Captopril test in screening hypertensive patients.
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Captopril↗
Biomedical subjects
M J Daly
Publications and source records attributed to M J Daly.
Calcium-mediated damage during post-ischaemic reperfusion.
Ca2+ gain during reperfusion after an ischaemic episode may be of primary importance in the development of cell death and tissue necrosis. These studies were undertaken to examine the possibility of modifying Ca2+ gain by introducing interventions only upon reperfusion. Electron microscopy did not reveal the presence of holes in the sarcolemma prior to reperfusion, indicating that Ca2+ entry at the moment of reperfusion is not through rents in the sarcolemma. Reperfusion with acidotic buffer (pH 6.4 or 6.6) after 60 min ischaemia attenuated Ca2+ gain. However, this attenuation persisted only as long as the acidotic conditions were maintained. Conversely, reperfusion under alkalotic conditions (pH 7.9) exacerbated Ca2+ gain. Reperfusion with hypoxic buffer after 60 min ischaemia did not alter Ca2+ gain, but readmission of oxygen after a period of hypoxic post-ischaemic reperfusion triggered a further gain in Ca2+. Addition of 5 microM nifedipine to the reperfusion medium slowed Ca2+ gain, while 1 microM Bay K 8644, a calcium agonist, enhanced the gain at early times of reperfusion. Addition of 20 microM W-7, a calmodulin antagonist, to the reperfusion medium had no effect on post-ischaemic Ca2+ gain. Therefore, we have shown that it is possible to alter post-ischaemic Ca2+ gain by introducing interventions only upon reperfusion. However, Ca2+ gain could only be delayed, rather than prevented and ultimately no long-term protection was achieved. These results indicate that post-ischaemic Ca2+ gain is highly pH-sensitive and that entry of Ca2+ through voltage-activated slow channels may contribute to the early gain.
Animals↗
A mixed pattern of endocrine cells in metaplastic Barrett's oesophagus. Evidence that the epithelium derives from a pluripotential stem cell.
In order to characterize the differentiation of endocrine cells present in Barrett's oesophagus and to determine if they express a single or multiple hormonal pattern, endoscopic biopsies were taken from both the lesion and the fundus of 45 patients and studied at the light microscopical level. Conventional histology revealed three different epithelial patterns: gastric atrophic fundic, intestinal and junctional. A mixture of these patterns was present in 28 cases (62%) and the single type was identified in 17 cases (38%). The use of three silver staining methods and antibodies to human chromogranins allowed us to identify numerous endocrine cells in all but 1 case. Eleven sera against all the most common hormones stored in the endocrine cells of the gut were used to identify the main products of the cells. The following immunoreactivities were identified: 5-hydroxytryptamine (5-HT) (in 75% of the studied cases), somatostatin (87%), motilin (31%), pancreatic polypeptide (PP) (20%), glucose-dependent insulinotropic polypeptide (20%), gastrin (15%), glucagon (15%), peptide tyrosine tyrosine (13%), secretin (7%) and neurotensin (2%). No cholecystokinin-immunoreactive cells were identified. Our results indicated that, in Barrett's epithelium, both gastric and intestinal endocrine cells differentiate, in accordance with the variability of differentiation in the non-endocrine cells present in the different types of columnar epithelium. These findings provide support for the conclusion that Barrett's epithelium arises from a pluripotential stem cell capable of both gastric and intestinal differentiation.
Aged↗
Inhibition of aromatase activity in the rat by aminoglutethimide and related compounds.
Two compounds possessing aromatase inhibitory activity have been evaluated for their effects on oestradiol (E2) biosynthesis in the rat. These compounds, structurally related to aminoglutethimide (1), were administered intra-peritoneally at two dose levels to 10 week old female rats previously treated with pregnant mares' serum gonadotrophin (PMSG, 100 i.u. subcutaneously every other day for 9 days). Three hours after dosing, blood was collected and plasma oestradiol levels determined by RIA. Aminoglutethimide, 3-(4'-aminophenyl-3-ethylpyrrolidine-2,5-dione (2) and N-methyl-3-(4'-aminophenyl)-3-ethylpyrrolidine-2,5-dione (3) decreased E2 blood levels by 98, 97 and 82% of control levels respectively (n = 6) at a dose of 50 mg/kg. Similarly effective inhibition was also observed at a dose of 25 mg/kg (n = 4). Ovarian aromatase activity, assessed by incubating the homogenised ovaries of treated rats with tritium-labelled androstenedione (0.2 microM) or testosterone (1 microM), indicated that residual enzyme activity was reduced compared with controls. Aminoglutethimide, and the new pyrrolidinedione aromatase inhibitors 2 and 3, are therefore effective inhibitors of E2 biosynthesis in the rat with functioning ovarian activity.
Aminoglutethimide↗
MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations.
With the advent of RFLPs, genetic linkage maps are now being assembled for a number of organisms including both inbred experimental populations such as maize and outbred natural populations such as humans. Accurate construction of such genetic maps requires multipoint linkage analysis of particular types of pedigrees. We describe here a computer package, called MAPMAKER, designed specifically for this purpose. The program uses an efficient algorithm that allows simultaneous multipoint analysis of any number of loci. MAPMAKER also includes an interactive command language that makes it easy for a geneticist to explore linkage data. MAPMAKER has been applied to the construction of linkage maps in a number of organisms, including the human and several plants, and we outline the mapping strategies that have been used.
Chromosome Mapping↗
Contracture and the calcium paradox in the rat heart.
The role of contracture in the manifestation of calcium paradox-induced damage was examined using 2,3-butanedione monoxime (BDM) to inhibit myofibrillar activity. Calcium and sodium gain, loss of intracellular components, and changes in structure were monitored. If 30 mM BDM was added at the time of calcium repletion after 10 minutes of calcium-free perfusion, some protection was afforded, particularly at the early stages of calcium repletion. However, much greater protection was obtained if BDM was present during the final 2 minutes of calcium-free perfusion and throughout repletion. Sodium gain and loss of intracellular components were markedly attenuated, as was the incidence of severely contracted cells. Calcium gain, although significantly reduced during the period of repletion, was not abolished. After 10 minutes of repletion, a calcium content of 11.44 +/- 1.57 mumol/g dry wt was observed. This suggests that other noncontracture related routes of calcium entry are involved. If BDM is removed after 5 minutes of calcium repletion and perfusion is continued with BDM-free perfusate, there is a rapid gain of sodium, further gain of calcium, loss of intracellular components and the cells contract severely, tearing away from neighboring cells. It is evident, therefore, that returning calcium to hearts after a period of calcium-free perfusion under conditions that significantly reduce the typical calcium paradox-associated damage does not necessarily repair the underlying defect. These results support the hypothesis that contracture-induced sarcolemmal disruption may be responsible for the terminal manifestation of the calcium paradox.
Animals↗
Imaging in acute renal infection in children.
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Child↗
Effect of inhibition of acid secretion on the regulatory peptides in the rat stomach.
The effect of inhibiting acid secretion by pharmacologic agents on the gastric content of regulatory peptides has been determined by radioimmunoassay and immunocytochemistry. Plasma, antral, and fundic concentrations of gastrin were elevated in rats rendered virtually achlorhydric by treatment with high-dose omeprazole (400 mumol/kg daily for 10 wk). This was associated with an increase in the number and staining intensity of gastrin immunoreactive cells. A clear reciprocal relationship was observed between antral gastrin and somatostatin as assessed by both quantitative and qualitative methods. These changes had disappeared 10 wk after treatment was stopped. No alteration was found in the concentrations of other regulatory peptides proposed as important in control of acid secretion. Plasma and antral gastrin concentrations were elevated in rats treated with high-dose ranitidine (700 mumol/kg daily), but to a lesser extent than during omeprazole therapy, and somatostatin concentrations were unchanged.
Animals↗
Synthesis and biochemical evaluation of analogues of aminoglutethimide based on phenylpyrrolidine-2,5-dione.
A series of (aminophenyl)pyrrolidine-2,5-diones has been prepared that bear structural similarities to aminoglutethimide (1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The inhibitory activity of these compounds was evaluated toward human placental aromatase and bovine adrenal cholesterol side chain cleavage (CSCC) enzyme assay systems. Selective, competitive inhibition of the aromatase enzyme system was demonstrated by 5 (3-(4-aminophenyl)-1-methyl-pyrrolidine-2,5-dione, Ki = 1.75 microM), 6 (3-(4-aminophenyl)-1,3-dimethylpyrrolidine-2,5-dione, Ki = 1.75 microM), 7 (3-(4-aminophenyl)-3-methylpyrrolidine-2,5-dione, Ki = 0.8 microM), and 8 (3-(4-aminophenyl)-3-ethylpyrrolidine-2,5-dione, Ki = 1.0 microM). Compound 15 (3-(4-aminophenyl)pyrrolidine-2,5-dione) proved unexpectedly difficult to prepare following standard methods and was only moderately inhibitory toward aromatase (IC50 = 20 microM). Compound 16 (3-(4-aminophenyl)-3-ethyl-1-methylpyrrolidine-2,5-dione) was weakly inhibitory toward testosterone aromatization and totally inactive toward androstenedione aromatization. These compounds were either weak or ineffective inhibitors of the CSCC enzyme systems, while 1 gave Ki values toward aromatase and CSCC enzymes of 0.68 and 14 microM, respectively. The unsubstituted phenylpyrrolidinediones were inactive in either system, and the 4-nitrophenyl derivatives exhibited weak, nonselective inhibition, indicating the importance of the primary amine moiety for potent inhibition of aromatase activity.
Aminoglutethimide↗
Gastric regulatory peptides in rats with reduced acid secretion.
Gastric acid secretion is known to be controlled by a complex system of interacting factors. Amongst these, regulatory peptides make a significant contribution. In the present study, immunocytochemistry and radioimmunoassay were used to investigate gastric regulatory peptides in animals with pharmacologically reduced gastric acid secretion. Increased numbers of densely immunostained antral gastrin-immunoreactive (G) cells were seen in rats which had been rendered virtually achlorhydric by administration of high-dose (400 mumol/kg daily) omeprazole over a 10-week period. These morphological changes were accompanied by increases in the plasma, antral and fundic concentrations of gastrin, as measured by radioimmunoassay. In contrast, antral somatostatin-containing cells were reduced, and there was a corresponding fall in the tissue content of the peptide. Ten weeks after treatment had ceased, the peptide profiles had returned to normal. No other regulatory peptide, whether endocrine or neural, appeared to alter during treatment with high-dose omeprazole. Treatment with high-dose (700 mumol/kg daily) ranitidine also caused an elevation in the G cell population and the antral and plasma content of gastrin, but to a lesser extent than that observed during omeprazole treatment. Somatostatin cells and tissue levels did not alter in these animals, and no other morphological changes could be detected. Radioimmunoassay, however, measured reduced quantities of vasoactive intestinal peptide, peptide histidine isoleucine and calcitonin gene-related peptide. Achlorhydria, induced by omeprazole at a dosage of 250-500 times that required for effective acid inhibition in man and animals, therefore resulted in reciprocal changes in gastrin and somatostatin cells. These changes are support for the postulated roles of these peptides in the control of gastric acid secretion.
Achlorhydria↗
Aids. Case for diagnosis.
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Acquired Immunodeficiency Syndrome↗
Pharmacology of aminoglutethimide: structure/activity relationships and receptor interactions.
The structure/activity relationships for inhibition of aromatase and cholesterol side-chain cleavage enzyme (CSCC) by aminoglutethimide and some of its analogues are reviewed. Although more effective against aromatase than CSCC, aminoglutethimide markedly inhibits both enzymes. Optimal competitive antagonism of aromatase is obtained with a free amino or basic group at the 4' position of the phenyl ring substituent. This is important because two major metabolites of aminoglutethimide where the amino group is conjugated have low or no inhibitory effect on aromatase. Relocation of the free amino group to the nitrogen atom of the piperidinedione ring enhances CSCC inhibition. The piperidinedione ring is not essential for inhibitory activity, several 4'-aminophenyl pyrrolidinediones being as potent as aminoglutethimide for aromatase but less effective against CSCC. In this series 3-(4'-aminophenyl)-pyrrolidine-2,5-dione is a selective aromatase inhibitor. Inactivity of 4'-aminophenyl derivatives of imidazolidinedione and pyrimidinetrione indicate that the 4'-aminophenyl moiety alone is insufficient for antagonist activity against aromatase. Replacement of the aminophenyl group by the stronger basic 4-pyridyl moiety in aminoglutethimide yields a selective aromatase inhibitor. The structure/activity data suggest that there is a critical distance between the basic centre and the dione moiety for effective aromatase inhibition. Aminoglutethimide and its analogues possessing a free basic centre elicit a Type II difference spectrum with various cytochrome P-450 isozymes. The spectrally-determined binding affinity correlates with inhibitory activity of these compounds and indicates binding of the amino group to the iron centre of this haem enzyme. In reviewing the postulated mechanisms for the enzyme-mediated aromatisation of substrates it is seen that the initial oxidative attack is at the C-19 position of the steroid. It is proposed that two binding or association sites on the protohaem moiety of this P-450 enzyme (iron and propionic acid residues respectively) are required for the orientation of the substrate. Crystallographic evidence indicates there is a distance of about 6.3 A between the C-17 oxygen and the C-19 methyl of the aromatase substrates (these points interacting with the association sites). There is a similar distance between the basic function and the C-6 keto group for aminoglutethimide (and the C-5 keto group for the pyrrolidinediones). It is proposed that aminoglutethimide and its active analogues interact with aromatase at these binding sites competitively inhibiting the aromatisation of androstenedione and testosterone.
Aminoglutethimide↗
Antisecretory drugs and gastric cancer.
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Achlorhydria↗
Antisecretory drugs and gastric cancer.
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Animals↗
The effect of verapamil on ischaemia-induced changes to the sarcolemma.
The effect of verapamil on sarcolemmal activities of sarcolemmal fragments isolated from aerobically perfused (control) and ischaemic rat hearts was examined. Adding verapamil to the perfusate of aerobically perfused hearts for 75 min enhanced some of the sarcolemmal activities; Na+-K+ ATPase (31%), K+ stimulated phosphatase (31%) and Na+-Ca2+ exchange rate (46%). Adding verapamil directly to the enzymatic incubation media, or to the cardiac homogenate prior to sarcolemmal isolation did not alter these activities, suggesting that these changes are dependent upon addition of verapamil to the intact system. Addition of verapamil to hearts 15 min prior to a 60 min ischaemic episode maintained a number of sarcolemmal activities close to those obtained after aerobic perfusion. Na+-K+ ATPase activity and Na+-Ca2+ exchange received a relative protection while K+ stimulated phosphatase activity was not protected. 5'-nucleotidase activity was completely protected against ischaemia-induced depression. The mechanism whereby verapamil induces these changes in sarcolemmal enzymatic activities is unclear but its ability to maintain these activities at or near normal levels may contribute to its ability to protect against the deleterious effects of ischaemia.
5'-Nucleotidase↗
Predictive value of ventilation-perfusion scanning for pulmonary embolism.
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Angiography↗
Effects of catechol estrogen methyl ethers on lipid metabolism in prepubertal rats.
Thirty-five day old ovariectomised rats were given daily subcutaneous injections (0.05-5.0 micrograms/100 gm body weight) of estradiol (E2) 2-methoxyestradiol (2-ME2) or 4-methoxyestradiol (4-ME2) for six days. At the end of the last injection, the animals were sacrificed and serum lipoproteins were analysed. It was observed that cholesterol decreased significantly in normal fed animals who received E2 and 4-ME2, while no effect was seen in cholesterol fed animals. In the E2 treated group there was a decrease in esterified and free cholesterol, while in the 4-ME2 group only esterified cholesterol decreased. High density lipoproteins were significantly elevated in the E2 treated group. However, there was an increase in very low density lipoproteins and a decrease in low density lipoproteins in 2-ME2 and 4-ME2 treated groups. These results suggest that catechol estrogens may play an important role in the lipoprotein metabolism and atherosclerotic diseases, and the mechanism of action may differ from that of estradiol.
2-Methoxyestradiol↗
Influence of ethanol and ambient temperature on skin blood flow.
Patients frequently arrive in the emergency department under the influence of alcohol after exposure to extreme conditions of heat or cold. While ethanol ingestion and ambient heat are recognized to have vasodilatory action, previous studies of their interactive effect are limited and guidelines for patient care are vague. Xenon-133 skin perfusion studies allow direct quantitative assessment of the net effect of multiple variables on skin vasculature. Using Xenon-133 to measure cutaneous blood flow in the lower extremity, we studied four groups of 12 healthy men at 20, 25, 30, and 35 C. Half of each group ingested 60 mL of 95% ethanol in fruit juice, while the other half received placebo only. Skin perfusion at baseline and 50 minutes after ingestion of ethanol were measured. Vasodilatation was observed at 25 and 30 C in subjects who had ingested ethanol. At 20 and 35 C vasoconstriction or vasodilation, respectively, occurred in all subjects with no additional influence of ethanol observed. The influence of heat or cold on skin blood flow appears to dominate over the influence of moderate amounts of ethanol at these temperature extremes. Specifically, in patients exposed to extreme temperatures while under the influence of ethanol, there is no benefit from the agent on cutaneous blood flow at or below 20 C, and there is no enhanced heat loss at 35 C or above.
Adult↗