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Biomedical subjects

J Donaldson

Publications and source records attributed to J Donaldson.

At least 55 records · Page 3Linked to original sources
PubMed1988

Experimental Rift Valley fever in rhesus macaques.

Rift Valley fever (RVF) is a major cause of human morbidity and mortality in endemic areas of sub-Saharan Africa and has the potential to cause epidemic disease in receptive areas world-wide. In this study, a RVF viral isolate from the 1977 Egyptian epidemic (ZH-501) inoculated intravenously into rhesus macaques caused a benign viremic infection in most, but resulted in the hemorrhagic fever syndrome in 20 per cent (3 of 15). Serious disease of this type has not previously been observed in nonhuman primates inoculated with RVF virus and may be a consequence of the viral strain used or the route of inoculation. Severe disease was accompanied by extensive liver necrosis, disseminated intravascular coagulation, and microangiopathic hemolytic anemia. We also attempted to prevent RVF by passive transfer of serum from vaccinated rhesus monkeys (plaque-reduction neutralization test titer 1:2,560). As little as 0.025 ml/kg prevented the development of viremia in naive rhesus monkeys after subcutaneous inoculation of virus. The monkey model should be helpful in understanding the pathogenesis and prevention of human RVF.

Animals↗
PubMed1988

Kinetic studies on the mechanism by which histamine H1 receptors potentiate cyclic AMP accumulation in guinea pig cerebral cortical slices.

Histamine, acting via H1 receptors, augments adenosine-induced cAMP accumulation in slices of guinea pig cerebral cortex by an indirect mechanism that appears to involve an intracellular messenger(s). To better characterize this process, the time course of this augmentation was examined in slices prelabeled with [3H] adenine. When histamine (1 mM) was added after the cAMP level had reached steady state with adenosine (0.1 mM), the cAMP level rose to a new steady level within 10 min (t 1/2, 2-3 min). There was no measurable delay in this response, indicating rapid activation of the augmentation after receptor occupation. Studies using the H1 receptor antagonist mepyramine indicated that the continued presence of the histamine stimulus was required to maintain the augmentation. Addition of mepyramine (10 microM) between 1 and 14 min after histamine caused cAMP levels to fall to a level similar to that obtained previously with adenosine alone, but with a delay of 2-3 min. This gives an upper estimate of the lifetime of any intracellular messenger involved in the augmentation process. To determine whether histamine acts by stimulating synthesis of cAMP or by inhibiting its breakdown, the fall in tissue cAMP content was studied after rapid removal of the adenosine stimulus by addition of adenosine deaminase. The initial fall was significantly faster in slices incubated with 0.1 mM adenosine plus 1 mM histamine than in slices with 0.1 mM adenosine alone, indicating increased synthesis and breakdown of cAMP in the presence of histamine. However, the higher breakdown rate probably reflects stimulation of the degradation process by the higher initial level of cAMP with histamine because, at equivalent levels, cAMP content fell at similar rates in both conditions. This was confirmed in other experiments in which similar steady state cAMP levels were achieved with and without histamine by appropriate choice of adenosine concentrations. It is therefore concluded that the direct effect of histamine is primarily to potentiate cAMP synthesis.

Adenosine↗
PubMed1987

1,4-Dithiothreitol-induced changes in histamine H1-agonist efficacy and affinity in the longitudinal smooth muscle of guinea-pig ileum.

The effect of 1,4-dithiothreitol (DTT) on histamine H1-receptor agonist affinity and efficacy has been investigated in longitudinal muscle strips of guinea-pig ileum. Exposure of ileal smooth muscle to DTT significantly increased the maximal responses to the partial agonists SKF71473 and DE-2PEA, indicative of an increase in agonist efficacy. This effect was paralleled by a small decrease in EC50 values. In contrast, DTT produced a parallel displacement of the concentration-response curve to the full agonist histamine in the same muscle strips. Studies in which phenoxybenzamine and benzilylcholine mustard were used to reduce the maximum response to histamine suggested that DTT altered both agonist affinity and efficacy. The affinity constant for histamine, calculated by the method of Furchgott & Bursztyn (1967), increased by 2.7 fold in the presence of DTT. Furthermore, agonist efficacy also appeared to increase in the presence of DTT since the maximum response to histamine following phenoxybenzamine treatment increased on application of DTT. [3H]-mepyramine binding studies confirmed that DTT increased agonist affinity. DTT produced a significant parallel shift to the left of the displacement curves for histamine, 2-methylhistamine, 2-pyridylethylamine and 2-thiazolylethylamine. The results of this study therefore suggest that DTT potentiates H1-receptor-mediated contractile activity in guinea-pig ileum by increasing both agonist efficacy and affinity.

Animals↗
PubMed1986

1,4-Dithiothreitol-induced alteration in histamine H1-agonist binding in guinea-pig cerebellum and cerebral cortex.

The effect of the disulphide bond reducing agent 1,4-dithiothreitol (DTT) on the binding characteristics of the H1-selective ligand [3H]mepyramine has been examined in homogenates of guinea-pig cerebral cortex and cerebellum. DTT was found to be without effect on antagonist binding. This was evident from studies using different concentrations of [3H]mepyramine (0.5-10.0 nM), which showed no change in either the equilibrium dissociation constant (KD) or specific binding site capacity (Bmax). Furthermore, the IC50 values and slope parameters determined from the inhibition of the binding of 1 nM [3H]mepyramine by non-radioactive mepyramine were similarly insensitive to DTT in both cerebral cortex and cerebellum. In contrast, DTT shifted the inhibition curve for histamine to lower agonist concentrations and reduced the Hill coefficient in these two tissues. Analysis of these inhibition curves as double hyperbolae revealed two binding sites in the presence of DTT and only one low affinity site in the absence of DTT. Similar changes in the location (IC50) and slope (Hill coefficient) parameters were obtained with the H1-selective agonist 2-thiazolylethylamine in cerebellum and with 2-methylhistamine in both brain regions. The results of this study show that DTT affects agonist but not antagonist binding in guinea-pig cerebellum and cerebral cortex, and suggest that DTT stabilises a proportion of the agonist binding sites in a high affinity state.

Animals↗
PubMed1986

Histamine-induced hydrolysis of polyphosphoinositides in guinea-pig ileum and brain.

The effect of histamine and the H1-selective agonist, 2-pyridylethylamine, on the accumulation of inositol monophosphate (InsP), inositol bisphosphate (InsP2) and inositol trisphosphate (InsP3) has been examined in lithium-treated slices of guinea-pig cerebellum and ileal smooth muscle. Following 45 min incubation, histamine produced a large accumulation of [3H]InsP and a smaller accumulation of [3H]InsP2 and [3H]InsP3 in both tissues. In cerebellar slices all three responses to histamine were potently and competitively inhibited by the selective H1-receptor antagonist, mepyramine. In contrast, incubation of ileal slices with mepyramine (0.1 microM) produced only a small reduction (circa 20%) in the maximal accumulation elicited by histamine of each [3H]inositol phosphate with no significant effect on the EC50 or Hill coefficient. However, when 2-pyridylethylamine, instead of histamine, was used to stimulate inositol phospholipid hydrolysis in ileal smooth muscle, the agonist-induced responses appeared to be competitively antagonised by mepyramine. The results presented indicate that there is an apparent dissociation between histamine-induced InsP3 accumulation and H1-receptor-mediated contractile activity in ileal smooth muscle and suggest that agonist-induced inositol phospholipid hydrolysis in this tissue may be involved in other cellular events separate from those involving calcium.

Animals↗
PubMed1986

CB 1954 revisited. II. Toxicity and antitumour activity.

We have assessed the antitumour activity of the nitrophenylaziridine CB 1954 in vitro and in vivo. For EMT6 mouse mammary tumour multicellular spheroids under hypoxic conditions in vitro, a 6-h exposure to 40 micrograms/ml reduced the surviving fraction to as low as 10(-3) and the growth delay was 5.4 days. Oxic cells were twofold less sensitive. Phenyl AIC protected oxic and hypoxic cells equally. Under oxic conditions minimal cell killing was seen with HT29 cells, either in multicellular spheroids or in monolayer; a 6-h exposure to 40 micrograms/ml gave a spheroid growth delay of 1.5-1.7 days. No growth delay was seen with single maximum tolerated doses of CB 1954 against HT29 grown as a xenograft in immunosuppressed mice. Only minimal growth delays of 1-2 days were seen with similar doses against the EMT6 tumour and the RIF-1 and KHT sarcomas in mice. Little activity was seen with maximum tolerated doses given once a day for 5 days against EMT6 and RIF-1. No chemosensitization was measurable with CCNU, cyclophosphamide or melphalan in the KHT tumour.

Animals↗
PubMed1986

Enhancement of histamine H1-receptor agonist activity by 1,4-dithiothreitol in guinea-pig cerebellum and cerebral cortex.

The disulphide bond-reducing agent 1,4-dithiothreitol (1 mM) produced a marked potentiation of histamine-stimulated accumulation of [3H]inositol phosphates in lithium-treated slices of guinea-pig cerebellum and cerebral cortex. This was seen as a parallel shift of the concentration-response curve for histamine to lower agonist concentrations, with no significant effect on the maximal response or Hill coefficient. Dithiothreitol similarly potentiated the augmentation of adenosine-stimulated cyclic AMP accumulation elicited by histamine in guinea-pig cerebral cortex. Studies with partial agonists suggested that this potentiating effect was associated with an increase in agonist efficacy rather than a change in agonist binding affinity. Thus, dithiothreitol increased the maximal accumulation of [3H]inositol phosphates produced by both 2-pyridylethylamine and 2-methylhistamine, which appeared to act as partial agonists in guinea-pig cerebral cortex. Dithiothreitol similarly increased the maximal extent of the augmentation of adenosine-stimulated accumulation of cyclic AMP produced by 2-methylhistamine. The site of action of dithiothreitol is not known; however, a comparison of the effect of dithiothreitol on muscarinic and histamine H1-receptor-mediated phosphoinositide responses in guinea-pig cerebral cortex suggests that it is before the stage at which the receptor-effector pathways are shared by these two receptor systems.

Animals↗
PubMed1986

Selective enhancement of histamine H1-receptor responses in guinea-pig ileal smooth muscle by 1,4-dithiothreitol.

1,4-Dithiothreitol (DTT; 1 mM, 30 min preincubation) produced a small, non-specific potentiation of spasmogenic activity in longitudinal muscle strips of guinea-pig small intestine. A direct comparison of contractile responses elicited by histamine and a range of H1- and non-H1-receptor agonists indicated that DTT produced a significantly greater potentiation of H1-receptor responses. This apparently selective increase in tissue sensitivity to histamine H1-receptor agonists did not appear to be a consequence of the inhibition of histamine N-methyl transferase or diamine oxidase activity. Potentiation of the responses to histamine by DTT was still observed in the presence of SKF 91488 (10 microM) and aminoguanidine (1 microM). The potentiation elicited by DTT was readily reversed by the sulphydryl oxidizing agent dithiobis-(2-nitrobenzoic acid) (DTNB). This suggests that the mechanism of action of DTT involves the reduction of disulphide bonds. Exposure of ileal smooth muscle to DTT following desensitization with histamine (100 X EC50 [- DTT]) resulted in a 6.9 +/- 0.7 fold shift of the concentration-response curve to lower agonist concentrations. Conversely, following potentiation of the response to histamine with DTT, exposure of the tissue to desensitizing concentrations of histamine resulted in a dextral shift of the dose-response curve (dose ratio = 39.5 +/- 1.2) to higher agonist concentrations. The results of this study suggest that DTT may be a useful tool with which to investigate histamine H1-receptor mechanisms in ileal smooth muscle.

Acetylcholine↗
PubMed1985

The specific vulnerability of the substantia nigra to MPTP is related to the presence of transition metals.

We demonstrate that the high concentration of transition metals in the substantia nigra could be a major factor responsible for the specificity of cell damage by the Parkinsonism-causing neurotoxin MPTP. It will be shown that these metals in vitro, and MPTP, each potentiate the autoxidation of dopamine and the production of aminochrome through the generation of superoxide, hydroxyl radicals, hydrogen peroxide and reactive semiquinones. Moreover, the same metals contribute to the oxidation of MPTP itself, further enhancing dopamine autoxidation.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

The effect of systemic hyperthermia on melphalan pharmacokinetics in mice.

The effect of 45 min systemic heating at 41 degrees C on plasma and RIF-1 tumour pharmacokinetics of intraperitoneally administered melphalan (MEL) was studied in C3H mice. This heat dose causes greater potentiation of MEL in tumour than in marrow cells, resulting in a therapeutic gain for the combined therapy (Honess & Bleehen, 1985). MEL (7.5 mg kg-1) was administered at the start of heating and concentrations assayed from 20-90 min by high-performance liquid chromatography (HPLC). With or without heat peak concentrations were achieved by 20 min and were 3 to 4 micrograms ml-1 in plasma and 1-3 micrograms g-1 in tumour. Higher MEL concentrations in both plasma and tumour were found in heated animals at times after 20 min from injection, but the effect was greater in plasma (2.5-4 fold) than in tumour (1.5-2 fold) where differences were not always significant. At 40 min after a dose of 7.5 mg kg-1, plasma and tumour concentrations in heated animals were equivalent to those after 12.5 mg kg-1 and 8.5 mg kg-1, respectively, without heating. Tumour/plasma ratios were usually lower in heated than in unheated animals where they often exceeded 100%. The apparent plasma elimination half-life (t1/2) was 17.5-25 min in unheated and 24-44 min in heated animals. The area under the curve (AUC) was increased by a factor of 1.2-1.5 in heated animals, at least partly due to a decrease in volume of distribution. The heat induced increase in MEL exposure may be involved in the enhanced response to the drug, but does not appear to explain the therapeutic gain compaired to MEL alone.

Animals↗
PubMed1985

Histamine-induced inositol phospholipid breakdown in the longitudinal smooth muscle of guinea-pig ileum.

The characteristics of histamine-stimulated inositol phospholipid breakdown in slices of guinea-pig ileal smooth muscle and cerebellum have been investigated. In cerebellar slices the inhibition of the inositol phospholipid response to histamine by mepyramine was consistent with competitive antagonism of histamine H1-receptors. In slices of the longitudinal smooth muscle of guinea-pig ileum, mepyramine produced only a weak inhibition of the response to histamine, at concentrations up to 1 microM. This was in striking contrast to the potent competitive antagonism of the H1-mediated contractile responses obtained with mepyramine in this tissue. The H1-receptor antagonists (+)-chlorpheniramine and promethazine similarly had no effect on the EC50 value for histamine in guinea-pig ileum, while promethazine competitively antagonized the muscarinic receptor-mediated inositol phospholipid response in this tissue (Ka 3.6 X 10(7)M-1). Cimetidine, on its own, did not significantly inhibit the inositol phosphate accumulation elicited by histamine in ileum. In the presence of 0.2 microM mepyramine, cimetidine (0.1 mM) produced a small parallel shift of the histamine concentration-response curve (Ka 3 X 10(4) M-1). This inhibition, however, was not consistent with antagonism of an H2-receptor-mediated response. The effect of a range of histamine analogues on inositol phospholipid breakdown was determined. Dose-response curves were constructed and characterized in terms of the EC50, slope and maximal response attainable relative to histamine. The H1-agonists, N alpha,N alpha-dimethylhistamine, N alpha-methylhistamine, 2-pyridylethylamine and 2-thiazolyethylamine produced the largest accumulations of [3H]-inositol-1-phosphate. A very weak response was produced by the H2-selective agonist impromidine, while dimaprit (also H2-selective) was without significant effect. Mepyramine appeared to antagonize competitively the response to the H1-selective agonist 2-pyridylethylamine. This was in contrast to the data obtained with other H1-agonists, where mepyramine produced only a small dextral shift of the agonist curves at low agonist concentrations and an increase in the Hill coefficient. This was particularly striking in the case of 2-methylhistamine. The results suggest that an H1-receptor component in guinea-pig ileum, may coexist with a larger inositol phospholipid response to histamine which is independent of the activation of H1- or H2-receptors.

Animals↗
PubMed1985

Vanadium exposure enhances lipid peroxidation in the kidney of rats and mice.

Vanadium (V) as sodium orthovanadate induces an increase in lipid peroxidation in the kidneys after a single subcutaneous or intraperitoneal injection to rats or mice. The rate of malondialdehyde (MDA) formation, an index of lipid peroxidation, by kidney homogenates increased by more than 100% 1 h after injection. Chronic exposure of rats to vanadium sulfate, initially through maternal milk and later in the drinking water, resulted after 10 weeks in a significant increase in MDA formation by kidney but not by other tissues. In both acute and chronic studies in rats and mice, no significant increase in lipid peroxidation by V treatment was detected in brain, heart, lung, spleen, or liver. In mice, administration of ascorbate prior to acute exposure to V diminished both toxicity, i.e., respiratory depression and limb paralysis, and the formation of MDA in kidney.

Animals↗
PubMed1984

Electrical stimulation of the salivatory nucleus in the rat.

Unilateral electrical stimulation of the salivatory nucleus evoked a secretion from the ipsilateral parotid gland which was well maintained. Flow rate was not affected by sympathetic decentralization or by adrenoceptor antagonists but was abolished by atropine. Protein secretion was reduced by beta-adrenoceptor antagonists but not by sympathetic decentralization or adrenalectomy. In support of previous histochemical findings it is concluded that the cells of the reticular formation are the origin of the preganglionic parasympathetic fibres to the salivary glands but that a beta-adrenoceptor mechanism as yet unidentified is also involved in the protein secretion.

Adrenalectomy↗