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Biomedical subjects

R J Huxtable

Publications and source records attributed to R J Huxtable.

At least 109 records · Page 6Linked to original sources
PubMed1984

Hepatic metabolism and pulmonary toxicity of monocrotaline using isolated perfused liver and lung.

Monocrotaline is a pyrrolizidine alkaloid obtained from the seeds of Crotalaria spectabilis. When perfused through an isolated liver, monocrotaline is metabolized to Ehrlich reactive (E+) metabolites. Metabolism of monocrotaline was faster in livers from male rats than female rats, was inducible with phenobarbital pretreatment, and was inhibited by coperfusion with the P-450 mixed-function oxidase inhibitor SKF-525A, anoxic perfusion conditions, and low temperatures. When metabolites generated by an isolated liver were perfused through isolated lungs in a recirculatory manner, serotonin transport by the pulmonary endothelium was reduced in correlation with the amount of E+ material contained in the perfusion medium. When metabolism of monocrotaline by the liver was inhibited with SKF-525A, low temperature perfusions or anoxic conditions, serotonin transport by the pulmonary endothelium was unchanged from controls. Monocrotaline alone had no effect on the lung. Thus, isolated perfused livers metabolized monocrotaline to chemical species which produced pulmonary damage in vitro. This provides direct evidence that liver metabolites can cause one of the pneumotoxic effects of monocrotaline observed in vivo.

Adenosine Monophosphate↗
PubMed1984

Differentiation of the cardiac and pulmonary toxicity of monocrotaline, a pyrrolizidine alkaloid.

Monocrotaline, given to rats as a 20 mg/l solution in drinking water for 3 weeks, doubled the mass of the right heart and lung. The rise in lung mass preceded that of the heart. These increases were accompanied by increases in the absolute protein content of the two organs, together with increases in the rates of both protein and RNA syntheses. The increase in lung mass was not accompanied by a change in total collagen content, as measured by two independent methods: 4-hydroxyproline content and detergent fractionation. In contrast, the right ventricle showed more than a 4-fold increase in total collagen content. Total pulmonary lipids increased by 86%, but the lipid: protein ratio was unchanged. Right ventricular lipids were unchanged in amount but the lipid: protein ratio fell by 29%. Lung DNA:RNA ratio decreased 49% and right ventricle DNA:RNA ratio decreased 69%, indicating that both of these organs were responding to monocrotaline with hypertrophy. These results suggest that the processes of hypertrophy differ in the two organs: in the lung, there was no fibrosis despite a marked increase in dry weight, while right ventricular hypertrophy was characterized by increased collagen deposition. There was no alteration in the left ventricle in any of the parameters investigated.

Animals↗
PubMed1984

Effect of guanidinoethane sulfonate on taurine uptake by rat retina.

Guanidinoethane sulfonate (GES) markedly decreased 3H-taurine accumulated in the retina by the high-affinity uptake process. The effect of GES was dose-dependent. Analysis of the kinetics of GES effect revealed that it is a competitive inhibitor. The uptake of taurine by GES was less affected in rat cerebral cortex slices, where the inhibition by 1 mM GES was only 28%. Taurine accumulation by tissues of rats treated with GES (0.1% and 1% in the drinking water) was found to be particularly decreased in the retina, although accumulation by heart and liver was also affected by the higher dose. Taurine uptake by cerebellum and cerebral cortex slices was unaffected by GES. Treatment of rats with GES is known to produce an alteration in the structure and function of the retina, but apparently not in other organs. We discuss whether the marked effect of GES on taurine transport by the retina is related to the deleterious effect of the inhibitor in this organ.

Animals↗
PubMed1984

The action of equinatoxin, a peptide from the venom of the sea anemone, Actinia equina, on the isolated lung.

On perfusion through isolated lungs from male Sprague-Dawley rats, equinatoxin caused a dose-dependent increase in the wet to dry weight ratio. Ratios were significantly elevated above control values at equinatoxin concentrations of 80-200 ng/ml. The increased ratios were accompanied by an increase in the permeability of the lung vasculature. When equinatoxin was perfused through isolated lungs at concentrations of 100 ng/ml or greater, significantly more [3H]polyethylene glycol (PEG; approximately 900 mol. wt) was retained in the extravascular space as compared to controls. Perfusion pressures of the lung were significantly elevated above controls at equinatoxin concentrations greater than 100 ng/ml. These effects of equinatoxin were not mediated by degranulation of mast cells, as preperfusion of the lung with 100 or 200 microM Na cromolyn or 1 microM lanthanum chloride did not modify the pulmonary response to equinatoxin. At concentrations of equinatoxin below 150 ng/ml the fluid movement appears to be restricted primarily to intracellular, or possibly interstitial, spaces, as no significant amounts of [3H]polyethylene glycol were recovered by tracheal lavage. At concentrations of equinatoxin equal to or greater than 150 ng/ml, significant amounts of PEG were washed from the trachea. As it is a potent inducer of pulmonary edema, equinatoxin may become an important probe to study fluid regulation in the lung.

Animals↗
PubMed1984

Subcellular distribution of neuroactive amino acids in brains of genetically epileptic rats.

The subcellular distribution of amino acids was compared in brains of genetically seizure-susceptible (SS) and genetically seizure-resistant (SR) rats. The total taurine content (mumol/brain) in the P2B, or synaptosomal, fraction in SS rats was only 37% of that of SR rats. Glutamate, glutamine, glycine, alanine, and gamma-aminobutyric acid (GABA) contents were unaltered. No alterations in total content were found in other subcellular fractions for the amino acids studied. SS animals that had never been stimulated to audiogenic seizure had decreased concentrations of taurine (nmol/mg protein) in the P2, P2B, and P2C fractions as compared with SR animals. These fractions contain crude synaptosomes, enriched synaptosomes, and enriched mitochondria, respectively. Phosphoethanolamine concentrations were also decreased in the P2B fractions, but concentrations of other amino acids were unaltered, as compared with SR animals. Twenty-four hours after the intracerebroventricular injection of taurine (6 mumol) in SS animals that had never been convulsed, taurine concentrations were significantly increased in whole brain homogenate and P2 and P2B fractions as compared with SS animals not given taurine. This treatment left unaltered the concentrations of glutamate, glutamine, GABA, and glycine in brain homogenate and P2 fraction. Because decreases in taurine concentration were seen in animals that had not been convulsed, these alterations are intrinsic to the SS strain and are not a consequence of convulsive activity. In view of the antiepileptic action of taurine, and the fact that an impairment of taurine transport in the brain of SS rats had previously been demonstrated, we suggest that a defect in the biochemistry of taurine is partially responsible for the seizure susceptibility of the SS rat.

Alanine↗
PubMed1984

Characterization of hepatic DNA damage induced in rats by the pyrrolizidine alkaloid monocrotaline.

Hepatic DNA damage induced by the pyrrolizidine alkaloid monocrotaline was evaluated following i.p. administration to adult male Sprague-Dawley rats. Animals were treated with various doses ranging upward from 5 mg/kg, and hepatic nuclei were isolated 4 hr later. Hepatic nuclei were used as the DNA source in all experiments. DNA damage was characterized by the alkaline elution technique. A mixture of DNA-DNA interstrand cross-links and DNA-protein cross-links was induced. Following an injection of monocrotaline, 30 mg/kg i.p., DNA-DNA interstrand cross-linking reached a maximum within 12 hr or less and thereafter decreased over a protracted period of time. By 96 hr postadministration, the calculated cross-linking factor was no longer statistically different from zero. No evidence for the induction of DNA single-strand breaks was observed, although the presence of small numbers of DNA single-strand breaks could have been masked by the overwhelming predominance of DNA cross-links. These DNA cross-links may be related to the hepatocarcinogenic, hepatotoxic, and/or antimitotic effects of monocrotaline.

Animals↗
PubMed1983

Effects of the taurine transport antagonist, guanidinoethane sulfonate, and beta-alanine on the morphology of rat retina.

Newborn rats treated for the first weeks of life with guanidinoethane sulfonate (GES), a blocker of taurine transport producing taurine depletion, showed a severe disruption of photoreceptor structure. Photoreceptor damage consisted of a marked reduction of the size of the photoreceptor layer, deformation of the outer segments, and a profound disorganization of the disc membranes. The GES-induced degeneration pattern was very similar to that observed in cats fed a taurine-deficient diet. Injection of beta-alanine, another antagonist of taurine transport, also produced a disruption of photoreceptor structure. These results confirm the requirement of taurine for maintaining photoreceptor structure in different species.

Alanine↗
PubMed1983

Changes in angiotensin-converting enzyme activity in lungs damaged by the pyrrolizidine alkaloid monocrotaline.

Administration of monocrotaline, a pyrrolizidine alkaloid, to male Sprague-Dawley rats for up to three weeks increased dry lung weights by 64% and reduced the specific activity of lung angiotensin-converting enzyme activity by 64%. When the total activity per lung is calculated, however, there is no significant difference between control and monocrotaline-treated animals. The decrease in specific activity is due to increase in total lung protein (52% above control) and not to an actual reduction in the total angiotensin-converting enzyme activity in th lung.

Animals↗
PubMed1983

Relative contribution of the mother, the nurse and endogenous synthesis to the taurine content of the newborn and suckling rat.

The relative contributions have been determined of taurine derived from the mother in utero, via milk during nursing, and from endogenous biosynthesis to the total taurine content of the rat pup between birth and weaning. At birth, 32% of the taurine in the pup has been biosynthesized, and this proportion rises to 83% by day 20 of life. At birth, 67% has been derived from the mother in utero, and by day 20 this has fallen to 4% of the total. This maternal taurine is lost with a half-life of 16 days. There is wide variation in the turnover from different tissues, the pancreas having a half-life of 7 days, and the brain 50 days. However, the amount of maternal taurine in the brain actually increases by 38% over the first 8 days of life. By day 20, 13% of the taurine content of the pup has been obtained from the milk. Taurine turnover in the suckling pup differs from turnover after weaning in that wholebody turnover from the suckling rat is not slower than exchange between organs. In other words, tissues are not in kinetic equilibrium. After animals are weaned, regardless of the taurine content of the diet, taurine is interchanged between organs faster than it is excreted from the animal.

Animal Population Groups↗