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Biomedical subjects

W J Scott

Publications and source records attributed to W J Scott.

At least 91 records · Page 5Linked to original sources
PubMed1986

Caffeine effects on cyclic AMP levels in the mouse embryonic limb and palate in vitro.

Caffeine is a teratogen that causes limb and palate malformations in rodents. Since the ability to raise cyclic nucleotide levels is a known biological action of caffeine, cyclic AMP levels were measured in CD-1 mouse embryonic forelimb from whole embryo culture and embryonic limb and palate cells grown in primary culture following treatment with various concentrations of caffeine (0, 1, 3, or 10 mM). In forelimb buds from whole embryo culture, a dose-dependent response was observed. Caffeine at 1 mM concentration stimulated cyclic AMP levels to 151% of control value at 60 min. Even greater stimulation of cyclic AMP occurred at higher caffeine concentrations. A dose-dependent response was seen in both limb and palate cell culture. In limb cell culture, all caffeine concentrations significantly stimulated cyclic AMP after 10 min compared to control. In palate cell culture, there was a twofold increase in cyclic AMP at the 1-mM caffeine concentration. At higher caffeine concentrations, cyclic AMP was significantly increased after 60 min. In addition, stimulation of cyclic AMP in cultured limb and palate cells by isoproterenol, a beta-adrenergic agonist, was used as a positive control. Isoproterenol stimulated a 2.5-fold greater response in the palate cells than in the limb bud cells at isoproterenol levels of 10(-5) or 10(-4) M. The increase of cyclic AMP may be influential in the process of abnormal limb or palate development.

Animals↗
PubMed1986

Acetazolamide teratogenesis in Wistar rats: potentiation and antagonism by adrenergic agents.

Acetazolamide, a carbonic anhydrase inhibitor, induced right forelimb ectrodactyly in rat fetuses when the mothers were treated on late day 10 and early day 11 of gestation. Coadministration of the selective alpha-1-adrenergic agonist phenylephrine significantly increased the incidence of acetazolamide-induced right forelimb ectrodactyly while failing to induce the lesion when administered alone. Pretreatment with the alpha-adrenergic antagonists phenoxybenzamine and prazosin prevented the phenylephrine-induced increase in right forelimb ectrodactyly. In addition, treatment with either phenoxybenzamine or prazosin in the absence of stimulation with phenylephrine significantly decreased the incidence of acetazolamide-induced ectrodactyly. The results suggest an adrenergic component in acetazolamide teratogenesis. Alterations in uterine blood flow are discussed as a plausible mechanism for the modification of the incidence of ectrodactyly by these adrenergic agents.

Abnormalities, Drug-Induced↗
PubMed1986

Teratogenicity of paraxanthine (1,7-dimethylxanthine) in C57BL/6J mice.

The teratogenicity of caffeine, as well as two of its three dimethylated metabolites (theobromine and theophylline), has been established in animal studies. The third metabolite, paraxanthine, has not been reported as being tested for teratogenicity even though it is actually the major demethylated metabolite of caffeine metabolism in man. Pregnant C57BL/6J mice were treated i.p. with 175 or 300 mg/kg/day paraxanthine (1,7-dimethylxanthine) dissolved in deionized water at 4 p.m. on day 11 and 9 a.m. on day 12 of gestation. All dams were sacrificed on day 18, and fetuses were fixed for Wilson's razor blade sectioning or double-staining skeletal examination. A dose-related increase in total malformations, primarily cleft palate and limb malformations, was found. The pattern of malformations was similar to that reported for caffeine, theobromine, and theophylline, i.e., an asymmetric response with the left forelimb most often affected. A 21% resorption and a 46% malformation rate was observed at 300 mg/kg/day of paraxanthine, indicating that paraxanthine was slightly less toxic to the embryo than caffeine. Therefore, the parent compound, caffeine, as well as all three of its dimethylated metabolites--paraxanthine, theophylline, and theobromine--are teratogenic.

Abnormalities, Drug-Induced↗
PubMed1986

Benign intracranial hypertension: a complication of subclavian vein catheterization and arteriovenous fistula.

Thrombosis of the right innominate vein occurred in a patient on maintenance hemodialysis following repeated subclavian vein catheterization. The patient had a functional right brachial arteriovenous fistula for blood access that resulted in a massive retrograde blood flow into the cerebral venous system with the development of the benign intracranial hypertension. The symptoms and signs of intracranial hypertension abated following ligation of the arteriovenous fistula. This unusual association of benign intracranial hypertension with an arteriovenous fistula and innominate vein thrombosis has not been reported previously. Pertinent literature dealing with benign intracranial hypertension and complications of subclavian vein catheterization is reviewed.

Arteriovenous Fistula↗
PubMed1986

Fetal growth retardation in rats from different levels of hypoxia.

Three groups of pregnant Wistar rats were subjected to 3 different levels of hypoxia: 11.6, 10.7 and 9.0%, respectively. Pair-fed and ad libitum fed control groups were included to control for the reduced food intake due to hypoxia. Within the range studied, fetal body weights decreased with decreased oxygen availability. Liver weights were more, brain weights less markedly reduced than body weights. Pair-fed but normally oxygenated animals showed slight reductions in body and organ weights compared to ad libitum fed controls. The fetuses subjected to hypoxia showed a placental hypertrophy relative to their body weights, while the least hypoxic fetuses showed an absolute placental hypertrophy. Placenta-fetal body ratios that were 150% greater than those observed in control animals were documented. In contrast, the fetuses of food-deprived animals were associated with abnormally small placentas.

Animals↗
PubMed1986

Dopamine receptor blockade does not affect the natriuresis accompanying sodium chloride infusion in dogs.

Intravenous (IV) saline infusions cause parallel increments in urinary excretion of dopamine (DA) and sodium. Exogenous administration of DA exerts a natriuretic effect by action on DA receptors. The possibility that DA mediates the natriuretic response to saline infusion was studied by infusing 0.9% saline solution IV (60 ml/kg) in conscious dogs with and without selective blockade of DA1 and DA2 receptors. With no antagonist, the total increase in sodium excretion during the 120-minute saline infusion and the 60 minutes after the saline infusion was 99.5 +/- 7.6 mmol. The increase in total sodium excretion was not affected by IV infusion of the selective DA1 antagonist SCH 23390 in doses of 0.5 micrograms/kg/min and 5 micrograms/kg/min. The total increment in sodium excretion produced by saline was also unaltered by large doses (1 micrograms/kg/min and 10 micrograms/kg/min) of the selective DA2 antagonist domperidone. Our results do not support a role of DA as a mediator of saline-induced natriuresis in the dog.

Animals↗
PubMed1986

Ion-selective membrane electrode for rapid automated determinations of total carbon dioxide.

Previously described ion-selective membrane electrodes useful for determination of total carbon dioxide in biological fluids in automated analyzers show interference from several sources--e.g., fatty acids, keto acids, salicylate, heparin. Judicious selection of membrane components has produced a membrane with superior performance characteristics: short conditioning time, long lifetime in storage, rapid and stable response, low drift, and significantly less susceptibility to interference than other electrodes thus far reported. Samples can be analyzed at 240 samples or more per hour and results correlate well with those by, e.g., the Technicon SMAC II method for total carbon dioxide. Mounted on the Technicon RA-1000, the carbon dioxide sensor is arranged in tandem with sodium and potassium ion-selective electrodes. When all three species are measured in the same buffered sample stream, the sampling rate thus becomes 720 tests per hour, done on 25-microL samples.

Autoanalysis↗
PubMed1986

Effect of nitroglycerin on ventricular oxygen extraction during aortic occlusion.

Nitroglycerin (NTG) is often administered to improve hemodynamics during aortic occlusion (AO). This investigation was designed to characterize the effect of NTG on left ventricular oxygen extraction during thoracic aortic occlusion. Open-chest dogs (n = 12) underwent measurement of mean arterial pressure, heart rate, and coronary blood flow. The great cardiac vein (GCV) was cannulated. AO was produced by a balloon in the descending aorta. Arterial and GCV oxygen content were determined before, 30 seconds, and 10 minutes after AO (control occlusions). Oxygen extraction (A-V)O2, oxygen consumption, and cardiac work were calculated. AO was repeated during NTG infusion (2 micrograms/kg/min IV) in seven animals. (A-V)O2 was decreased 10% at 30 seconds in control occlusions. NTG exacerbated these decreases in oxygen extraction. With NTG, (A-V)O2 decreased by 33% despite a 12% increase in cardiac work. The fact that early decreases in oxygen extraction occurring after AO are accentuated by NTG may predispose patients undergoing aortic reconstruction who receive NTG to myocardial ischemia.

Animals↗
PubMed1985

Reduction of caffeine teratogenicity in mice by inducing maternal drug metabolism with beta-naphthoflavone.

The effect of stimulating maternal drug metabolism on caffeine teratogenicity was investigated in C57BL/6J (cytochrome P1-450 inducible) and AKR/J (cytochrome P1-450 noninducible) mice. The inducing agent, beta-naphthoflavone (beta-NF) in corn oil, was administered intraperitoneally (IP) to dams at 20 or 80 mg/kg/d on days 9 and 10 of gestation. Teratogenic injections of 175 mg/kg/d caffeine in deionized water were administered IP on days 11 and 12 of gestation. All dams were sacrificed on day 18 of gestation, and fetuses were fixed for razor blade sectioning and skeletal examination. Caffeine, without maternal metabolism stimulation, caused similar types and rates of malformations in both strains of mice. Inducing drug metabolism during pregnancy with beta-NF protected the embryos from the congenital toxicities of large injections of caffeine. Reductions in embryolethality, limb malformations, and hematoma formation were evident in the inducible strain but not in the strain incapable of being induced. A dosage of eighty mg/kg/d was more effective than 20 mg/kg/d beta-NF in decreasing malformations, suggesting that stimulation of metabolism and caffeine-induced teratogenicity are inversely related. Rapid elimination of caffeine resulting from increasing drug metabolism with the concomitant decrease in toxicity would indicate that caffeine, and not a metabolite, is the toxicant.

Abnormalities, Drug-Induced↗
PubMed1985

Potentiation of acetazolamide induced ectrodactyly in Wistar rats by vasoactive agents and physical clamping of the uterus.

The vasoactive agents serotonin, ergotamine, and nicotine potentiate acetazolamide induced forelimb ectrodactyly (missing digits) in Wistar rats. These vasoactive agents administered alone do not produce forelimb ectrodactyly and are not known to be inhibitors of carbonic anhydrase. Additionally, physical clamping of the uterine horns in addition to oral acetazolamide administration increases the frequency of forelimb ectrodactyly, suggesting that decreased uterine blood flow can potentiate acetazolamide teratogenesis. Since the vasoactive agents used in this study are reported to possess uterine vasoconstrictive activity, a decrease in uterine blood flow is a plausible mechanism for the potentiative ability of these agents.

Abnormalities, Drug-Induced↗
PubMed1985

Teratogenicity of dimethoxyethyl phthalate and its metabolites methoxyethanol and methoxyacetic acid in the rat.

It is hypothesized that the known teratogen di(2-methoxyethyl) phthalate (DMEP) acts by in vivo hydrolysis to 2-methoxyethanol (2-ME), also a known teratogen, which in turn is metabolized to methoxyacetic acid (MAA), the proximate teratogen. Teratological studies were conducted with Wistar rats, with the administration of these three agents on day 12 of gestation. On an equimolar dosage basis, DMEP, 2-ME, and MAA were equally potent, which is consistent with the hypothesis. There was a striking similarity in the defects produced by these agents, mainly hydronephrosis, heart defects, and short limbs and tails. In particular all three agents produced unusual heart defects (dilated ductus arteriosus and dilated aortic arch) not seen with other agents, as well as ventral polydactyly, a rarely seen defect, suggesting teratogenic action by a common mechanism or component; 4-methylpyrazole, an alcohol dehydrogenase inhibitor, provided significant protection against 2-ME. This combination of effects strongly suggests that following the administration of DMEP, 2-ME, or MAA, MAA is the proximate teratogen.

Abnormalities, Drug-Induced↗
PubMed1985

Cadmium-induced forelimb ectrodactyly: a proposed mechanism of teratogenesis.

We have attempted to elucidate the mechanism of cadmium teratogenesis utilizing inbred mouse strains sensitive (C57BL/6J) or resistant (SWV) to the embryotoxic effect of this common heavy metal contaminant. Carbonic anhydrase activity of whole-embryo homogenates was moderately depressed in C57BL/6J mice compared to a slight and transient decrease in the resistant SWV mice. Embryonic erythrocytes were similarly examined, and the cadmium did not have any effect on carbonic anhydrase activity in either strain. Likewise, histochemical examination of carbonic anhydrase activity did not reveal any effect of cadmium in the embryos of their strain. Generally, the zinc concentration of embryos was not affected by cadmium administration. However, increased levels of zinc were observed in cadmium-exposed yolk sacs of both strains suggesting that cadmium produces an adverse effect on yolk sac function. Untreated C57BL/6J units (embryo plus surrounding extraembryonic membranes), embryos, and yolk sacs had much lower hemoglobin concentrations than those observed in untreated SWV units, embryos, and yolk sacs. Additionally, cadmium exposure significantly decreased C57BL/6J embryonic hemoglobin levels on gestation day 10 (PM) and increased C57BL/6J yolk sac hemoglobin levels on gestation days 10 (AM) and 10 (PM). No difference in hemoglobin concentration was observed between untreated and cadmium-treated SWV embryos or yolk sacs. We propose that cadmium induces forelimb ectrodactyly by creating an acidotic embryonic environment and that the primary site at which cadmium exerts its teratogenic effect might be the yolk sac.

Abnormalities, Drug-Induced↗
PubMed1984

The effects of prenatal ethanol in cynomolgus monkeys.

Ethanol was administered to pregnant cynomolgus monkeys (Macaca fasicularis) from day 20 to 150 of gestation. The ethanol was delivered by intragastric intubation twice a day at 8 AM and 5 PM. Dosage was begun at a relatively low level, 2 g/kg/day and increased gradually to attain a final dosage of 4 or 5 g/kg/day. The offspring were allowed to be delivered naturally and remained with their mother until 23 days of age when they were sacrificed. Maternal blood ethanol and acetaldehyde levels were monitored at weekly intervals throughout pregnancy. Pregnancy wastage in the form of abortions and stillbirths was increased by ethanol treatment especially at the high dose. Birthweight was significantly lowered in offspring of mothers receiving 5 g/kg/day of ethanol. However, no structural malformations or facial changes suggestive of those seen in the human fetal alcohol syndrome were found in any of the offspring. We conclude that the conditions of our study did not produce a satisfactory model of human fetal alcohol syndrome.

Abnormalities, Drug-Induced↗
PubMed1984

Potentiation of acetazolamide induced ectrodactyly in SWV and C57BL/6J mice by cadmium sulfate.

CdSO4 and acetazolamide each induce postaxial ectrodactyly in rodents when administered at a critical time in forelimb development. C57BL/6J mice are extremely sensitive to the teratogenic action of both agents, whereas SWV mice are relatively resistant. Additionally, both of these agents can inhibit carbonic anhydrase. In the present study administration of CdSO4 and acetazolamide in combination to either strain of mice potentiates the incidence of forelimb ectrodactyly. These results, in combination with the aforementioned similarities of teratogenesis, suggest a common mechanism of teratogenesis.

Abnormalities, Drug-Induced↗
PubMed1984

Acetazolamide teratogenesis: association of maternal respiratory acidosis and ectrodactyly in C57BL/6J mice.

Exposure of C57BL/6J mice to CO2 during a critical period of gestation results in predominantly right-sided, postaxial, forelimb ectrodactyly in the offspring. The incidence and severity of CO2-induced limb malformations has been shown to be dependent on the concentration of inspired CO2, the developmental age of the embryo at exposure and the duration of CO2 exposure. Offspring of acetazolamide-treated C57BL/6J mice also display this highly specific form of ectrodactyly (Green et al., '73). Since the drug has been shown to elevate tissue CO2 tension (Mithoefer and Davis, '58), the teratogenic effect of acetazolamide may be related to induction of a hypercapnic embryonic environment.

Abnormalities, Drug-Induced↗
PubMed1984

Acetazolamide teratogenesis: interaction of maternal metabolic and respiratory acidosis in the induction of ectrodactyly in C57BL/6J mice.

Exposure of C57BL/6J mice to 20% CO2 for 8 hours on day 10 of gestation has been shown to produce right-sided postaxial forelimb ectrodactyly in 23% of the offspring. Carbon dioxide exposure produces a dramatic increase in maternal plasma CO2 accompanied by an inevitable decrease in plasma pH, both of which appear to be involved in the induction of ectrodactyly. However, the low incidence of ectrodactyly associated with NH4Cl-induced metabolic acidosis suggests that the primary teratogenic factor in respiratory acidosis is elevated CO2 tension. This conclusion is supported by the observation that moderation of maternal plasma pH in the face of sustained elevated PCO2 fails to reduce the incidence of ectrodactyly; moreover, there is a strong correlation between maternal serum CO2 content and the incidence of ectrodactyly.

Abnormalities, Drug-Induced↗