mental deficiency, which derives from the author's vast clinical experience, and there are descri... more mental deficiency, which derives from the author's vast clinical experience, and there are descriptions and photographs of many other unusual syndromes. The book is unlikely to find itselfon the bedside table of the general physician or family doctor, but will be read by many with specialist interests in obesity. The price of £17.50 for a paperback may deter some individuals.
Advances in Experimental Medicine and Biology, 1992
Many phenomena involving taurine appear to be based on a membrane-modifying action, although the ... more Many phenomena involving taurine appear to be based on a membrane-modifying action, although the nature of this action has remained largely undefined. Taurine stabilizes membranes under a variety of conditions, reducing malondialdehyde release induced by carbon tetrachloride (Nakashima et al., 1983), and antagonizing the loss of membrane function produced by phospholipase C (Huxtable and Bressler, 1973) among other actions. Taurine also modifies the calcium binding characteristics of membranes, increasing the affinity of calcium binding while decreasing the maximum binding capacity (Huxtable and Peterson, 1988; Sebring and Huxtable, 1985). Perhaps associated with this is a taurine-induced shift in the membrane transition temperature (Lombardini, 1985), and a stimulation of high affinity, energy-dependent calcium transport in the presence of bicarbonate (reviewed in Huxtable, 1989).
Advances in Experimental Medicine and Biology, 1998
Pyrrolizidines are a group of hepatotoxic plant alkaloids6,9. Certain pyrrolizidines are also tox... more Pyrrolizidines are a group of hepatotoxic plant alkaloids6,9. Certain pyrrolizidines are also toxic to lung, heart, the central nerve system, and other organs. Hepatic bioactivation is required for the expression of toxicity8.
The Journal of pharmacology and experimental therapeutics, 1985
A sarcolemma-enriched membrane fraction (SL) was prepared from the hearts of Sprague-Dawley rats ... more 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. T...
The Journal of pharmacology and experimental therapeutics, 1990
Na+/K(+)-Adenosine triphosphatase-dependent activities of K(+)- return relaxation and 86Rb uptake... more Na+/K(+)-Adenosine triphosphatase-dependent activities of K(+)- return relaxation and 86Rb uptake were studied in pulmonary arteries taken from rats with pulmonary hypertension induced by monocrotaline. Rats were given monocrotaline in drinking water, 20 mg/l, for 4 or more days. Isolated arteries were placed in tissue baths and contracted with norepinephrine or 5-hydroxy-tryptamine under K(+)-free conditions. The arteries relaxed when K+ was "returned" to the bath. Compared to arteries from untreated rats, arteries taken from rats pretreated with monocrotaline developed less force in response to contracting agents and did not relax to the same extent. After 4 days treatment with monocrotaline, the rate of relaxation of the arteries in response to K(+)-return was slower than that of arteries taken from untreated rats. Endothelial trauma or in vitro treatment with ouabain produced a similar decrease in the rate of relaxation. Uptake of radiolabeled Rb by perfused arteries w...
Advances in Experimental Medicine and Biology, 1998
Pyrrolizidine alkaloids (PA) comprise a major group of toxins derived from plants. They are botan... more Pyrrolizidine alkaloids (PA) comprise a major group of toxins derived from plants. They are botanically and geographically widespread and cause many public health and economic problems5. PAs cause hepatomegaly, veno-occlusive disease of the liver, and cirrhosis7. The toxicity of PAs can also be expressed in other organ systems, including the heart, lung, and central nervous system.
Monocrotaline is a pyrrolizidine alkaloid obtained from the seeds of Crotalaria spectabilis. When... more 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.
The principal water-soluble amine on the webs of some orb weaving spiders has been variously iden... more The principal water-soluble amine on the webs of some orb weaving spiders has been variously identified as GABamide and 2-pyrrolidone. We present evidence supporting the identification of this compound as GABamide
Advances in Experimental Medicine and Biology, 1987
... 13. Franconi, F., Stendardi, I., Failli, P., Antonini, G., Bennardini, F., Matucci, R., Manzi... more ... 13. Franconi, F., Stendardi, I., Failli, P., Antonini, G., Bennardini, F., Matucci, R., Manzini, S., and Giotti, A., 1983, Taurine antagonizes the alpha-adrenergic positive inotropic effect of phenylephrine," In Sulfur Amino Acids: Biochemical and Clinical Aspects", Kuriyama, K., Huxtable ...
Caissarone, a sea anemone iminopurine, produced an increase in the twitch response of the electri... more Caissarone, a sea anemone iminopurine, produced an increase in the twitch response of the electrically stimulated guinea-pig ileum-myenteric plexus. In the same assay, caissarone reduced the inhibitory response to the endogenous neuromodulator, adenosine, the A~ adenosine receptor agonist, R-phenylisopropyladenosine (R-PIA), and the A2 agonist, 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA) in a dose-dependent manner. Schild plot analysis of antagonism by caissarone yielded slopes of near unity, indicating that caissarone acts as a simple competitive antagonist at the adenosine receptor. The dissociation constants (K~) for caissarone ranged from 0.53 mM to 0.78 mM. In functional nicotinic receptor assays in two human cell lines, caissarone failed either to potentiate or to reduce carbamylcholine-mediated S6Rb+ efflux. Thus, the enhancing activity of caissarone on the gut could not be attributed to activity at the ganglionic nicotinic receptor. Based on structure and pharmacological activity, caissarone appears to be the first marine product described as an adenosine receptor antagonist.
Pyrrolizidine alkaloids unsaturated in the 1,2 position are hepatotoxins. Certain of them, such a... more Pyrrolizidine alkaloids unsaturated in the 1,2 position are hepatotoxins. Certain of them, such as monocrotaline, are also pneumotoxins, producing pulmonary arterial hypertension and right ventricular hypertrophy as a delayed response two weeks after administration. Pneumotoxicity is the result of hepatic metabolism, the lung itself being unable to bioactivate pyrrolizidine alkaloids. The changes produced in the lung following exposure to pneumotoxic pyrrolizidine alkaloids are reviewed, together with the factors and interventions which modify or influence these changes. In the main, the earliest changes are seen in vascular smooth muscle and in the interactions between smooth muscle and the endothelium. The search to identify the pneumotoxic metabolite is reviewed. It is generally accepted that pyrroles, or dehydroalkaloids, are responsible for the toxicity of pyrrolizidines. However, the primary pyrroles are intensely reactive, hydrolyzing and polymerizing within seconds in aqueous solution. Evidence for and against the pneumotoxin being a primary pyrrole or a stabilized secondary conversion product of a primary pyrrole is discussed. CONTENTS 1. Occurrence of Pyrrolizidine Alkaloids 2. Metabolic Activation of Pyrrolizidine Alkaloids and Structure-Activity Requirements 3. Cardiopulmonary Toxicity 3.1. Overview of pulmonary changes following pyrrolizidine exposure 3.1.1. Microvascular remodelling 3.2. Cause or consequence 4. Changes Produced in Lungs by Pyrrolizidines and Pyrroles 4.1. Biochemical changes 4.2. Structural changes 4.3. Changes in endothelial function 4.3.1. Monoamine transport 4.3.2. Angiotensin converting enzyme activity 4.3.3. Other endothelial activities 4.4. Platelets 4.5. Inflammation 4.6. Changes in smooth muscle function 4.7. Changes in endothelial-smooth muscle interactions 4.8. Summary of pulmonary actions of pyrrolizidines 5. Dose Relationships 6. Modification of Pyrrolizidine Toxicity 6.1. Collagenization 6.2. Hyperoxia 6.3. Angiotensin converting enzyme inhibitors 6.4. Drugs affecting arachidonate metabolism 6.5. Other interventions 7. What is the Pneumotoxic Metabolite? 7.1. Primary pyrroles 7.2. Secondary pyrroles 383 7.3. Other metabolites 383 7.4. Summary of findings on the identity of the pneumotoxic metabolite of monocrotaline 384 Acknowledgements 385 References 385
Biochemical and Biophysical Research Communications, 1976
... COMMUNICATIONS INCREASE IN TYPE I ADENOSINE 3',5'MONOPHOSPHATEDEPENDENT PROTEIN KIN... more ... COMMUNICATIONS INCREASE IN TYPE I ADENOSINE 3',5'MONOPHOSPHATEDEPENDENT PROTEIN KINASE DURING ISOPROTERENOLINDUCED CARDIAC HYPERTROPHY Craig V. Byus, James M. Chubb, Ryan J. Huxtable ... 38 (eds., JG Hardman and B. O'Malley) pp. ...
mental deficiency, which derives from the author's vast clinical experience, and there are descri... more mental deficiency, which derives from the author's vast clinical experience, and there are descriptions and photographs of many other unusual syndromes. The book is unlikely to find itselfon the bedside table of the general physician or family doctor, but will be read by many with specialist interests in obesity. The price of £17.50 for a paperback may deter some individuals.
Advances in Experimental Medicine and Biology, 1992
Many phenomena involving taurine appear to be based on a membrane-modifying action, although the ... more Many phenomena involving taurine appear to be based on a membrane-modifying action, although the nature of this action has remained largely undefined. Taurine stabilizes membranes under a variety of conditions, reducing malondialdehyde release induced by carbon tetrachloride (Nakashima et al., 1983), and antagonizing the loss of membrane function produced by phospholipase C (Huxtable and Bressler, 1973) among other actions. Taurine also modifies the calcium binding characteristics of membranes, increasing the affinity of calcium binding while decreasing the maximum binding capacity (Huxtable and Peterson, 1988; Sebring and Huxtable, 1985). Perhaps associated with this is a taurine-induced shift in the membrane transition temperature (Lombardini, 1985), and a stimulation of high affinity, energy-dependent calcium transport in the presence of bicarbonate (reviewed in Huxtable, 1989).
Advances in Experimental Medicine and Biology, 1998
Pyrrolizidines are a group of hepatotoxic plant alkaloids6,9. Certain pyrrolizidines are also tox... more Pyrrolizidines are a group of hepatotoxic plant alkaloids6,9. Certain pyrrolizidines are also toxic to lung, heart, the central nerve system, and other organs. Hepatic bioactivation is required for the expression of toxicity8.
The Journal of pharmacology and experimental therapeutics, 1985
A sarcolemma-enriched membrane fraction (SL) was prepared from the hearts of Sprague-Dawley rats ... more 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. T...
The Journal of pharmacology and experimental therapeutics, 1990
Na+/K(+)-Adenosine triphosphatase-dependent activities of K(+)- return relaxation and 86Rb uptake... more Na+/K(+)-Adenosine triphosphatase-dependent activities of K(+)- return relaxation and 86Rb uptake were studied in pulmonary arteries taken from rats with pulmonary hypertension induced by monocrotaline. Rats were given monocrotaline in drinking water, 20 mg/l, for 4 or more days. Isolated arteries were placed in tissue baths and contracted with norepinephrine or 5-hydroxy-tryptamine under K(+)-free conditions. The arteries relaxed when K+ was "returned" to the bath. Compared to arteries from untreated rats, arteries taken from rats pretreated with monocrotaline developed less force in response to contracting agents and did not relax to the same extent. After 4 days treatment with monocrotaline, the rate of relaxation of the arteries in response to K(+)-return was slower than that of arteries taken from untreated rats. Endothelial trauma or in vitro treatment with ouabain produced a similar decrease in the rate of relaxation. Uptake of radiolabeled Rb by perfused arteries w...
Advances in Experimental Medicine and Biology, 1998
Pyrrolizidine alkaloids (PA) comprise a major group of toxins derived from plants. They are botan... more Pyrrolizidine alkaloids (PA) comprise a major group of toxins derived from plants. They are botanically and geographically widespread and cause many public health and economic problems5. PAs cause hepatomegaly, veno-occlusive disease of the liver, and cirrhosis7. The toxicity of PAs can also be expressed in other organ systems, including the heart, lung, and central nervous system.
Monocrotaline is a pyrrolizidine alkaloid obtained from the seeds of Crotalaria spectabilis. When... more 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.
The principal water-soluble amine on the webs of some orb weaving spiders has been variously iden... more The principal water-soluble amine on the webs of some orb weaving spiders has been variously identified as GABamide and 2-pyrrolidone. We present evidence supporting the identification of this compound as GABamide
Advances in Experimental Medicine and Biology, 1987
... 13. Franconi, F., Stendardi, I., Failli, P., Antonini, G., Bennardini, F., Matucci, R., Manzi... more ... 13. Franconi, F., Stendardi, I., Failli, P., Antonini, G., Bennardini, F., Matucci, R., Manzini, S., and Giotti, A., 1983, Taurine antagonizes the alpha-adrenergic positive inotropic effect of phenylephrine," In Sulfur Amino Acids: Biochemical and Clinical Aspects", Kuriyama, K., Huxtable ...
Caissarone, a sea anemone iminopurine, produced an increase in the twitch response of the electri... more Caissarone, a sea anemone iminopurine, produced an increase in the twitch response of the electrically stimulated guinea-pig ileum-myenteric plexus. In the same assay, caissarone reduced the inhibitory response to the endogenous neuromodulator, adenosine, the A~ adenosine receptor agonist, R-phenylisopropyladenosine (R-PIA), and the A2 agonist, 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA) in a dose-dependent manner. Schild plot analysis of antagonism by caissarone yielded slopes of near unity, indicating that caissarone acts as a simple competitive antagonist at the adenosine receptor. The dissociation constants (K~) for caissarone ranged from 0.53 mM to 0.78 mM. In functional nicotinic receptor assays in two human cell lines, caissarone failed either to potentiate or to reduce carbamylcholine-mediated S6Rb+ efflux. Thus, the enhancing activity of caissarone on the gut could not be attributed to activity at the ganglionic nicotinic receptor. Based on structure and pharmacological activity, caissarone appears to be the first marine product described as an adenosine receptor antagonist.
Pyrrolizidine alkaloids unsaturated in the 1,2 position are hepatotoxins. Certain of them, such a... more Pyrrolizidine alkaloids unsaturated in the 1,2 position are hepatotoxins. Certain of them, such as monocrotaline, are also pneumotoxins, producing pulmonary arterial hypertension and right ventricular hypertrophy as a delayed response two weeks after administration. Pneumotoxicity is the result of hepatic metabolism, the lung itself being unable to bioactivate pyrrolizidine alkaloids. The changes produced in the lung following exposure to pneumotoxic pyrrolizidine alkaloids are reviewed, together with the factors and interventions which modify or influence these changes. In the main, the earliest changes are seen in vascular smooth muscle and in the interactions between smooth muscle and the endothelium. The search to identify the pneumotoxic metabolite is reviewed. It is generally accepted that pyrroles, or dehydroalkaloids, are responsible for the toxicity of pyrrolizidines. However, the primary pyrroles are intensely reactive, hydrolyzing and polymerizing within seconds in aqueous solution. Evidence for and against the pneumotoxin being a primary pyrrole or a stabilized secondary conversion product of a primary pyrrole is discussed. CONTENTS 1. Occurrence of Pyrrolizidine Alkaloids 2. Metabolic Activation of Pyrrolizidine Alkaloids and Structure-Activity Requirements 3. Cardiopulmonary Toxicity 3.1. Overview of pulmonary changes following pyrrolizidine exposure 3.1.1. Microvascular remodelling 3.2. Cause or consequence 4. Changes Produced in Lungs by Pyrrolizidines and Pyrroles 4.1. Biochemical changes 4.2. Structural changes 4.3. Changes in endothelial function 4.3.1. Monoamine transport 4.3.2. Angiotensin converting enzyme activity 4.3.3. Other endothelial activities 4.4. Platelets 4.5. Inflammation 4.6. Changes in smooth muscle function 4.7. Changes in endothelial-smooth muscle interactions 4.8. Summary of pulmonary actions of pyrrolizidines 5. Dose Relationships 6. Modification of Pyrrolizidine Toxicity 6.1. Collagenization 6.2. Hyperoxia 6.3. Angiotensin converting enzyme inhibitors 6.4. Drugs affecting arachidonate metabolism 6.5. Other interventions 7. What is the Pneumotoxic Metabolite? 7.1. Primary pyrroles 7.2. Secondary pyrroles 383 7.3. Other metabolites 383 7.4. Summary of findings on the identity of the pneumotoxic metabolite of monocrotaline 384 Acknowledgements 385 References 385
Biochemical and Biophysical Research Communications, 1976
... COMMUNICATIONS INCREASE IN TYPE I ADENOSINE 3',5'MONOPHOSPHATEDEPENDENT PROTEIN KIN... more ... COMMUNICATIONS INCREASE IN TYPE I ADENOSINE 3',5'MONOPHOSPHATEDEPENDENT PROTEIN KINASE DURING ISOPROTERENOLINDUCED CARDIAC HYPERTROPHY Craig V. Byus, James M. Chubb, Ryan J. Huxtable ... 38 (eds., JG Hardman and B. O'Malley) pp. ...
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