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Biomedical subjects

R J Huxtable

Publications and source records attributed to R J Huxtable.

At least 91 records · Page 5Linked to original sources
PubMed1987

Higher susceptibility of taurine-deficient rats to seizures induced by 4-aminopyridine.

The susceptibility of rats made deficient of taurine by treatment with guanidinoethane sulfonate (GES), to seizures induced by 4-aminopyridine was examined. Guanidinoethane sulfonate, at a concentration of 1% was administered to pregnant rats, in the drinking water 2-3 days prior to delivery and the treatment was continued during nursing. Pups were weaned to the same treatment until 6 weeks of age. This treatment decreased levels of taurine in the cerebral cortex by 70%. 4-Aminopyridine was injected intraperitoneally at doses ranging from 4-7 mg/kg. Taurine-deficient rats showed a greater susceptibility to seizures, as demonstrated by a lowered latency for clonic seizures, an increased incidence of tonic seizures and a higher postseizure mortality. These results suggest an involvement of endogenous taurine in nervous excitability.

4-Aminopyridine↗
PubMed1987

Pulmonary vascular responses induced by the pyrrolizidine alkaloid, monocrotaline, in rats.

Studies were conducted with isolated segments of pulmonary artery to characterize vessel contractility in monocrotaline-induced pulmonary hypertension. Contractions of pulmonary artery segments from rats given monocrotaline in drinking water (20 mg/l) for up to 20 days were measured in tissue baths. Dose response curves were produced with norepinephrine or serotonin and the response to 120 mM potassium chloride (KCl) was measured. Monocrotaline treatment significantly reduced the KCl-induced maximum contractile responses of pulmonary artery. Norepinephrine-induced maximal contractions (both in terms of mg developed force and as percentage of KCl-induced contractions) decreased with increasing length of monocrotaline treatment. Serotonin-induced maximal contractions were not altered by monocrotaline treatment. A minimum of 4 days treatment with monocrotaline drinking water reduced the contractile responses of pulmonary artery removed 16 days later. In separate experiments using continuous exposure to monocrotaline, a minimum of 15 days treatment was required before contractile activity was significantly altered. Results indicate monocrotaline treatment reduces the contractile activity of muscular pulmonary artery. Alterations in vessel responsiveness were produced after a minimum of 4 days treatment with monocrotaline in drinking water (an estimated exposure of 14-20 mg/kg) but required 15-20 days to develop.

Animals↗
PubMed1987

Anti-platelet agents reduce morphological changes of chronic hypoxic pulmonary hypertension.

The pathophysiologic mechanism by which chronic hypoxia causes pulmonary hypertension is unknown. If anti-platelet agents, or other pharmacologic interventions, altered the pulmonary vascular changes induced by hypoxia, information concerning the pathogenesis of the pulmonary hypertension or the potential therapeutic usefulness of the drugs might be obtained. In Study 1, rats exposed to chronic hypobaric hypoxia (PB = 520 mmHg) had a pulmonary arterial medial thickness of 6.7 +/- 0.6 mu compared to 4.1 +/- 0.2 mu* for control, normoxic rats (*p less than 0.05). Administration of dipyridamole (2mg/kg/day), or sulfinpyrazone (11 mg/kg/day) in the drinking water reduced the medial thickness to 5.0 +/- 0.3 mu* and 5.4 +/- 0.5 mu* respectively, thus suggesting the possible involvement of platelets in the response of the media to chronic hypoxia. In Study 2, hypoxic rats treated with the calcium blocker, flunarizine, were found to have less medial hypertrophy than a control group of hypoxic rats. This observation suggests that a decrease in transmembrane calcium flux may also reduce medial hypertrophy.

Animals↗
PubMed1986

Low affinity binding of taurine to phospholiposomes and cardiac sarcolemma.

A sarcolemma-enriched membrane fraction was prepared from the hearts of Sprague-Dawley rats and its ability to bind taurine (0.5-150 mM) was measured. In the absence of cations, the sarcolemma bound a maximum of 661 nmol taurine/mg protein, with a dissociation constant of 19.2 mM and a Hill coefficient of 1.9, indicating positive cooperativity. Scatchard analysis of taurine binding to sarcolemma gave a bell-shaped curve. Neither beta-alanine nor guanidinoethane sulfonate, inhibitors of taurine transport, affected the degree of taurine binding to sarcolemma. However, hypotaurine was an effective antagonist. Equimolar concentrations of Ca2+, Na+ or K+ also reduced taurine binding. Heterogeneous phospholipid vesicles of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine (18:19:2:1) also bound taurine with positive cooperativity, yielding a bell-shaped Scatchard curve. The affinity of taurine for these mixed phospholipid vesicles was enhanced by the inclusion of cholesterol (50%). Taurine associated in a maximum ratio of 1:1 with homogeneous vesicles of phosphatidylcholine or phosphatidylserine. Vesicles of phosphatidylethanolamine bound taurine in a maximum ratio of 2:1, whereas those of phosphatidylinositol bound insignificant amounts of taurine. These studies demonstrate a low affinity binding to sarcolemma of taurine at concentrations normally present in rat heart. Similar levels of binding were observed in phospholipid vesicles, suggesting that the interaction of taurine with biological membranes involves phospholipids.

Animals↗
PubMed1985

Modification of the antiepileptic actions of phenobarbital and phenytoin by the taurine transport inhibitor, guanidinoethane sulfonate.

We investigated whether chronic administration of guanidinoethane sulfonate, an inhibitor of taurine uptake, could modify the antiepileptic actions of phenobarbital and phenytoin on maximal electroshock seizures in mice. Treatment with 1% guanidinoethane sulfonate decreased the taurine concentration in the brain to 76% of the control value. Under these conditions, neither the severity of tonic convulsions of maximal electroshock seizures nor the threshold for tonic extension caused by electroshock was altered. However, treatment with guanidinoethane sulfonate lessened the antiepileptic actions of phenobarbital and phenytoin on electroshock seizures. The brain concentrations of phenobarbital and phenytoin were unaltered by administration of guanidinoethane sulfonate. The brain concentrations of guanidinoethane sulfonate and total guanidino compounds were unchanged by the injection of either phenobarbital or phenytoin. It is suggested that the observed loss of anticonvulsive potency of phenobarbital and phenytoin may have been related to the decrease in taurine concentration produced by guanidinoethane sulfonate.

Amino Acids↗
PubMed1985

Biliary excretion of novel pneumotoxic metabolites of the pyrrolizidine alkaloid, monocrotaline.

Perfusion of the pyrrolizidine alkaloid, monocrotaline, through the isolated rat liver resulted in the appearance of Ehrlich-positive metabolites in both the perfusate and bile. Livers from male rats released greater quantities of metabolite into both bile and perfusate. Metabolite release was stimulated by pretreatment with phenobarbital. Livers of phenobarbital-pretreated male rats perfused with 30 microM monocrotaline produced biliary metabolite concentrations in excess of 5 mM. Metabolite release was inhibited by anoxic perfusion, low temperature and pretreatment with SKF-525A. Above 150 microM monocrotaline, bile became the predominant route of excretion. On perfusion through the isolated lung of the rat, bile and perfusate metabolites were equally effective in inhibiting serotonin transport. A single Ehrlich-positive peak was obtained on silica gel column chromatography of bile containing metabolite. Mass spectrometry revealed the major component of this peak to have a molecular weight of 281, indicating a novel pyrrole metabolite in which the esterifying acid present in monocrotaline, monocrotalic acid, had been partially degraded. This compound mimics the pneumotoxic action of monocrotaline given in vivo, and its availability should prove a valuable tool in the elucidation of the mechanism of pyrrolizidine toxicity.

Animals↗
PubMed1985

Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements.

Venocclusive disease, a form of Budd-Chiari syndrome, was diagnosed in a 49-yr-old woman. The patient had portal hypertension associated with obliteration of the smaller hepatic venules. A liver biopsy specimen showed centrilobular necrosis and congestion. Analysis of food supplements the woman regularly consumed showed the presence of pyrrolizidine alkaloids. The major source was a powder purporting to contain ground comfrey root (Symphytum sp). We calculated that during the 6 mo before the woman was hospitalized, she had consumed a minimum of 85 mg of pyrrolizidine alkaloids (15 micrograms/kg body wt X day). The clinical and analytic findings were consistent with chronic pyrrolizidine intoxication, indicating that low-level, chronic exposure to such alkaloids can cause venocclusive disease.

Budd-Chiari Syndrome↗
PubMed1985

Taurine modulation of calcium binding to cardiac sarcolemma.

A sarcolemma-enriched membrane fraction (SL) was prepared from the hearts of Sprague-Dawley rats and its ability to bind Ca++ was measured by equilibrium dialysis. We found that the effect of taurine on SL Ca++ binding varied with the buffer and with Na+ concentration. In Tris, in the presence of Na+ (140 mM), taurine (10 mM) increased the affinity but decreased the maximal binding of Ca++ (0.5-7 mM). In the absence of Na+, taurine decreased the affinity without altering the maximal binding. These effects on Ca++ binding were absent in bicarbonate or Krebs-Henseleit buffers. However, incubations with A23187, a Ca++ ionophore, and lanthanum, a Ca++ antagonist, indicated that SL membranes incubated in Tris, but not in buffers containing bicarbonate, were sealed vesicles with internal environments low in Ca++. High-affinity binding of Ca++ (10(-6)-10(-4) M) was measured in modified Krebs-Henseleit buffers. Taurine decreased Ca++ binding in a high-Na+ (145 mM), low-K+ (4.7 mM) buffer. Taurine increased Ca++ binding in both 4.7 mM Na+-145 mM K+ and 25 mM Na+-4.7 mM K+ buffers. Taurine also increased Ca++ binding in the presence of ATP. Thus, taurine increased high-affinity Ca++ binding in "intracellular" buffers, but it did not affect low-affinity Ca++ binding in "extracellular" buffers. These results suggest taurine may exert its cardiotonic actions through modulation of the high-affinity Ca++ binding sites on the internal aspect of the SL.

Animals↗
PubMed1985

Reduced taurine contents and modification of anticonvulsive effects of phenobarbital and phenytoin by guanidinoethane sulfonate in mice.

In the present study, we investigated whether administration of guanidinoethane sulfonate, and inhibitor of taurine uptake, worsens electroshock-induced convulsions or modifies the antiepileptic actions of phenobarbital or phenytoin against maximal electroshock seizures in mice. Treatment with 1% guanidinoethane sulfonate in drinking water for 9 days decreased taurine concentration in the brain to 76% of control value. Under these conditions, neither the severity of tonic convulsions of maximal electroshock seizures nor the threshold for tonic extension caused by electroshock was altered. On the other hand, the antiepileptic potency of phenobarbital and phenytoin against tonic convulsions of maximal electroshock seizures in mice was significantly lessened by chronic administration of guanidinoethane sulfonate. This decrease in potency was not due to an alteration in pharmacokinetics, as the brain levels of these drugs were unchanged. Furthermore, administration of the anticonvulsive drugs did not change brain concentrations of guanidinoethane sulfonate and total guanidino compounds. It is suggested that the observed loss of anticonvulsive potency of phenobarbital and phenytoin may be related to the decreased concentration of taurine produced by administration of guanidinoethane sulfonate.

Amino Acids↗