Biomedical subjects
Publications and source records attributed to M J Lewis.
The case histories are presented of three separate incidents of poisoning by ingestion of Hemlock Water Dropwort tubers (Oenanthe crocata). Two of these cases involved a fatality. An analytical profile is provided for oenanthotoxin, the major toxic principal of the tubers. Chromatographic, spectroscopic and mass spectral data for related compounds are also given.
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Catecholamine-induced myocardial hypertrophy and necrosis in rats have been measured and compared following treatment with different catecholamines. Significant degrees of both hypertrophy (whether measured as biventricular weight or biventricular/body weight ratio) and necrosis (measured by enzyme histochemical techniques on a standardized series of cryostat sections through the apex of each heart) occurred following 10 days' treatment with daily isoproterenol (0.5 or 5 mg/kg s.c.) or dobutamine (5 mg/kg s.c.) (N = 6-12). These agents given to conscious restrained animals lowered blood pressure and increased heart rate for 3, 6, or 1 hr, respectively. Neither hypertrophy nor necrosis occurred after norepinephrine (1 mg/kg) or dopamine (5 mg/kg); both these agents acutely increased blood pressure for about 30 min. Hemodynamic factors may therefore contribute to catecholamine-induced necrosis, which may in turn contribute to the associated hypertrophy.
Using an isolated perfused coronary-artery preparation, we have demonstrated the ability of endothelium inhibit markedly to vasomotion in rabbit coronary arteries. Using a bioassay system, we have shown this effect to be mediated via the release of an unstable humoral agent (t 1/2 approximately equal to 6 sec) from endothelial cells, and we have partially characterized its chemical nature.
Isolated papillary-muscle preparations from the cat and rabbit were used to study the phenomenon of reoxygenation contracture and whether is is amenable to intervention independently of the preceding hypoxic insult. Reduction of extracellular Ca2+ to "0" mM abolished reoxygenation contracture, but subsequent replacement of Ca2+ resulted in severe contracture and death due to the "calcium paradox." Lowering of Ca2+ to 0.125 mM and its stepwise replacement to 2.5 mM resulted in no contracture with good mechanical recovery. Gradual reoxygenation, Mg2+ (30 mM), Mn2+ (8 mM), or H+ (pH 6.5) ions, or diltiazem (10(-4) M) delayed but did not prevent the development of contracture and contractile failure. Unlike diltiazem, verapamil (10(-4) M) and lidoflazine (2 X 10(-5) M) did not significantly affect the contracture.
Male Sprague-Dawley rats were raised from weaning in one of the three housing conditions: one, two or four per housing unit. At 60 days of age, animals were moved to individual cages and tested in the open field. Following a baseline period in which animals were allowed to adapt to their new housing condition, animals had their water replaced with a 0.8 mg/ml morphine sulfate solution. Following 12 days of access to the drug, animals were injected with naloxone and abstinence precipitated. While no differences were found in body weight among the three groups of animals at 60 days of age, significant differences in open field behavior were noted. Animals that were raised in groups were found to be more active in the open field than animals raised in isolation. Early housing experience was also found to modify later morphine consumption and physical dependence. Animals raised in isolation exhibited a trend to start drinking morphine sooner and experienced less severe withdrawal symptoms following naloxone administration than group-raised animals.
Ergometrine has generally been regarded as a vasoconstrictor and is used clinically to provoke coronary vasospasm in susceptible patients [3, 8, 9]. The ergometrine response appears however to be complex in that it can be biphasic, the constrictor response being preceded by an initial dilator response in experimental models [4]. The explanation for this is unknown, as is the underlying mechanism responsible for the clinical condition of coronary vasospasm. We have investigated this biphasic response in isolated artery preparations and shown that the dilator component is due to ergometrine-induced release of endothelium-derived relaxant factor (EDRF).
The effect of myocardial catecholamine depletion on cellular electrophysiology and arrhythmias was assessed in Langendorff perfused guinea pig hearts during ischaemia and reperfusion. Myocardial noradrenaline was reduced to 0.17 +/- 0.04 microgram X g-1 by intracardiac injection of 6-hydroxydopamine (450 mg X kg-1 in six doses over 20 days) compared with 1.5 +/- 0.2 microgram X g-1 in vehicle injected controls. Myocardial catecholamine depletion significantly reduced the incidence of ventricular tachycardia and fibrillation during 30 min of global ischaemia and subsequent reperfusion. Myocardial catecholamine depletion prolonged action potential duration and refractory period during control perfusion and blunted ischaemia induced reduction in action potential amplitude, Vmax, and duration, but accentuated the prolongation in conduction time and QRS width. Catecholamine depletion abolished or attenuated reperfusion induced shortening of action potential duration and refractory period. Catecholamine depletion increased myocardial glycogen levels from 2.47 +/- 0.3 mg X g-1 wet weight to 4.39 +/- 0.3 mg X g-1; fasting animals for 48 h prior to study reversed this with no attenuation of the electrophysiological or antiarrhythmic action. These results provide further evidence that release of endogenous myocardial catecholamines contributes to the electrophysiological changes and arrhythmias associated with myocardial ischaemia and reperfusion.
We have measured the psychological effects of acebutolol and atenolol in sixteen patients with essential hypertension. The drugs were administered in a randomized, placebo-controlled, double-blind manner, in single daily doses of 100 mg atenolol, 400 mg acebutolol or placebo for periods of 6 weeks, each drug period being separated by a placebo period. At each 2 weekly clinic visit, a questionnaire designed for assessment of state anxiety and state arousal was administered for self-completion. Arousal was significantly reduced by atenolol over the whole 6 weeks of administration. It was not affected by acebutolol. Anxiety was significantly reduced by acebutolol but only at the first of the three 2 weekly assessments on treatment. It was not affected by atenolol. Differences in the psychological effects of these two beta-adrenoceptor blockers are discussed in terms of their lipid solubility and haemodynamic effects.
Isolated perfused coronary arteries and aortic ring preparations of rabbits were studied, both with intact endothelium and with endothelium removed by K-rich solution and friction respectively. Constrictor dose-responses to histamine, acetylcholine, phenylephrine and 5-hydroxytryptamine (5-HT) were measured. They were greatly depressed by the presence of endothelium in coronary preparations. In aortic preparations endothelium affected dose-responses relatively little, depressing the response to acetylcholine but apparently increasing the responses to the other three agents. Acetylcholine relaxed pre-constricted coronary or aortic preparations but only when endothelium was present. This relaxation was inhibited by quinacrine or hydroquinone. Aortic preparations had resting tone which could be increased by hydroquinone if endothelium was present, suggesting continual release of endothelium-derived relaxant factor (EDRF) at rest. When allowance was made for basal EDRF activity in aortic preparations, the maximal constrictor response to acetylcholine remained lower in the presence of endothelium, consistent with acetylcholine stimulation of EDRF, but maximal constrictor responses to the other three agents were the same with and without endothelium, suggesting that the direct constrictor response overrides EDRF activity.
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Using isoprenaline and glyceryl trinitrate (GTN) induced tachycardia we have compared the rebound beta-adrenoceptor hypersensitivity on stopping slow-release and conventional oxprenolol in young normotensive subjects. Heart rate on standing with GTN rose after stopping slow-release and conventional oxprenolol to peak levels on day 2 or 3 significantly greater than corresponding control levels off treatment on day 5. The isoprenaline CD25 (the dose required to increase heart rate by 25 beats/min) fell after stopping conventional oxprenolol to a significantly lower level on day 3 than the control level off treatment on day 5. Contrary to a recent report describing no rebound beta-adrenoceptor hypersensitivity on stopping slow-release oxprenolol we have demonstrated it after stopping slow release as well as conventional oxprenolol.
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The incidence of campylobacter gastroenteritis in the population of Nottingham over a period of 3 years was studied. There was a seasonal variation with the highest number of cases occurring in the summer months. Campylobacter sp. were isolated from the stools of a total of 780 patients over this period. Of these 160 patients with gastroenteritis required admission to hospital. These patients' illness had an acute onset, and the predominant features were diarrhoea, severe abdominal pain, nausea and bright red blood with the stool. However not all the patients had diarrhoea. More than a third of the patients studied were less than 10 years old. The mean duration of symptoms was 4 days and the average stay in hospital was 5 days; some patients required prolonged admission (14 days). In a few cases campylobacter enteritis mimicked other clinical conditions including acute appendicitis. This study emphasises the importance of campylobacter enteritis as a cause of gastroenteritis in the community and the degree of morbidity associated with this illness.
The beta-blocking potencies (pA2 values) and cumulative dose responses of the direct effects of dl-propranolol, practolol, acebutolol and sotalol have been characterised in respect of the mechanical performance of isolated cat papillary muscle preparations. pA2 values calculated from antagonism of each of the drugs to the inotropic effect of isoprenaline at 29 degrees C were: dl-propranolol 8.3, practolol 5.6, acebutolol 7.5 and sotalol 4.8. The responses in reserpinized muscles were similar to those in non-reserpinized preparations. dl-Propranolol at concentrations of 10(-5) and 10(-4) M depressed peak developed force (DF) and rate of force development (+dF/dt) by 20% and 60% respectively, with similar but smaller changes in maximum unloaded shortening velocity ('Vmax'). Practolol and sotalol increased DF and +dF/dt by less than 10% at 10(-5) M and by 10-20% at 10(-4) M, with similar but smaller changes in Vmax. Sotalol induced prolonged biphasic contractions at 10(-4) M. Acebutolol had no effect on DF, +dF/dt, or Vmax. Time to peak force and half isometric relaxation time were not altered by any drug. Practolol and acebutolol, generally considered to have partial agonist activity, exerted this to a negligible degree in respect of inotropic effect at less than or equal to 10(-5) M.
M-mode echocardiograms and systolic time intervals were recorded before and six weeks after stopping digoxin in 11 patients in sinus rhythm to see whether the inotropic effect of digoxin was maintained with long-term treatment. Significant changes indicating a reduction in inotropic state on stopping digoxin were observed in the group. Clinical deterioration occurred in only one patient, associated with evidence of initially impaired cardiac function rather than an atypical response to digoxin. This study provides evidence that chronic digoxin treatment does continue to exert a positive inotropic effect.
The effects of d-amphetamine on ad libitum consummatory behavior of genetically obese Zucker rats and their lean littermates were examined in two experiments. In Experiment 1 food intake was measured every two hours for six hours following intraperitoneal injections of 0.0, 0.5, and 1.0 mg/kg of d-amphetamine sulfate. Both lean and obese animals significantly suppressed food intake for the first two hours after injection of 0.5 and 1.0 mg/kg doses. Lean animals displayed no suppression of food intake at four or six hours after injection. In contrast to lean animals, obese rats continued to show a suppression of feeding at four hours after injection of 1.0 mg/kg. Total six-hour food intake of obese animals was significantly suppressed from baseline after 0.5 and 1.0 mg/kg of amphetamine, but only after the 1.0 mg/kg injection with lean animals. Experiment 2 examined the effects of these same doses on both food and water intake of different groups of obese and lean Zucker rats. The enhanced anorexia with the 1.0 mg/kg injection of amphetamine was replicated. Water intake, however, was suppressed only during the first two hours after both the 0.5 and 1.0 mg/kg injection in obese and lean rats. Results of the present experiments are discussed in light of previous studies of the effects of amphetamine on hypothalamically obese animals.
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