Biomedical subjects
Publications and source records attributed to M J Lewis.
Catamenial pneumothorax (CPT) is a rare complication of systemic endometriosis, as shown by this classic case. A nonsteroidal antiinflammatory prostaglandin synthetase inhibitor was used to treat the patient.
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We investigated the effects of atrial natriuretic peptide (ANP) on release of endothelium-derived relaxing factor (EDRF) from rabbit aorta and central ear artery using inhibition of platelet aggregation and vascular smooth muscle relaxation respectively as measures of EDRF activity. ANP at concentrations greater than 10(-9) M inhibited carbachol-induced EDRF release from rabbit aorta and acetylcholine-induced EDRF release from the central ear artery. These findings are consistent with previous observations that 8-bromo cyclic GMP inhibits EDRF release from rabbit aorta and ANP inhibits release of EDRF from cultured endothelial cells.
We have used a bioassay-cascade system to investigate the inhibitory effects of human red blood cells on EDRF activity. The vascular smooth muscle relaxant effect of EDRF released from an endothelium-intact pig coronary artery by the calcium ionophore A23187 was inhibited by washed red cells. This inhibition of EDRF activity by red cells was similar to that expected from their haemoglobin content. This study provides further evidence that in vivo EDRF acts as a local autocoid.
The characteristics of the inotropic response to endothelin were studied in isolated ferret papillary muscle preparations. Endothelin (0.1-10 nM) induced concentration-dependent positive inotropic effects. At 10 nM, isometric tension increased by 17%, maximum rate of tension development by 18%, maximum velocity of unloaded shortening by 23% and peak isotonic shortening by 11%. Time to peak isometric tension and half isometric relaxation time were unaltered by endothelin. This pattern of change is similar to that of elevating extracellular calcium concentration.
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Release of endothelium-derived relaxing factor was measured from freshly isolated human saphenous vein and from vein subject to routine surgical preparation for coronary artery bypass grafting. Surgical preparation led to a significant decline in endothelium-derived relaxing factor release as compared with freshly isolated vein, and these changes were associated with loss of endothelial coverage. Storage of freshly isolated vein in blood but not in Hartmann's solution also resulted in a decline in maximally stimulated endothelium-derived relaxing factor release that was not associated with loss of endothelium. Reduced production of endothelium-derived relaxing factor, a potent vasodilator and inhibitor of platelet adhesion and aggregation, may be implicated in the etiology of early vein graft thrombosis.
The concentration range of GTN causing inhibition of platelet aggregation in vitro is much higher than the plasma concentrations achieved clinically. This action is potentiated by the sulphydryl donor N-acetylcysteine. We have investigated the effects of GTN given with and without N-acetylcysteine on ex vivo platelet aggregation in man. In a double-blind randomised crossover trial eight healthy volunteers were treated with 20 mg of transdermal GTN/24 h, together with N-acetylcysteine 200 mg three times daily or matching placebo. Platelet aggregation, measured ex vivo by whole blood impedance aggregometry in response to adenosine diphosphate, was not significantly altered by GTN acutely or after 4 days' treatment with or without N-acetylcysteine. Platelet cyclic guanosine monophosphate levels were not significantly altered by GTN either in the absence or presence of N-acetylcysteine. This result implies that previously reported beneficial effects of GTN in myocardial infarction or unstable angina are unlikely to be attributable to direct pharmacological inhibition of platelet aggregation.
1. The effects of chronic dosing with N-acetylcysteine (NAC), on nitrate-induced haemodynamic changes during the acute and chronic treatment of healthy volunteers with glyceryl trinitrate (GTN) patches (Transiderm nitro) has been investigated. 2. Seven volunteers were treated in a double-blind randomised crossover manner for two periods of 4 days with 20 mg of transdermal GTN/24 h together with NAC (200 mg three times daily) or matching placebo. There was a washout period of greater than 3 days between treatment periods. 3. Haemodynamic measurements (blood pressure (BP); heart rate (HR] at rest and following maximal treadmill exercise were performed before treatment and 4 h after starting treatment on days 1 and 4. 4. Significant haemodynamic changes as evidenced by a fall in BP and rise in HR, were seen on day 1 in both the NAC and placebo phases. By day 4 the haemodynamic changes had returned towards the pre-treatment values during both the NAC and placebo phases suggesting the development of tolerance in both treatment groups. 5. These findings suggest that concurrent administration of NAC fails to prevent the development of tolerance to GTN.
1. The release of endothelium-derived relaxing factor (EDRF) from rabbit aorta and pig coronary artery vessels in response to acetylcholine (ACh), substance P (SP) and the calcium ionophore A23187 has been studied by means of a bioassay cascade system. 2. A technique is described which allows the quantification of EDRF release rates from vessels of different sizes, perfused at different flow rates and with different donor-recipient transient times. 3. Rabbit aorta and pig coronary arteries, perfused at flow rates which equalize endothelial shear stress, released EDRF at a similar basal rate. 4. In response to ACh, rabbit aortic endothelium released EDRF at a significantly greater maximum rate than pig coronary artery endothelium. 5. In response to SP, both endothelium types released EDRF; SP was a significantly more potent agonist in pig coronary artery than in rabbit aorta, but maximum SP-induced EDRF release from rabbit aorta was twice that of pig coronary artery. 6. These data indicate that different endothelium types can release EDRF at widely different rates, according to the agonist used, and that the previously obtained lack of relaxant response to ACh in pig coronary artery was due to a lack of EDRF release rather than concomitant smooth muscle constriction.
1. The effects of endothelium-derived relaxing factor (EDRF), sodium nitroprusside, 8-bromo-cyclic GMP and atrial natriuretic factor (ANF) on inositol trisphosphate (IP3) levels were studied in isolated rabbit aortic preparations stimulated with noradrenaline. 2. In endothelium-containing preparations, acetylcholine, which stimulated EDRF release, inhibited noradrenaline-stimulated IP3 formation. The EDRF inhibitor haemoglobin reversed this effect. 3. In endothelium-denuded preparations, sodium nitroprusside, 8-bromo-cyclic GMP and ANF each similarly inhibited the rise in IP3 levels stimulated by noradrenaline. 4. These findings show that in rabbit aorta, agents which increase cyclic GMP inhibit the noradrenaline-induced rise in IP3 levels and may provide an explanation for the previously reported observations that cyclic GMP inhibits the noradrenaline-stimulated increase in calcium influx and release of intracellular calcium in vascular smooth muscle.
The effects of the angiotensin converting enzyme inhibitor enalapril on myocardial sympathetic tone, as represented by noradrenaline overflow, were studied in 14 men with congestive heart failure (mean ejection fraction 20%) in a double blind crossover comparison with placebo. Arterial and coronary sinus catecholamine concentrations and oxygen content, and coronary sinus blood flow, were measured at rest and during peak symptom limited upright exercise on a bicycle ergometer. There were no significant changes four hours after the first dose of enalapril, but after six weeks of treatment (10-20 mg/day) enalapril reduced myocardial overflow of noradrenaline at peak exercise. The external workload (exercise duration) increased from baseline values after both placebo and enalapril, and there was no difference between placebo and enalapril at six weeks. Heart work, however, was lower after enalapril: stroke work index was reduced at rest and the double product was lower at peak exercise. The reduction in maximal myocardial oxygen consumption after enalapril did not reach statistical significance. Coronary sinus adrenaline concentrations after enalapril and after placebo were not significantly different. The long term reduction of myocardial sympathetic activity on exercise may represent a significant benefit from angiotensin converting enzyme inhibition in heart failure and may reflect a reduced cardiac workload.
A 27-year-old white woman developed Heinz-body hemolytic anemia following multiple courses of oral phenazopyridine and trimethoprim-sulfamethoxazole. Her diagnosis was supported by the finding of bite cells on peripheral blood smear. The patient's rapid recovery and reversal of abnormal laboratory parameters were consistent with an acquired hemolytic disorder. This case should sensitize the clinician to the development of drug-induced oxidative hemolysis, its clinical features, and its reversibility. It is also important that the clinician recognize those drugs capable of causing this disorder and appreciate the methods available to establish the diagnosis.
A natural exposure study was conducted in a herd of 150 lactating dairy cows for 18 mo to determine the effectiveness of chlorous acid and chlorine dioxide in a soluble polymer gel as a postmilking teat disinfectant for the prevention of bovine mastitis. Right quarters of cows were dipped in the experimental teat dip after milking machine removal. Left quarters were not dipped and served as within-cow negative controls. The experimental teat dip reduced Staphylococcus aureus infections 67.4%, Streptococcus dysgalactiae infections 63.8%, and Streptococcus uberis infections 27.8%. Overall efficacy of the chlorous acid and chlorine dioxide teat dip against major mastitis pathogens was 52.2%. The experimental teat dip reduced Corynebacterium bovis infections and coagulase-negative staphylococcal infections also by 45.8 and 38.7%, respectively. Overall efficacy against minor mastitis pathogens was 43.4%. Under conditions of this trial, the experimental teat dip containing chlorous acid and chlorine dioxide was effective in preventing new intramammary infections against a variety of mastitis pathogens.
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In animal cells, luminal endoplasmic reticulum (ER) proteins are prevented from being secreted by a sorting system that recognizes the C-terminal sequence KDEL. We show that yeast has a similar sorting system, but it recognizes HDEL, rather than KDEL: derivatives of the enzyme invertase that bear the HDEL signal fail to be secreted. An invertase fusion protein that is retained in the cells is partially modified by outer-chain mannosyl transferases, which reside in the Golgi element. This supports the view, based on studies in animal cells, that ER targeting is achieved by continuous retrieval of proteins from the Golgi. We have used an invertase fusion gene to screen for mutants that are defective in this sorting system. Over 60 mutants were obtained; eight of these are alleles of a single gene, erd1. The mutant strains grow normally at 30 degrees C, but instead of retaining the fusion protein in the cells, they secrete it.
Processing of M13 procoat protein, synthesized in a bacterial cell-free extract, to transmembrane coat protein by dog pancreas microsomes is stimulated by a system which is present in rabbit reticulocytes and depends on nucleoside triphosphates. This system consists of (at least) two components which act synergistically: members of the 70-kd heat shock protein family and (at least) one additional component. This component depends on ATP (or GTP) for its action.
Acebutolol (400 mg once daily), atenolol (100 mg once daily) and placebo were self administered to 12 healthy male volunteers in a double-blind crossover study. Each drug treatment was administered for 4 days so that subjects' plasma levels of the drug were at steady state. Subjects were tested on the 4th day. On each of the 3 test days subjects underwent an anxiety induction procedure involving both easy and difficult versions of the Stroop test and syntactic reasoning. Measures of state anxiety were taken during the difficult task, an easy version of the task and after a period of quiet relaxation. High, medium and low levels of anxiety corresponded to the three levels of task difficulty. Highly significant differences were exhibited in state anxiety between high, medium and low anxiety induction procedures with both Stroop test and syntactic reasoning. This was shown by highly significant main effects for task difficulty with both tasks. There was no significant anxiolytic action of either acebutolol or atenolol when compared to placebo (there were no drug effects or any interaction of drugs with task difficulty). There were no significant drug effects upon any of the cognitive test measures. Overall, there was no evidence of either anxiolysis or sedation with either of these two relatively hydrophilic drugs.