on NaHCO3 reabsorption and associated NaCl reabsorption remaining during continuous ethacrynic acid infusion, hypertonic NaCl solution was infused in three groups of anesthetized volume-expanded dogs. In six dogs examined at constant hematocrit and plasma pH, bicarbonate and water reabsorptions were inversely related to PNa and reduced by 37% and 39% respectively by raising PNa from 140 to 200 mM. Chloride reabsorption remained essentially constant until PNa exceeded 170 to 180 mM. At PNa 200 mM, sodium reabsorption was reduced by 22 +/- 6%. In six other dogs, mechanical variations of GFR showed that the inhibitory effects of hypernatremia (PNa 199 +/- 3 mM) were less pronounced at low GFR. After subsequent administration of acetazolamide (30 mg/kg body wt), only 20% of control bicarbonate reabsorption remained and glomerulo-tubular balance was completely abolished. Both hypernatremia and acetazolamide inhibited NaHCO3 and NaCl reabsorption in a molar ratio of about 1:2, as in normonatremic dogs. Finally, experiments in six dogs showed that the inhibitory effects of hypernatremia (PNa 213 +/- 4 mM) were not altered by varying PCO2 and plasma pH. We conclude that hypernatremia inhibits paracellular water and NaCl reabsorption in the proximal tubules by reducing the osmotic force caused by transcellular NaHCO3 reabsorption. A rise in PNa does not stimulate transcellular NaCl reabsorption during distal inhibition by ethacrynic acid.
Acetazolamide↗
Anti-idiotypic antibodies that inhibit immediate-type skin reactions in unsensitized monkeys on challenge with staphylococcal enterotoxin.
The staphylococcal enterotoxin B (SEB)-induced immediate-type skin reaction in unsensitized monkeys was used as a nonimmunological mast cell stimulus to examine whether the toxin exerts its effect via specific receptors on the target cell membrane. Anti-idiotypic antibodies (anti-Id) were raised in BALB/c mice against monoclonal anti-SEB antibodies (anti-SEB) and purified by idiotype affinity chromatography. The anti-Id nature of the antibody was demonstrated by its ability to inhibit the binding of 125I-labeled anti-SEB to the ligand in a concentration-dependent manner. Moreover, binding of anti-SEB to anti-Id was antagonized by the SEB ligand in a competitive way. These antibodies completely abolished skin reactions in unsensitized monkeys on challenge with SEB and impeded those provoked by staphylococcal enterotoxins A and C1 but did not have the biological activity of the toxin. These data are compatible with the view that receptors for staphylococcal enterotoxins may exist on the membrane of mast cells in the skin of unsensitized monkeys. The data suggest an experimental approach for producing anti-cell receptor antibodies that are of potential value to influence the course of staphylococcal enterotoxin-mediated effects.
Animals↗
Glomerulotubular balance during renal sympathetic stimulation.
In volume-expanded dogs receiving ethacrynic acid, a linear relationship, glomerulotubular balance (GTB), applies between the remaining sodium reabsorption and the glomerular filtration rate (GFR) during mechanical aortic constriction. To examine whether GTB applies during sympathetic stimulation, the GFR was progressively reduced by 70-75% in anaesthetized dogs by renal nerve stimulation, intrarenal norepinephrine infusion or by selective stimulation of alpha-adrenoceptors by intrarenal methoxamine infusion. Linear relationships (GTB) were obtained (r greater than 0.9). Reabsorption was not different during the various kinds of sympathetic stimulation, but less than during aortic constriction; the largest difference in NaCl reabsorption at comparable GFR amounted to 10-15% and was obtained 30-40% below control GFR, whereas inhibition of NaHCO3 reabsorption was uncertain. To inhibit NaHCO3 reabsorption and associated NaCl reabsorption in the proximal tubules, acetazolamide (30 mg kg-1) was administered instead of ethacrynic acid. No difference in reabsorption was observed at comparable GFR during norepinephrine infusion and mechanical aortic constriction. Hence, GTB applies during sympathetic stimulation. Compared with data obtained during aortic constriction, alpha-adrenergic stimulation reduces proximal reabsorption of NaCl and, possibly, NaHCO3 and exerts no effect on distal transcellular NaCl reabsorption.
Acetazolamide↗
Regulation of nitrogenase activity by ammonium chloride in Azospirillum spp.
Ammonium chloride (greater than or equal to 0.05 mM) effectively and reversibly inhibited the nitrogenase activity of Azospirillum brasilense, Azospirillum lipoferum and Azospirillum amazonense. The glutamine synthetase inhibitor L-methionine-DL- sulfoximine abolished this "switch-off" in A. lipoferum and A. brasilense, but not in A. amazonense. Azaserine, an inhibitor of glutamate synthase, inhibited nitrogenase activity itself. This provides further evidence for glutamine as a metabolite of regulatory importance in the NH4+ switch-off phenomenon. In A. brasilense and A. lipoferum, a transition period before the complete inhibition of nitrogenase activity after the addition of 1 mM ammonium chloride was observed. The in vitro nitrogenase activity also was decreased after treatment with ammonium. During sodium dodecyl sulfate-polyacrylamide gel electrophoresis, a second dinitrogenase reductase (Fe protein) subunit appeared, which migrated in coincidence with the modified subunit of the inactive Fe protein of the nitrogenase of Rhodospirillum rubrum. After the addition of ammonium 32P was incorporated into this subunit of the Fe protein of A. brasilense. In A. amazonense, the inhibition of nitrogenase activity by ammonium was only partial, and no transition period could be observed. The in vitro nitrogenase activity of ammonium-treated cells was not decreased, and no evidence for a modified Fe protein subunit was found. Nitrogenase extracts of A. amazonense were active and had an Fe protein that migrated as a close double band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
Ammonium Chloride↗
Is there a need for alternative approaches in the therapy of cerebrovascular disorders?
Acute ischemia of the brain induces a cascade of biochemical and physiological events. The final consequences depend on the fact whether ischemia is of transient or permanent, total or partial nature. Alteration of extracellular potassium concentration, intracellular calcium and potassium concentration, development of cytotoxic and vasogenic edema, postischemic hyperfusion and no-reflow phenomenon are important factors which decide about the final fate of functional capacity. CO2 reactivity, autoregulation and hemorheology must be considered when therapeutic approaches are used to influence basic flow during ischemic condition. At present there exists no therapy which has been fully accepted and is able to guarantee benefit to the hypoperfused tissue. Since the calcium metabolism is altered by ischemic processes, substances which act on this metabolism might be of value in the treatment of ischemia and its consequences. However, their beneficial effect on cerebral infarction has not been proven yet. In subarachnoid hemorrhage and migraine calcium antagonists are used to prevent and treat ischemia. In epilepsia calcium overload blockers have been tried by one group with promising results.
Acute Disease↗
Effect of flunarizine on regional cerebral blood flow in common and complicated migraine. Pilot study.
Alterations of regional cerebral blood flow (rCBF) are at least epiphenomena of common and complicated migraine, but may lead to serious clinical complications. Since flunarizine seems to be effective in migraine prevention it may exert a beneficial influence on rCBF in migraine as well. rCBF was assessed using the 133Xe inhalation method in 5 patients with common and 8 patients with complicated migraine. Measurements were done interictally prior and after therapy with 15 mg flunarizine p.o. daily over a period of 4 weeks. Major abnormalities of grey matter flow were observed even interictally. Significant improvement of rCBF in initially hypoemic regions may be attributed to flunarizine therapy. These preliminary data suggest that calcium entry blockers may prevent the ischemic complications of migraine.
Brain↗
Cell cycle-dependent initiation of adenosine triphosphatase-deficient populations in adult rat liver by a single dose of N-methyl-N-nitrosourea.
Changes in the sensitivity of hepatocytes to initiation during the cell cycle were investigated in partially resected hydroxyurea-synchronized regenerating rat liver. At defined periods of the cell cycle the animals were given injections of a single dose of N-methyl-N-nitrosourea (MNU) (25 mg/kg) and were subsequently exposed to diethylnitrosamine for 30 days (2 mg/kg/day) or to phenobarbital (0.05% in the diet) for 80 days. Adenosine triphosphatase-deficient cell populations in the liver, determined 90 days after MNU treatment, served as a marker for the initiating action of the carcinogen. Few foci were observed when MNU treatment was performed during early G1. Their frequency increased steeply after MNU injection at G1-S boundary and reached a maximum after carcinogen exposure in early S phase, when the number of adenosine triphosphatase-deficient foci was higher by a factor of 5 (after diethylnitrosamine feeding) or 10 (after phenobarbital feeding) than after MNU exposure in early G1 phase. A rapid decline was observed in middle S phase. The frequency of altered foci after MNU in late S phase and during G2-M was in the same range as in early G1. Their size distribution was similar in all groups. The results confirm and extend earlier observations of an increased initiating effect of a carcinogen during liver regeneration. Under in vivo conditions, hepatocytes are, after HU synchronization, at the highest risk of being initiated by a carcinogen when they traverse the early S phase of the cell cycle.
Adenosine Triphosphatases↗
Assessment of regional cerebral blood flow with 123I amphetamine single photon emission computed tomography in cerebrovascular disease. Semiquantitative analysis comparing IMP SPECT with the 133Xe inhalation method.
To compare the capacity of three-dimensional IMP single photon emission computed tomography (SPECT) with that of the two-dimensional 133Xe method in detecting focal perfusion abnormalities in cerebrovascular disease, flow measurements were performed with both methods in twenty patients. In order to enable correlation with 133Xe regional cerebral blood flow (rCBF) IMP SPECT images were subdivided into areas extending from the outer to the inner part corresponding to 32 regions of the 133Xe Cerebrograph. Between IMP counts/pixel and 133Xe rCBF, inter-hemispheric ratios correlated better in severe ischemia. Absolute mean values correlated in the affected hemisphere but not in the unaffected hemisphere. Regional evaluations revealed tendencies of IMP SPECT to be sensitive for low flow areas but to underestimate high flow areas, i. e. the 'luxury perfusion syndrome', as compared with the 133Xe method.
Amphetamine↗
Hyperfrontal distribution of regional cerebral blood flow and vascular CO2 reactivity in normal subjects and disturbances in ischemic cerebrovascular disorders.
The distributions of regional cerebral blood flow (rCBF) and CO2 reactivity were estimated in normal subjects and in patients with ischemic cerebrovascular disorders, using the 133Xe inhalation method. In the normals, hyperfrontal and hyper-fronto-parietal distributions of rCBF and CO2 reactivity were observed. In the patients, the differences in mean rCBF values between anterior and posterior regions decreased in the affected hemisphere. Comparison between the hemispheres revealed that the anterior regions had a decreased mean rCBF value in the affected hemisphere. The CO2 reactivity in the patients was generally decreased in both hemispheres, but not significantly. The originally existing, different distributions of rCBF and CO2 reactivity in normals must be considered in the evaluation of disturbances of vascular reactivity in patients with cerebral disorders.
Adult↗
Renal Na,K-adenosine triphosphatase transport rate limits transcellular NaCl reabsorption in distal nephrons of volume-expanded dogs.
To examine whether the adenosine triphosphatase (Na,K-ATPase) transport rate regulates transcellular NaCl reabsorption, experiments were performed on anesthetized volume-expanded dogs. Ouabain was injected into the renal artery in doses inhibiting 10 to 80% of the renal Na,K-ATPase activity. Acetazolamide was administered before ouabain to render the NaHCO3 reabsorption and associated NaCl reabsorption constant during variations in the glomerular filtration rate. Ouabain reduced sodium reabsorption significantly after inhibiting 20% of the Na,K-ATPase. By inhibiting 80% of the Na,K-ATPase, NaCl reabsorption was reduced by 40 to 50% without affecting NaHCO3 reabsorption. During mechanical constriction of the suprarenal aorta, the remaining NaCl reabsorption was constant until the glomerular filtration rate was lowered by about 50%. Bound ouabain and the remaining Na,K-ATPase activity were distributed between the cortex and medulla in proportion to the Na,K-ATPase activity before ouabain injection. The reduction in NaCl reabsorption and ouabain binding were correlated (r = 0.90), the slope suggesting a turnover for ATP similar to the in vitro turnover of 5700 ATP min-1 estimated from the relationship between the remaining Na,K-ATPase activity and bound ouabain (r = 0.95). We conclude that transcellular reabsorption of NaCl in the distal nephron reaches a maximum in volume-expanded dogs by saturating the sodium sites of Na,K-ATPase because even a small dose of ouabain inhibits NaCl reabsorption and because the calculated turnover for Na,K-ATPase activity is similar to in vitro maximum estimates. The Na,K-ATPase transport rate, therefore, limits transcellular NaCl reabsorption in volume-expanded dogs.
Absorption↗
A comparative study of the brain uptake and early kinetics of 99mTc-dl HM-PAO and other PnAO derivatives in baboons.
Derivatives of propylene-amine-oxime (PnAO) have been synthesized which form a neutral lipid-soluble complex with 96mTc and can be supplied as freeze-dried kits. The complexes cross the intact blood-brain barrier. This report shows the brain uptake, early kinetics and biodistribution in normal adult baboons of 5 99mTc-PnAO derivatives and 2 isomers of one of the tested derivatives (HM-PAO). The brain uptake of the favoured dl-isomer of HM-PAO reaches its maximum of 4.3% (whole brain/whole body) 1 min p.i. and a clearance of less than 8% was observed 23 min p.i.
Animals↗
[Comparison of an ionic (ioglicinate) with a non-ionic (iohexol) contrast medium in renal computed tomography].
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Adult↗
Analysis of proliferative compartments in human tumors. II. Seminoma.
Growth pattern and cell kinetics of 12 human seminomas were determined by means of vascular organ perfusion after orchiectomy. The arteria testicularis of the tumor-bearing testis was perfused up to 5 hours with dextran-diluted blood under normothermic and normotonic, simulated physiologic conditions. At defined periods, the specimen was exposed to tritiated and/or carbon 14-labeled thymidine. Autoradiograms prepared of whole tumor sections revealed a dependence of growth pattern on the stage of development. A homogeneous distribution of DNA synthesizing seminoma cells was found in small tumor foci. With increasing size, the zone of proliferation shifted to the periphery of the nodule giving rise to nodular subpopulations of high proliferative activity. In nodules of a diameter of more than about 2 cm the growth compartment consists of a highly proliferating invading cell layer at the edge of the tumor and intratumoral patches of proliferating cells near the vascular stroma. The largest part of the tumor remains at this stage in a quiescent state (G0). The mean labeling index of the seminoma cells was 11.6 +/- 1.4%, with the highest values found immediately adjacent to tumor vessels. High mitotic activity in an anaplastic seminoma was coupled with maximum labeling indices up to 41.9%. DNA synthesis time ts was 15.9 +/- 2.0 hours. The potential population doubling time for the proliferating fraction was in the range of 5 days. Lymphocytic infiltration reduced the proliferative activity in some parts, but was without effect in other areas of the seminoma. The seminoma is an example of a malignant human tumor with a rather regular growth pattern: The distribution of the proliferating compartment appears less dependent on cytologic or histologic structure, but more on tumor geometry and size.
Adult↗
Effect of dexamethasone on serum protein extravasation in experimental brain infarcts of monkey: an immunohistochemical study.
Experimental brain infarcts were produced in 12 adult baboons (Papio cynocephalus) by transorbital permanent clipping of the left middle cerebral artery. One group (seven monkeys) received daily injections of 1 mg/kg dexamethasone, starting 1 h after vascular occlusion and continuing till the end of the experiment. Another group (five monkeys) was not treated. One week after vascular occlusion the volume of infarcts and peri-infarct edema was estimated morphometrically on histological sections, using Masson's trichrome stain and the peroxidase-anti-peroxidase (PAP) technique for visualization of serum protein extravasation. In the untreated animals the average volume of infarct was 6.57 +/- 4.23% (mean +/- SD) and the volume of edema 7.83 +/- 2.93% of ipsilateral hemisphere. In the treated animals the infarct volume was not different (7.95 +/- 3.00%), but the volume of peri-infarct edema was significantly lower (2.82 +/- 3.06%, p less than 0.05). The results obtained indicate that dexamethasone treatment reduces the development of peri-infarct edema but does not influence the size of infarcts.
Animals↗
Dependency of renal potassium excretion on Na,K-ATPase transport rate.
Potassium secretion may depend on the transport rate of Na, K-ATPase in basolateral cell membranes of distal tubular cells. To examine this hypothesis experiments were performed in anaesthetized dogs during inhibition of proximal potassium reabsorption by acetazolamide or mannitol (fractional potassium excretion 1.2 - 1.4) or additional stimulation of potassium secretion by ethacrynic acid (fractional potassium excretion 2.1). Ouabain in a dose which inhibits 70-80% of the Na, K-ATPase activity reduced fractional potassium excretion to 0.8 - 0.9 by an effect on distal tubular secretion since potassium transport in the proximal tubules was not affected. Ouabain-sensitive potassium excretion varied in proportion to ouabain-sensitive sodium reabsorption during variation in glomerular filtration rate, even at urinary sodium concentrations exceeding 80 mmol X 1(-1). In experiments without ouabain, saline infusion raised potassium excretion and sodium reabsorption until maximal Na,K-ATPase transport rate was reached, as judged from heat production measurements, but not during further increments in urine flow. After inhibition of Na,K-ATPase activity by hypokalaemia, potassium excretion and cortical heat production remained constant over a wide range of urine flow and sodium excretion. We conclude that potassium secretion is dependent on intact Na,K-ATPase activity and is stimulated by sodium delivery to the distal nephron until maximal transport rate of the enzyme is reached.
Animals↗
Purification and properties of the nitrogenase of Azospirillum amazonense.
The nitrogenase of the free-living, microaerobic, N2-fixing bacterium Azospirillum amazonense (strain Y1) was purified by chromatography on DEAE-52 cellulose, by heat treatment, and by preparative polyacrylamide gel electrophoresis. The specific nitrogenase activities were 2,400 nmol of C2H4 formed per min per mg of protein for dinitrogenase (MoFe protein) and 1,800 nmol of C2H4 formed per min per mg of protein for dinitrogenase reductase (Fe protein). The MoFe protein was composed of a minimum of 1,852 amino acid residues, had an isoelectric point of 5.2, and contained 2 atoms of Mo, 24 atoms of Fe, and 28 atoms of acid-labile sulfide per molecule. The Fe protein had 624 amino acid residues and an isoelectric point of 4.6 and contained four atoms of Fe and six atoms of acid-labile sulfide per molecule. The purified MoFe protein showed two subunits with molecular weights of 55,000 and 50,000. The purified Fe protein revealed two polypeptides on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with apparent molecular weights of 35,000 and 31,000. The two Fe protein polypeptides were demonstrated with immunological techniques in the purified, highly active enzyme as well as in extracts. Also, Azotobacter vinelandii Fe protein showed two closely migrating polypeptides that migrated differently from the Fe protein polypeptides of Azospirillum brasilense or Rhodospirillum rubrum. The nitrogenase activity of Azospirillum amazonense Y1 was independent of Mn2+, and the addition of activating enzyme had no effect. No activating enzyme could be found in Azospirillum amazonense. Obviously, the nitrogenase system of Azospirillum amazonense Y1 is different from that of Azospirillum brasilense Sp7 and resembles the Azotobacter system.
Amino Acids↗
Comparative randomized study of cerebral blood flow after long-term administration of pentoxifylline and co-dergocrine mesylate in patients with chronic cerebrovascular disease.
The behaviour of regional cerebral blood flow was studied in 90 patients with vascular type dementia. Patients were divided at random into three groups of 30 and treated 3-times daily over a period of 8 weeks with either 400 mg pentoxifylline ('Trental' 400) or 2 mg co-dergocrine mesylate, or remained untreated (control group). Measurements of regional cerebral blood flow were made before and after 4 and 8 weeks of the study using an atraumatic inhalative 133Xenon clearance technique and assessments made in 16 regions of interest per hemisphere (grey matter perfusion). A statistically significant increase over baseline in mean regional cerebral blood flow was found in patients on pentoxifylline medication at Weeks 4 and 8. At Week 8, the change from baseline was +16.4% in the pentoxifylline group whereas the respective values for the other two groups were +0.4% for co-dergocrine mesylate, -2.4% for the controls. Hypoemic regions showed the most pronounced regional cerebral blood flow changes with pentoxifylline (+40%), the corresponding values for the co-dergocrine mesylate and control group being +10.8% and +0.4%, respectively.
Aged↗