SUMMARY Plasma glutathione S-transferase (GST) measurements have been used to study early changes in hepatocellular integrity after paracetamol overdose and treatment with Nacetylcysteine (NAC). Patients admitted within seven hours and successfully treated had raised or equivocal GST on admission and each showed a transient peak in GST approximately 12 hours after the overdose. Similar, though smaller changes in GST, were seen in untreated patients whose paracetamol level fell below the treatment line. The plasma GST concentrations in successfully treated patients were small compared with values found in patients who subsequently developed severe liver damage. The changes in GST concentration observed in patients who developed severe liver damage indicated that distinct early and late phases of paracetamolinduced hepatotoxicity occurred. Although the mechanism by which paracetamol exerts its early toxic effect is unclear, our data suggest that prompt treatment with NAC can successfully prevent both clinical and subclinical hepatotoxicity in this early period.Paracetamol hepatotoxicity is caused by the production of an electrophilic arylating metabolite which binds covalently to macromolecules and initiates cell damage. This metabolite is normally rapidly inactivated by conjugation with glutathione but when the amount of paracetamol ingested is large, glutathione stores may be rapidly depleted and the toxic metabolite produces hepatocellular damage.
1. Blood flow was measured in the renal cortex and medulla of anaesthetized rats by the hydrogen washout method. The effects of dopamine infusion were measured. 2. Low doses of dopamine (20 and 65 n‐mole.kg‐1.min‐1) caused only small increases in renal blood flow, and a higher dose (200 n‐mole.kg‐1.min‐1) caused vasoconstriction. After alpha‐blockade with phenoxybenzamine (9 mumole.kg‐1), all doses of dopamine caused vasodilatation in the cortex and medulla of the kidney. 3. This dopamine‐induced renal vasodilatation was almost abolished by sulpiride (0.7 mumole.kg‐1.min‐1), but was only slightly attenuated by propranolol (10 mumole.kg‐1). 4. Sulpiride did not significantly alter the renal blood flow responses to noradrenaline or isoprenaline, or the blood pressure responses to histamine, acetylcholine, 5HT, noradrenaline and isoprenaline. 5. In normal rats, infusion of sulpiride generally caused a reduction in renal cortical blood flow. This response showed a positive correlation with the initial blood pressure. 6. It is concluded that there are specific dopamine receptors in the renal vasculature of the rat, and that dopamine may play a role in the normal control of renal blood flow.
SUMMARY1. Methods are described for estimating the half-life of angiotensin analogues and renin in the rat, from the time course of the blood pressure changes they evoke.2. The following half-life values were measured: angiotensin II, 16 + 1 see; angiotensin III, 14+ 1 see; angiotensin II-amide, 15±+1 see; Sarl-Ala8-angiotensin II, 6-4 + 0-6 min; renin, 3 0 + 0 4 min. The apparent distribution volume of angiotensin was found to be 18 ml./kg body wt.3. It is inferred that the Asp' residue does not reduce the rate of angiotenrsin II catabolism, but that substitution of this residue by sarcosine may inhibit catabolism while substitution by asparagine has no effect.4. Five experimental criteria were identified which indicate that these methods give reliable estimates of the half-life. It is suggested that these results are more accurate than most previous half-life estimates.5. When tachyphylaxis to angiotensin II-amide occurs, the pressor activity of the plasma is not reduced.
We use the results of recent publications as vehicles with which to discuss the thermodynamics of the proton-driven mitochondrial FoF1-ATP synthase, focusing particularly on the possibility that there may be dissociation between rotatory steps and ATP synthesis/hydrolysis. Such stoichiometric ‘slippage’ has been invoked in the literature to explain observed non-ideal behaviour. Numerical solution of the Rate Isotherm (the kinetic equivalent of the more fundamental Probability Isotherm) suggests that such ‘slippage’ is an unlikely explanation; instead, we suggest that the experimental results may be more consistent with damage to the enzyme caused by its isolation from the biomembrane and its experimental fixation, resulting in non-physiological friction within the enzyme's rotary mechanism. We emphasize the unavoidable constraint of the Second Law as instantiated by the obligatory dissipation of Gibbs Free Energy if the synthase is to operate at anything other than thermodynamic equilibrium. We use further numerical solution of the Rate Isotherm to demonstrate that there is no necessary association of low thermodynamic efficiency with high metabolic rates in a bio-world in which the dominating mechanism of metabolic control is multifactorial enzyme activation.
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