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Biomedical subjects

M Rundgren

Publications and source records attributed to M Rundgren.

At least 73 records · Page 4Linked to original sources
PubMed1985

Mechanisms of N-acetyl-p-benzoquinone imine cytotoxicity.

N-Acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite of acetaminophen, rapidly reacts at physiological pH with glutathione (GSH) forming an acetaminophen-glutathione conjugate and stoichiometric amounts of acetaminophen and glutathione disulfide (GSSG). The same reaction products are formed in isolated hepatocytes incubated with NAPQI. In hepatocytes which have been treated with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) in order to inhibit glutathione reductase, the initial rise in GSSG concentration in the presence of NAPQI is maintained, whereas GSSG is rapidly reduced back to GSH in untreated hepatocytes. Oxidation by NAPQI of GSH to GSSG and the reduction of GSSG back to GSH by the NADPH-dependent glutathione reductase appear to be responsible for the rapid oxidation of NADPH that occurs in hepatocytes incubated with NAPQI in that the effect is blocked by pretreatment of cells with BCNU. When added to hepatocytes, NAPQI not only reacts with GSH but also causes a loss in protein thiol groups. The loss in protein thiols occurs more rapidly in cells pretreated with BCNU or diethylmaleate. Whereas both of these treatments enhance cytotoxicity caused by NAPQI, BCNU pretreatment has no effect on the covalent binding of [14C-ring]NAPQI to cellular proteins. Furthermore, dithiothreitol added to isolated hepatocytes after maximal covalent binding of [14C-ring]NAPQI but preceding cell death protects cells from cytotoxicity and regenerates protein thiols. Thus, the toxicity of NAPQI to isolated hepatocytes may result primarily from its oxidative effects on cellular proteins.

Acetaminophen↗
PubMed1984

The prostaglandin-analogue-9-deoxo-16,16-dimethyl-9-methylene-PGE2 inhibits the antidiuretic effect of vasopressin (AVP) in the conscious sheep.

The effects of intravenous infusions of the stable prostaglandin analogue 9-deoxo-16,16-dimethyl-9-methylene-PGE2 (9-methylene-PGE2) in a dosage of 10 or 24 micrograms/min were studied in the consicious euhydrated, dehydrated, and hyperhydrated with the simultaneous administration of exogenous arginine vasopressin (AVP), sheep. The infusions decreased urine osmolality and increased urine flow and renal free water clearance. The results indicate that 9-methylene-PGE2 exhibits its diuretic effect by antagonizing the antidiuretic action of AVP. In the hyperhydrated sheep receiving AVP the syndrome of inappropriate antidiuretic hormone release (SIADH) was simulated. As the prostaglandin analogue effectively blocked the antidiuretic effect of the AVP-administration it appears that 9-methylene-PGE2 may play a future role as a diuretic agent, especially in conditions characterized by water retention and dilutional hyponatremia such as SIADH.

16,16-Dimethylprostaglandin E2↗
PubMed1984

Vasopressin release in response to acute hypotension induced at different time intervals in the conscious sheep.

The renal arginine vasopressin (AVP) excretion in response to acute systemic hypotension induced by intravenous infusion of sodium nitroprusside (SNP) (30-40 micrograms/kg min-1) at different experiment intervals (0, 2, 4, 7 and greater than or equal to 12 days) was studied in the conscious hyperhydrated sheep. During the first post-infusion hour, 2.5 times more AVP was excreted in response to hypotension induced at greater than or equal to 12 day intervals than that observed at intervals of 0-7 days. No interexperimental time dependence of the AVP response to SNP infusion was seen with intervals of 0-7 days. The attenuated AVP release obtained with reduced experiment intervals (0-7 days) was accompanied by shorter antidiuresis and a less accentuated natriuresis during the post-hypotensive period in comparison to what was observed with greater than or equal to 12 day experiment intervals. There were no interval-dependent differences in maximal fall of mean arterial pressure, or onset and recovery of the hypotension induced by SNP administration. It is suggested that acute systemic hypotension causes such a massive AVP release that more than one week is needed for complete restoration of a releasable neurohypophyseal pool of the hormone.

Animals↗
PubMed1983

Some kinetic properties of 4-hydroxyphenylpyruvate dioxygenase from Pseudomonas sp. strain P.J. 874.

Steady-state kinetic properties of purified 4-hydroxyphenylpyruvate dioxygenase from Pseudomonas sp. strain P.J. 874 were examined by a 14CO2 method at pH 7.5 and 37 degrees C. The results conform to a mono-iso-ordered bi-bi mechanism with binding of 4-hydroxyphenylpyruvate before O2 and release of CO2 before homogentisate. A Theorell-Chance mechanism can not be excluded. The apparent DV and DV/Km ratios were about 1.1 and 1.2, respectively, for 4-hydroxy[2,6-2H2]phenylpyruvate when the initial O2 consumption was measured. The stoichiometry between the consumption of O2 and the formation of homogentisate and CO2 was 1:1:1. Loss of hydrogen at C2 or C6 of the ring of the substrate is thus not the rate-limiting step during the reaction. Instead, this appears to be the conversion of an isomerized enzyme form.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1982

Blue color, metal content, and substrate binding in 4-hydroxyphenylpyruvate dioxygenase from Pseudomonas sp. strain P. J. 874.

Purified preparations of 4-hydroxyphenylpyruvate dioxygenase from Pseudomonas sp. strain P. J. 874 are blue, epsilon 595-850 approximately 2.6 +/- 0.5 (n = 6) mM-1 cm-1. Iron and zinc were the only metals detected by x-ray fluorescence of an enzyme preparation and the mean content in different preparation as determined by atomic absorption spectroscopy was determined by atomic absorption spectroscopy was 0.95 +/- 0.17 (n = 6) and 0.68 +/- 0.27 (n = 7) mol/mol 150-kilodalton tetramer, respectively. It is yet unclear if zinc is a contaminant or may be given a structural role. Results with iron chelators and reductants showed that the 595-nm absorbance is linked to enzyme-bound Fe3+ and that reduction of iron, which occurs concomitantly with disappearance of the color, is required for enzyme activity. The enol tautomer of 4-hydroxyphenylpyruvate appeared to form 2:1 a complex with enzyme-bound Fe3+, which may be the cause of the long known substrate inhibition of the enzyme. Iron chelation also seemed to be involved in the inhibition by other substrate analogues, i.e. substituted catechols and those with one phenolic hydroxyl group in ortho position to short carboxylic acid side chains. Together, substrate analogue, pH, and modification studies indicated that the tautomerizable keto group with a double bond in 3-4 position favors productive substrate binding to Fe2+ and a base with a pK alpha of approximately 6.4.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1982

Tritium isotope effects in the reaction catalyzed by 4-hydroxyphenylpyruvate dioxygenase from pseudomonas sp. strain P.J. 874.

Tritium isotope effects in the reaction catalyzed by 4-hydroxyphenylpyruvate dioxygenase (4-hydroxyphenyl-pyruvate:oxygen oxidoreductase (hydroxylating, decarboxylating), EC 1.13.11.27) from Pseudomonas sp. strain P.J. 874 were studied with 14C- and different 3H-labelled 4-hydroxyphenylpyruvate. Tritium of ring-2,6-3H2-labelled substrate was released into water in 1:2 stoichiometry to 14CO2 formation. The tritium release from ring-3,5-3H2- and side chain-3-3H1-labelled 4-hydroxyphenylpyruvate was low as compared with 14CO2 formation. The apparent tritium isotope effects were below two, as judged by comparison of 3H/14C ratios of 4-hydroxyphenylpyruvate and homogentisate. The ratios showed no dependence on oxygen concentrations between 1 and 21% in the gas phase. Thus, a tritium assay can be used to determine the activity of 4-hydroxyphenylpyruvate dioxygenase. Apparently, none of the substrate hydrogens is involved in any rate-limiting step up to the first irreversible step. enol-4-Hydroxyphenylpyruvate was excluded as the active substrate tautomer.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1982

Inhibition of 4-hydroxyphenylpyruvate dioxygenase from Pseudomonas sp. strain P.J. 874 the enol tautomer of the substrate.

Progressive inactivation of purified 4-hydroxyphenylpyruvate dioxygenase (4-hydroxyphenylpyruvate:oxygen oxidoreductase (hydroxylating, decarboxylating), EC 1.13.11.27) from Pseudomonas sp. strain P.J. 874 by enol-4-hydroxyphenylpyruvate was initially pseudo-first-order with respect to the remaining enzymic activity, as measured with an enol-borat assay at pH 7.5 and 37 degrees C. No inhibitory product was detected. Saturation kinetics suggests formation of a reversible complex prior to an inactivation event at the active site of the enzyme. The initial concentration of enol-4-hydroxyphenylpyruvate, which gave half-maximum inactivation, varied linearly with the assay concentration of ascorbate from 30 microM at zero (extrapolated value) to 0.8 mM at 20 mM ascorbate. The limiting rate constant for the inactivation increased linearly from 0.01 to 0.02 s-1 in this interval. Inhibition by ascorbate present during preincubations was partially relieved by enol-4-hydroxyphenylpyruvate. Inhibition by 1,2-dihydroxybenzene-3,5-disulfonic acid present during preincubations was prevented by ascorbate but not reversed by enol-4-hydroxyphenylpyruvate. The reductively-activated enzyme used keto-4-hydroxyphenylpyruvate as substrate for formation of 14CO2 and homogentisate. enol-4-Hydroxyphenylpyruvate was a noncompetitive inhibitor vs. keto-4-hydroxyphenylpyruvate with an intercept inhibition constant of about 40 microM when a 14CO2 assay was used. It is suggested that interaction of enol-4-hydroxyphenylpyruvate with enzyme-bound Fe3+, formed by autooxidation, caused the substrate inhibition of 4-hydroxyphenylpyruvate dioxygenase, long known to be relieved by a variety of reductants. The possible role for the inhibition mechanism in the regulation of tyrosine catabolism in vivo is discussed.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1982

On 4-hydroxyphenylpyruvate dioxygenase of adult frog liver.

1. It has been reported that 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27) activity in the liver from Rana esculenta is present only after autolysis of trypsin digestion, which releases a heat-and acid-stable inhibitor of low molecular mass. 2. Attempts to demonstrate similar effects with the liver enzyme from adult Rana pipiens were unsuccessful. Trypsin had only an inhibitory effect on the enzyme activity in crude extracts. 3. Both untreated and trypsin-treated enzyme had a molecular mass of about 100,000 daltons as determined by gel filtration. The pI was around pH 4.6. One pH-optimum between pH 7 and 8 was observed. 4. At pH 7.5 and 37 degrees C the basal enzyme activity was 1.3 mumol/min per g of protein. It was increased six-fold by a reductant in the presence of catalase. Fe2+ (50 muM) increased the activity further 1.6-fold when the reaction was carried out in Tris-HCl buffer, but not in potassium phosphate buffer. 5. The Km for 4-hydroxyphenylpyruvate was 50 muM and the Vmax was around 10 mumol/min per g of soluble protein with reductively activated enzyme. 6. Substrate inhibition was observed above 20 muM concentrations of 4-hydroxyphenylpyruvate.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1982

Potentiation of antidiuretic response to systemic angiotensin II by elevation of CSF NaCl concentration.

The antidiuretic effect of the simultaneous intracerebroventricular (ICV) infusion of 0.24 M NaCl (0.02 ml/min) and intravenous (i.v.) infusion of angiotensin II (12 ng/kg X min) was studied in hydrated goats, and was compared to the antidiuretic effects of the separate infusions. The combined infusions inhibited the water diuresis for 30 min, whereas the separate infusions only reduced the water diuresis by 25% (ICV NaCl) and by 50% (i.v. angiotensin). The combined infusions increased the urine osmolality on the average by 415%. Corresponding increases induced by ICV NaCl and by i.v. angiotensin were 100 and 160%. The results suggest that systemic angiotensin II and elevated CSF NaCl concentration interact and potentiate each other as stimuli for antidiuretic hormone secretion. It is postulated that this synergism may help to preserve body water in hypovolemic conditions associated with hyperactivity of the renal renin-angiotensin system.

Angiotensin II↗
PubMed1982

Effects of hemorrhage on vasopressin secretion and arterial blood pressure during experimental diabetes insipidus in goats.

The effect of hypotensive hemorrhage on plasma vasopressin (AVP) concentration and carotid blood pressure before and after induction of experimental diabetes insipidus (DI) was studied in the conscious goat. Bleeding to the point of blood pressure fall (blood loss 15-25% of the estimated blood volume) caused an immediate, approximately hundred fold, increase in the plasma AVP concentration in the normal animal. Hemorrhage to the same extent during DI did not affect the plasma AVP levels. A rather transient hypotensive response to bleeding was seen before disruption of the pituitary stalk, but during DI the recovery of the hemorrhage-induced hypotension was less effective. However, the normalization of the blood pressure after bleeding was slightly more efficient during the permanent than during the temporary phase of DI. It is concluded that an intact hypothalamo-neurohypophysial connection is necessary for the massive release of AVP normally seen in response to hypotensive hemorrhage. It is also confirmed that the lack of this hormonal response to bleeding is accompanied by an increased susceptibility to the hypotensive effect of hemorrhage.

Animals↗
PubMed1982

Vasopressin release in response to intracerebroventricular L-alanine and L-arginine, and its dependence upon CSF NaCl concentration.

Influences on renal water, electrolyte, and arginine vasopressin (AVP) excretions of 1 h infusions (20 microliters/min) of a neutral (L-alanine) and two basic (L-lysine and L-arginine) amino acids into the lateral cerebral ventricle were studied in hydrated goats, and were compared to effects of control infusions of hypertonic (0.25 M) NaCl. L-alanine (0.11 M) dissolved in hypotonic NaCl caused more pronounced inhibition of the water diuresis and greater increase in AVP excretion than did the control infusions, but, in comparison to the latter, the responses developed very slowly. The effects were further delayed and were much attenuated when L-alanine was administered in isotonic glucose, but became considerably accentuated when isotonic NaCl was used as the solvent. L-lysine (0.09 M) in hypotonic NaCl did not inhibit the water diuresis or cause any apparent AVP release, whereas the corresponding L-arginine infusions caused inhibition of the water diuresis and increase in AVP excretion of approximately the same magnitudes and time courses as the control infusions. Like for L-alanine, these effects became accentuated when L-arginine was dissolved in isotonic NaCl, and became delayed and much attenuated when isotonic glucose was used as the solvent. L-arginine induced a more pronounced increase in renal Na excretion than did L-alanine and 0.25 M NaCl. Since transport together with Na (increasing the Na influx) generally is much more important for cellular uptake of neutral than of basic amino acids, the possibility is discussed that L-alanine here might have caused AVP release by increasing transmembrane Na transport of juxtacerebroventricular Na sensors regulating the AVP secretion--a suggestion supported by the lack of response to the basic L-lysine. The antidiuretic effect of the other basic amino acid, L-arginine, can not be explained along this line. However, with regard to the characteristic differences observed between the responses to L-alanine and L-arginine, the possibility is discussed that the latter might not have acted at a sensory level, but on the final neuronal link in the release of neurohypophyseal hormones, the hypothalamic neurosecretory cells. In contrast to L-alanine and L-arginine, L-lysine appeared to stimulate the appetite of the goats.

Alanine↗
PubMed1982

Regulation of water intake.

Here we have reviewed mainly the cerebral regulation of water intake and its relationship with the regulation of the water-retaining antidiuretic hormone (ADH). Much new information of obvious interest has been gained by experiments in conscious animals, by studies in healthy humans, and by clinical investigations. Of particularly great value has been the development of a sensitive radioimmunoassay for determination of plasma ADH (59). The sketchy picture that emerges in light of this new information is as follows. The osmotic regulation of water intake and ADH secretion is exerted by juxtacerebroventricular sensors apparently mainly located on the anterior border of the third ventricle. These sensors may be accessible both to CSF-borne and blood-borne stimuli and inhibitors, and their activity seems to be correlated to the Na concentration of the ECF rather than to its tonicity. A less sensitive volume regulation of water intake and ADH secretion is effectuated by cardiovascular distention and pressure receptors monitoring the effective circulating blood volume, and in severe volume depletion states also by the renin-angiotensin system (RAS). Afferent impulses from the cardiovascular receptors exert a tonic inhibition of the ADH release by acting upon its final neuronal link (the cells of the supraoptic and paraventricular nuclei). Afferent inflow from these receptors also inhibits thirst to some extent, perhaps by preventing at some synaptic level information from cerebral "thirst" sensors from reaching other parts of the brain where the information is converted into a conscious urge to drink. Therefore, increased cardiovascular receptor activity becomes manifested as elevated osmotic thresholds for ADH liberation and thirst. Severe volume depletion may induce RAS hyperactivity to such an extent that generated angiotensin II stimulates the ADH release and water intake. Demonstrated cerebral Na/angiotensin interaction suggests that this may occur via an angiotensin-induced lowering of the stimulus threshold for the sensors involved in the osmotic control of water balance. Cerebral damage affecting the sensors responsible for the osmotic regulation of water intake and ADH release may result in hypo- or adipsia associated with latent diabetes insipidus, and is apparently the ultimate cause of "essential" hypernatremia. This fragmentary outline of the cerebral control of water intake is based to a considerable extent upon circumstantial evidence, and is for that reason speculative on many points.

Drinking↗
PubMed1981

Drinking in goats as effect of simultaneous intravenous infusions of angiotensin (I or II) and hypertonic NaCl or mannitol.

Drinking during the simultaneous intravenous infusion of angiotensin I (AI) or II (AII) and hypertonic NaCl or mannitol was studied in the goat, and was compared to the dipsogenic responses to the separate infusion of each of these four factors. Approximately the same amount of water was drunk during the infusion of AI/NaCl, AI/mannitol and AII/NaCl. The amount was roughly equal to the sum of the amounts taken when each of two paired stimuli was infused separately. Significantly less water was drunk in response to AII/mannitol. Somewhat more water was drunk during the separate AI than during the separate AII infusion. Administration of an AI converting enzyme inhibitor completely abolished the AI contribution to drinking during the AI/NaCl infusion but did not reduce AII/NaCl drinking, indicating that the response to AI was entirely due to its conversion into AII. The possibility is discussed that the considerable difference between AI/mannitol and AII/mannitol drinking might have been the result of choroidal and/or ependymal AI converting enzyme activity.

Angiotensin I↗
PubMed1981

Protein evaluation of mixed diets. Comparative study in man and in the pig and rat of vegetable-animal and vegetable protein diets.

The procedure suggested by FAO/WHO to evaluate the protein quality of mixed diets has been tested using vegetable and vegetable-animal protein diets. Chemical scores were calculated and protein digestibilities were compared in human adult, growing pigs and rats. Pigs were studied as alternatives to rats in the protein evaluation of human diets. The results showed that the choice of the samples to calculate the chemical score is important; that the composition of the samples for biological evaluations must be considered in order to avoid experimental problems, and that values for true protein digestibility in human subjects, pigs and rats are in agreement, and further studies of growing pigs as an experimental model are suggested. Minor differences in protein quality of the two diets were demonstrated.

Adult↗