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Biomedical subjects

M Rundgren

Publications and source records attributed to M Rundgren.

At least 55 records · Page 3Linked to original sources
PubMed1990

N-acetyl-p-benzoquinone imine-induced changes in the energy metabolism in hepatocytes.

The effect of N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite of acetaminophen, on the energy metabolism in isolated hepatocytes was investigated. Incubation of cells with NAPQI (400 microM) resulted in an immediate uptake into the mitochondria, followed by both reduction and glutathione conjugation of the quinone imine. These reactions were extremely rapid and were associated with depletion of the mitochondrial ATP content (greater than 80% depletion after 1 min exposure). The loss of ATP was accompanied by increases in ADP and AMP, as well as NADP. No effect on mitochondrial NAD was observed during this initial phase. Similar alterations were produced by NAPQI in the cytosolic compartment. Furthermore, incubation of hepatocytes with NAPQI inhibited oxygen consumption by nearly 90% within 10 s. In parallel to these biochemical changes, there was marked bleb formation on the surface of the hepatocytes, which was found to precede cell death (trypan blue uptake). In conclusion, our results demonstrate that during exposure of hepatocytes to NAPQI, dramatic changes in cellular energy metabolism occur. These biochemical alterations may be caused by a rapid decrease in mitochondrial function, and they may play an important role in the initiation of NAPQI-induced cytotoxicity.

Adenosine Diphosphate↗
PubMed1990

Water intake and changes in plasma and CSF composition in response to acute administration of hypertonic NaCl and water deprivation in sheep.

Water intake and changes in plasma and cerebrospinal fluid (CSF) composition were measured in response to intracerebroventricular (i.c.v.) and intracarotid infusions of hypertonic NaCl solutions and after 48 h of water deprivation in sheep. Significant interindividual differences in dipsogenic sensitivity to i.c.v. NaCl were found, whereas no such differences were observed in response to intracarotid infusion of hypertonic NaCl. In the more sensitive animals, the increase in CSF [Na] at initiation of drinking during i.c.v. infusion did not differ significantly from the increase in plasma [Na] seen at the thirst threshold during intracarotid infusion of 1 M NaCl. The thirst-eliciting infusions of hypertonic NaCl into the carotid arteries were associated with a small, significant, increase in CSF [Na], which however did not differ from that caused by an i.c.v. non-dipsogenic 'control' infusion of a slightly hypertonic (0.154 M) NaCl solution. Water deprivation for 48 h induced increases in CSF and plasma [Na] similar to those observed at the onset of drinking in response to i.c.v. and intracarotid infusions of hypertonic NaCl. However, the dehydrated animals drank about four times the amount of water consumed in response to the separate treatments with hypertonic NaCl. It is concluded that significant interindividual differences in dipsogenic sensitivity to osmotic stimuli are present in sheep, and that these differences may not necessarily be simultaneously expressed on both sides of the blood-brain barrier. The thirst-eliciting effect of intravascular infusion of hypertonic NaCl may be induced without concomitant increase in CSF [Na] and/or osmolality.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effect of intracerebroventricular deuterium oxide on water intake and AVP release induced by intravenous infusion of angiotensin II in sheep.

The effect of intracerebroventricular (i.c.v.) infusion (0.02 ml min-1) of deuterium oxide (D2O), with NaCl added to isotonicity, on the water intake and arginine vasopressin (AVP) release caused by intravenous (i.v.) infusion of angiotensin II (AII) (4.8 nmol min-1) was studied in euhydrated sheep. The i.c.v. infusion of D2O, which started 80 min before commencement of the AII infusion, induced a water diuresis in four out of six animals and a measurable decrease in plasma AVP concentration. The i.v. infusion of AII effectively stimulated the AVP release and the response was unaffected by prior and simultaneous i.c.v. administration of D2O. However, the water intake measured 2 min after cessation of the AII administration was reduced by 50% when D2O was infused i.c.v. compared to that seen after simply the AII infusion. The inhibitory effect of D2O on AII-induced drinking disappeared rapidly after discontinuation of D2O administration. Compensatory increased drinking was seen during the first post-infusion hour, resulting in an equivalent cumulative intake of water at 60 min post-infusion in the two types of experiments. The present results support the idea that at least some of the cerebral effects of circulating AII on fluid balance are medicated via targets which are simultaneously accessible to influences from the blood and the cerebrospinal fluid.

Angiotensin II↗
PubMed1989

Effects of isosmotic and hyperosmotic glycine solutions on the fluid balance in conscious sheep.

Glycine 0.55 g.kg-1 was given as an isosmotic (285 mosmol.kg-1) and a hyperosmotic (approx. 3,000 mosmol.kg-1) solution by intravenous infusion during 30 min to six euhydrated ewes. Urine and blood samples were collected, and the distribution of the administered water between the intra- and extracellular fluids (ICF and ECF) was calculated for up to 150 min after the infusions. Both solutions produced an osmotic diuresis with a marked increase of the urinary excretion of sodium, potassium, and amino acids. A paradoxical increase of the plasma vasopressin concentration occurred from the isosmotic but not from the hyperosmotic glycine solution. At the end of the follow-up period, the isosmotic glycine solution had resulted in hyperhydration of the ICF and the hyperosmotic solution in dehydration of the ICF, whereas with both fluids, the ECF resumed the same volume as before the experiments.

Amino Acids↗
PubMed1989

Vasopressin responses during transurethral resection of the prostate.

The serum vasopressin (S-AVP) concentration, serum sodium concentration and osmolality, central venous pressure and fluid balance were measured during 10-min periods in 32 patients undergoing transurethral resection of the prostate. Concentration of S-AVP was unaffected by uncomplicated resection; irrigant absorption resulted in immediate increase in S-AVP concentration, but this increase could not explain the hypertension that occurred in some patients with absorption; a sudden decrease in the systolic arterial pressure was followed by a marked increase in S-AVP concentration; and extensive blood loss did not stimulate release of AVP, provided there was no associated arterial hypotension.

Aged↗
PubMed1989

Vasopressin and amino acid concentrations in serum following absorption of irrigating fluid containing glycine and ethanol.

Absorption of glycine solution during transurethral resection of the prostate (TURP) changes the serum concentrations of most non-essential amino acids and inhibits diuresis by stimulating release of vasopressin. Ethanol was used as a marker to detect the absorption of irrigant. Measurements of the serum concentrations of vasopressin and amino acids were made in eight patients with absorption volumes from 427 to 1906 ml. Ethanol did not alleviate the vasopressin response to glycine absorption, but changes in the amino acid concentrations in serum became less pronounced than when glycine alone was used.

Absorption↗
PubMed1989

Renal denervation does not prevent dehydration-induced natriuresis in sheep.

Normal sheep or sheep in which the renal nerves had been extirpated were deprived of water for 2 days in order to determine whether changes in renal nerve activity contribute to natriuresis during water deprivation. Both groups of sheep showed a considerable natriuresis throughout the period of water deprivation and increases in plasma osmolality and plasma Na concentration. Renal denervation, as indicated by the absence of catecholamine fluorescence in kidney sections, was extensive. Previous experiments have suggested cerebral involvement in the induction of dehydration-induced natriuresis. The present results indicate that the efferent pathway mediating this cerebral influence on renal sodium excretion does not involve the renal nerves, suggesting a hormonal mechanism as the likely pathway.

Animals↗
PubMed1989

Repeated hypotension induced by nitroprusside and haemorrhage in sheep: effects on vasopressin release and recovery of arterial blood pressure.

The arginine vasopressin (AVP) release in response to repeated hypotension caused by intravenous (i.v.) infusion of sodium nitroprusside (SNP) or haemorrhage was studied in conscious euhydrated sheep. Parallel determinations of renal excretion and plasma concentration of AVP were made in experiments involving two consecutive 10-min i.v. infusions of SNP (about 35 micrograms kg-1 min-1) with a 3-h interval between and repeated the next day. The AVP response to the second SNP administration was significantly reduced, but partial recovery was observed in response to the initial infusion the next day. Maximal fall in mean arterial blood pressure (MABP) and its recovery pattern did not differ in response to any of the four SNP infusions. In contrast, impaired recovery of the MABP together with markedly reduced AVP response was seen as a consequence of a hypotensive haemorrhage repeated after 3 h, but not when the interval between haemorrhages was extended to 24 h. The haemorrhage-induced increase in plasma renin activity was not affected by variations in the interval between experiments. It is concluded that the massive AVP liberation normally seen as an effect of acute isovolaemic hypotension becomes markedly reduced upon a renewed fall in the MABP occurring within 3 h. An iteration of hypotensive haemorrhage accentuates this fatigue of the hormonal response, which may contribute to the impaired recovery of the MABP.

Animals↗
PubMed1988

Effects of transport stress on concentrations of cortisol, corticosteroid-binding globulin and glucocorticoid receptors in pigs with different halothane genotypes.

Effects of stress on concentrations of cortisol and corticosteroid-binding globulin (CBG) in blood plasma and on glucocorticoid receptor concentrations in muscle cytosol were studied in pigs representing three Halothane (Hal) genotypes (NN, Nn, nn). At 12 wk of age, animals were divided into four groups: pigs subjected to transport (5 h in a truck), pigs treated with amperozide prior to transport, pigs not transported but treated with amperozide and pigs neither transported nor given amperozide. Animals were slaughtered the week they reached 100 kg live weight (3 mo later). The Hal gene showed no major influence on the variables studied except for cortisol concentrations (P = .06) measured directly after transport at 12 wk of age (NN = 66.8 nM, Nn = 61.4 nM, nn = 69.4 nM). However, the response in each Hal genotype differed, depending on whether or not the pigs had been exposed to transport. Two weeks after transport, NN pigs developed higher cortisol concentrations than untransported animals, whereas the response was reversed in nn animals; Nn pigs showed no difference in this regard. At slaughter, the effect of transport (12 wk of age) on cortisol and CBG was still apparent. In NN pigs cortisol and CBG concentrations were elevated (P less than or equal to .05, P = .08, respectively), whereas concentrations tended to be lower in nn pigs (P = .17, P = .07, respectively) when compared with untransported pigs. Transported pigs had lower receptor concentrations at slaughter (P less than or equal to .01) than untransported pigs. However, pigs given amperozide in connection with transport had a receptor concentration comparable to that in untransported pigs. Our study shows conclusively that transport stress had long-term effects on cortisol, CBG and glucocorticoid receptor concentrations. In addition, amperozide had long-term effects on cortisol and receptor concentrations.

Animals↗
PubMed1988

Comparative cytotoxic effects of N-acetyl-p-benzoquinone imine and two dimethylated analogues.

N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite of acetaminophen, has previously been shown to be toxic to hepatocytes freshly isolated from rat liver [Mol. Pharmacol. 28:306-311 (1985)] NAPQI arylates and oxidizes cellular thiols, and either one or both reactions may be important in the pathogenesis of cytotoxicity. Two dimethylated analogues of NAPQI, N-acetyl-3,5-dimethyl-p-benzoquinone imine (3,5-diMeNAPQI) and N-acetyl-2,6-dimethyl-p-benzoquinone imine (2,6-diMeNAPQI), were prepared to determine whether one reaction might be more damaging to cells than the other. Of the three quinone imines, the least potent cytotoxin to rat hepatocytes was 3,5-diMeNAPQI. However, the cytotoxicity of 3,5-diMeNAPQI was markedly enhanced by pretreatment of cells with 1,3-bis-(2-chloroethyl)-N-nitrosourea, which inhibits glutathione reductase. Reactions of 3,5-diMeNAPQI with GSH, both chemically and in hepatocytes, indicated that this quinone imine primarily oxidized thiols. These findings were corroborated by results of covalent binding experiments, which showed that radiolabeled 3,5-diMeNAPQI bound only to a small extent to hepatocyte proteins. On the other hand, 2,6-diMeNAPQI, the most potent cytotoxin of the three quinone imines that was investigated bound extensively to hepatocyte proteins. In addition, 2,6-diMeNAPQI reacted with GSH, both chemically and in hepatocytes, to form significant amounts of GSSG. Reduction products of NAPQI and its dimethylated analogues were not important contributors to cytotoxicity or GSSG formation based on the following results: 1) the quinone imines did not increase oxygen consumption by hepatocytes nor did they lead to oxygen uptake in solution; 2) dicoumarol, an inhibitor of the reductase, DT-diaphorase, had no effect on cytotoxicity caused by the quinone imines. Evidence for the involvement of ipso-adducts of the quinone imines in their reactions with cellular thiols is provided by results of investigations on the effects of DTT on the metabolism, covalent protein binding, and cytotoxic effects of the quinone imines.

Acetaminophen↗
PubMed1987

Influence of the Hal locus and standardized stress on antibody response and in vitro reactivity of peripheral blood lymphocytes in pigs.

The antibody response to two Escherichia coli antigens (O149 and K88) and the in vitro reactivity of peripheral blood lymphocytes (PBLs) to pokeweed mitogen was studied in growing pigs after exposure to varying degrees of stress. Three experimental groups were used; transportation by lorry, transportation by lorry after a previous injection of a tranquillizing drug (amperozide), no transportation but an amperozide injection. Another group was used as a control group. This group was not transported and received no amperozide injection. The animals were the offspring of boars and sows heterozygous (Nn) for the Hal gene, and all 3 Hal genotypes (NN, Nn, nn) were identified and could thus be compared within litters. Immediately after the experimental treatment, the highest PBL reactivity was found for the amperozide-treated animals and for the non-transported animals, with no differences in reactivity between Hal genotypes. Two weeks later, the treatments caused different effects on pigs of the 3 Hal genotypes, both with regard to the PBL reactivity and the IgG response to O149. The NN pigs had a higher PBL reactivity than the nn pigs for all treatments except the 'drug + transport' class where the reverse rank order was found. The NN pigs also had a higher IgG response to O149 than the nn pigs in the 'drug + no transport' class. The amperozide treatment was followed by a higher PBL reactivity in non-transported NN pigs and in transported nn pigs. The amperozide-treated non-transported NN pigs also had a higher IgG response to O149. The highest PBL reactivity and IgG response to O149 were found mainly in pigs with the lowest cortisol levels. Pronounced differences between litters were found for both the antibody response and the PBL reactivity.

Anesthesia↗
PubMed1987

Analysis of peptide histidine-isoleucine/vasoactive intestinal polypeptide-immunoreactive neurons in the central nervous system with special reference to their relation to corticotropin releasing factor- and enkephalin-like immunoreactivities in the paraventricular hypothalamic nucleus.

The distribution of peptide histidine-isoleucine (PHI) and vasoactive intestinal polypeptide (VIP), two peptides derived from the same precursor molecule, was analysed with immunohistochemistry in the central nervous system of the rat, and to a limited extent in some other species including sheep, monkey and man. Special attention was focused on possible cross-reactivity between PHI antisera and corticotropin releasing factor in parvocellular neurons in the hypothalamic paraventricular nucleus projecting to the external layer of the median eminence. (1) Characterization of the PHI and VIP antisera revealed that they recognized different sequences of the peptide molecules. One of the PHI antisera (PHI-N), although mainly N-terminally directed, also probably contained an antibody population directed against the C-terminal amino acid in PHI which is an amidated isoleucine. Rat and human corticotropin releasing factor but not ovine also have an amidated isoleucine in C-terminal position. (2) PHI- and VIP-like immunoreactivity were found with parallel and overlapping distribution in all areas investigated in the rat central nervous system. In many cases coexistence of the two immunoreactivities could be directly demonstrated. PHI neurons were found in some areas so far not know to contain PHI/VIP neurons, including the dorsal septum, the septofimbrial nucleus, the stria terminalis and lamina V of the spinal cord. (3) Using an antiserum directed against the amino acid sequence 111-122 of the VIP/PHI precursor, immunoreactive cell bodies were seen in some areas containing VIP and PHI neurons. PHI- and VIP-like immunoreactivity were expressed in parallel in increasing amounts in the superficial laminae of the dorsal horn after transection of the sciatic nerve [G. P. McGregor et al. (1984) Neuroscience 13, 207-216; S. A. S. Shehab and M. E. Atkinson (1984) J. Anat. 139, 725; S. A. S. Shehab and M. E. Atkinson (1986) Expl Brain Res. 62, 422-430]. (5) The PHI-N antiserum stains large numbers of immunoreactive cells in the parvocellular part of the paraventricular nucleus and these cells are mostly identical with corticotropin releasing factor-positive neurons. Absorption experiments suggested that this PHI-N-like immunoreactivity to a large extent represented cross-reactivity with rat CRF and that earlier demonstration of many PHI-positive neurons in the paraventricular nucleus probably represents an artefact as proposed by F. Berkenbosch et al. (Neuroendocrinology 44, 338-346). However, some cells did, in fact, contain VIP- as well as PHI-like immunoreactivity as was shown with antisera not cross-reacting with corticotropin releasing factor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Cerebral osmoregulation of renal sodium excretion--a response analogous to thirst and vasopressin release.

Studies in sheep have shown that renal excretion of sodium may be under osmoregulatory control. When sheep become dehydrated, or are infused intravenously with hypertonic saline, they increase renal Na excretion in addition to secreting vasopressin and developing a thirst. These natriuretic, antidiuretic, and dipsogenic responses to dehydration and hypertonicity can be greatly reduced by lowering the cerebrospinal fluid NaCl concentration or by prior ablation of tissue in the anterior wall of the third ventricle. Lowering of cerebrospinal fluid NaCl concentration also prevents postprandial natriuresis which normally occurs in association with a postprandial increase in plasma Na concentration and tonicity. We propose that there is a cerebral osmoregulatory control of Na excretion which may interact with volume influences from the cardiovascular system to regulate renal Na output. The effector mechanism from brain to kidney mediating such cerebral control of Na excretion is probably hormonal.

Animals↗
PubMed1987

Investigation of mechanisms of acetaminophen toxicity in isolated rat hepatocytes with the acetaminophen analogues 3,5-dimethylacetaminophen and 2,6-dimethylacetaminophen.

The toxicity of acetaminophen (4'-hydroxyacetanilide), 3,5-dimethylacetaminophen (3'-5'-dimethyl-4'-hydroxyacetanilide), and 2,6-dimethylacetaminophen (2',6'-dimethyl-4'-hydroxyacetanilide) was investigated in hepatocytes isolated from phenobarbital-pretreated rats. At a concentration of 5 mM, acetaminophen was found to be the most cytotoxic of the three analogues. Inhibition of cellular glutathione reductase by pretreatment of hepatocytes with BCNU enhanced the toxicity of 3,5-dimethylacetaminophen without affecting the toxicity of either acetaminophen or 2,6-dimethylacetaminophen. In contrast, pretreatment with diethylmaleate preferentially enhanced the toxicity caused by 2,6-dimethylacetaminophen and, to a lesser extent, acetaminophen, without measurably affecting the toxicity of 3,5-dimethylacetaminophen. All three hydroxyacetanilides depleted cellular glutathione concentrations, but only the 3,5-dimethyl analogue caused measurable formation of glutathione disulfide. However, the cytotoxicity of all analogues could be decreased by the administration of the thiol agent, dithiothreitol. Moreover, all three analogues had antioxidant properties, and their ability to decrease cellular malondialdehyde formation correlated with their half-wave (E1/2) oxidation potentials. The administration of the ferric ion chelator, desferrioxamine, which completely inhibited lipid peroxidation as measured by malondialdehyde formation, had no significant effects on cytotoxicity caused by acetaminophen or 3,5-dimethylacetaminophen, but partially protected against cytotoxicity caused by 2,6-dimethylacetaminophen, the poorest antioxidant of the three analogues. Covalent protein binding of all three analogues was measured. Whereas both acetaminophen and 2,6-dimethylacetaminophen bound to hepatocyte proteins under conditions where they were cytotoxic, 3,5-dimethylacetaminophen did not. Dithiothreitol was found to decrease the binding of radiolabel from both acetaminophen and its 2,6-dimethyl analogue, whereas desferrioxamine had no effect. These data indicate that the three analogues cause their cytotoxic effects by different mechanisms, although toxicity in all cases is probably mediated through their oxidation products, the quinone imines, which have as a common feature their ability to deplete cellular thiols.

Acetaminophen↗
PubMed1986

4-Hydroxyphenylpyruvate dioxygenase is an iron-tyrosinate protein.

A resonance Raman investigation into the blue chromophore of 4-hydroxyphenylpyruvate dioxygenase, a non-heme iron enzyme from Pseudomonas P. J. 874, reveals the presence of enhanced vibrations characteristic of tyrosinate coordination to the iron center. The excitation profiles for these features show that they are associated with the 595 nm absorption feature. EPR studies of this enzyme indicate the presence of a high-spin ferric center in a rhombic environment, as evidenced by a signal at g = 4.3 with the correct intensity for the measured iron content. This enzyme thus belongs to the emerging class of iron-tyrosinate proteins.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1986

Arginine vasopressin excretion in response to volume expansion in the healthy human, and in patients with glomerulonephritis.

The urinary excretion of arginine vasopressin (AVP) was studied during volume expansion (VE) in nine healthy normotensive individuals and 14 patients with active IgA glomerulonephritis (GN). The studies were started after 17-18 h of food and fluid deprivation (hydropenia, HP) and VE was induced by a continuous infusion of Ringer solution up to an amount corresponding to 3% of the body weight. The clearance of inulin and PAH, urine osmolality and urinary excretion of sodium and AVP were determined. The AVP excretion decreased in response to VE in the healthy individuals, both when related to GFR (from 129 +/- 17 pg min-1 100 ml-1 GFR during HP to 65 +/- 9 after 3% VE, P less than 0.01) and to body surface area (BSA) (from 134 +/- 22 pg min-1 1.73 m-2 BSA to 75 +/- 11, P less than 0.05). In the patients with IgA GN, who had normal blood pressure and normal GFR, the AVP excretion tended to decrease, but the change was not significant (0.05 less than P less than 0.1). The patients with hypertension but essentially normal GFR, and those with hypertension and markedly decreased GFR did not change their renal excretion of AVP in response to VE. If related to the GFR, the latter patients had a markedly increased AVP excretion.

Adult↗
PubMed1986

The dipsogenic effect of intracerebroventricular infusion of hypertonic NaCl in the sheep is mediated mainly by the Na ion.

In order to examine the importance of the chloride ion in the dipsogenic effect of intracerebroventricular (ICV) infusion of hypertonic NaCl, the water intake in response to 30-min ICV infusions of hypertonic solutions of different Na salts (0.25 M NaCl, NaI, NaSCN and 0.125 M Na2S2O3), mannitol (0.5 M) and choline chloride (0.25 M) was studied in the sheep. All solutions of the Na salts caused significant water drinking compared with ICV control infusions of isotonic artificial cerebrospinal fluid (CSF), except Na thiosulphate (Na2S2O3), which was much less effective, even after equilibration of its osmolality with the other sodium solutions by adding mannitol (0.125 M Na2S2O3/0.25 M mannitol). An inconsistent and small intake of water was induced by ICV hypertonic mannitol and choline chloride. It is concluded that the dipsogenic effect of ICV infusion of hypertonic NaCl in the sheep is mainly caused by the increased Na rather than the Cl ion concentration or the hyperosmolality in the extracellular fluid of juxtaventricular brain tissue.

Animals↗