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Biomedical subjects

A W Jones

Publications and source records attributed to A W Jones.

At least 91 records · Page 5Linked to original sources
PubMed1995

Attenuated Ca2+ response to acetylcholine in endothelial cells from aorta of aldosterone-salt hypertensive rats.

Ca2+ is essential for endothelial production of vasorelaxing factors. We determined whether the impaired endothelium-dependent relaxation in aldosterone-salt hypertensive rats (AHR) is associated with a decreased free Ca2+ ([Ca2+]i) response in endothelial cells. In isolated aorta, the EC50 for the acetylcholine-induced endothelium-dependent relaxations did not differ between AHR and the age-matched control-salt rats (CSR). However, maximal relaxation was significantly reduced by 47% in AHR (P < .05). In contrast, the endothelium-independent relaxation to sodium nitroprusside was not impaired in aorta from AHR. The [Ca2+]i was measured with fura-2 microfluorometry in endothelial cells freshly dispersed from aorta. Although the basal [Ca2+]i was not different between CSR and AHR, the peak [Ca2+]i response to acetylcholine was significantly reduced in cells from AHR compared with CSR (P < .05). These results suggest that depressed endothelial [Ca2+]i responses to acetylcholine may be involved in the impaired endothelium-dependent relaxation in aorta from AHR.

Acetylcholine↗
PubMed1995

Ca(2+)-dependent K+ current in arterial smooth muscle cells from aldosterone-salt hypertensive rats.

Aorta from aldosterone-salt hypertensive rats (AHR) demonstrates an increased basal 42K efflux. We investigated the cellular mechanisms of this alteration by measuring 42K efflux from aortic segments as well as myoplasmic Ca2+ concentration ([Ca2+]m) and K+ current in aortic smooth muscle cells from AHR and normotensive control-salt rats (CSR). Both diltiazem and nisoldipine attenuated but did not normalize the increase in basal 42K efflux in AHR. The resting [Ca2+]m was elevated in cells from AHR (148 +/- 15 vs. 91 +/- 12 nM for CSR, P < 0.05). The rate of Mn2+ quenching under basal conditions was also increased in cells from AHR, and the increase was abolished by Cd2+. However, the resting membrane potential did not differ between CSR and AHR (-49 +/- 5 vs. -50 +/- 4 mV). The steady-state, whole cell K+ current was also increased in cells from AHR. This increase was abolished by charybdotoxin, tetraethylammonium, La3+, and by clamping [Ca2+]m at zero or 100 nM with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. The single-channel conductance of the large conductance Ca(2+)-activated, voltage-dependent K+ (KCa) channels was not altered in AHR. Further, 33% of cells from AHR vs. 1% from CSR showed spontaneous transient outward K+ currents, which reflect activation of KCa channels by Ca2+ released from caffeine-sensitive stores. While the acute caffeine-induced [Ca2+]m response was similar between CSR and AHR, the outward current and 42K efflux responses to caffeine were greater in AHR. After continued exposure to caffeine, the basal 42K efflux was attenuated more in AHR than in CSR. Charybdotoxin resulted in a greater depolarization in AHR cells than in CSR cells (9.8 +/- 2.2 vs. 3.5 +/- 1.6 mV, P < 0.05). These results indicate that the increases in both 42K efflux and K+ current reflect an increased activity of KCa channels that is associated with an increased Ca2+ influx and resting [Ca2+]m and altered Ca2+ handling by the sarcoplasmic reticulum in aortic smooth muscle cells from AHR.

Aldosterone↗
PubMed1995

Reliability of blood alcohol determinations at clinical chemistry laboratories in Sweden.

Known concentrations of ethanol, methanol, isopropanol and its metabolite acetone were added to plasma or whole blood and aliquots of each specimen were sent to clinical chemistry laboratories in Sweden as a declared collaborative study. All participants used gas-liquid chromatography (GC) for quantitative determination of ethanol and other low molecular weight volatiles. The mean within laboratory precision for analysis of ethanol, expressed as coefficient of variation (CV), was 4.7% (range 0-15%). The corresponding between-laboratory CV spanned from 8.0 to 19.4% for 23 control specimens analysed between 1987 and 1992. The mean concentration of ethanol reported was not significantly different from the target value assigned. Between 0 and 3 laboratories reported deviant results (Z-score > 1.96) for each of the control specimens. One laboratory reported the presence of methanol instead of ethanol and three laboratories saw traces of acetone instead of the actual concentration present. One laboratory failed to report that methanol was present and another failed to report the presence of isopropanol. The between-laboratory CV ranged between 9.4 and 30.3% for analysis of methanol in 8 control specimens. The larger variability between laboratories compared with within laboratories probably reflects the different calibration procedures used, such as the preparation and source of the alcohol standards.

1-Propanol↗
PubMed1995

Distinguishing ingested ethanol from microbial formation by analysis of urinary 5-hydroxytryptophol and 5-hydroxyindoleacetic acid.

During the metabolism of ethanol, the metabolic conversion of serotonin (5-hydroxytryptamine) is altered, and, as a consequence, the ratio of 5-hydroxytryptophol (5HTOL) to 5-hydroxyindole-3-acetic acid (5HIAA) excreted in urine increases appreciably. The ratio of metabolites remains elevated for several hours after ethanol is no longer detectable. In the present study, urine specimens were supplemented with glucose and Candida albicans, a common human pathogenic yeast, and the formation of ethanol and the changes in the 5HTOL/5HIAA ratio were examined during one week of storage. Despite the production of high concentrations of ethanol (peak level 171 mmol/L, or 788 mg/dL), the 5HTOL/5HIAA ratio remained constant. The urinary 5HTOL/5HIAA ratio was also compared with urinary and blood ethanol levels in specimens selected at random during forensic autopsies. Elevated 5HTOL/5HIAA ratios were found in all specimens with detectable urinary ethanol. Some specimens showed elevated ratios of serotonin metabolites even though no ethanol was detected, indicating that these subjects had consumed ethanol prior to death but that the concentration had already returned to zero or was below the detection limit. In one case, postmortem ethanol formation was suspected, because blood ethanol concentration was 16.8 mmol/L (77 mg/dL) whereas urinary ethanol was zero. The urinary 5HTOL/5HIAA ratio fell within normal limits, which confirmed the suspicion of postmortem ethanol synthesis in the blood specimen. The present results indicate that the 5HTOL/5HIAA ratio in urine provides a useful method to distinguish between ethanol that might have been synthesized postmortem, or generated in vitro, from ethanol excreted in urine as a result of drinking.

Adult↗
PubMed1995

Measuring and reporting the concentration of acetaldehyde in human breath.

Most of the acetaldehyde generated during the metabolism of ethanol becomes tightly bound to endogenous molecules such as haemoglobin, amino acids and certain phospholipids. Free acetaldehyde passes the blood-brain barrier and traces of this toxic metabolite are excreted through the lungs and can be detected in the expired air. The blood/air partition coefficient of acetaldehyde at 34 degrees C, the average temperature of end-expired air, is about 190:1. Because of various problems associated with measuring acetaldehyde in blood samples, several research groups have instead investigated the analysis of acetaldehyde in breath which offers an indirect and alternative approach for clinical and research purposes. However, care is needed when interpreting the results of breath acetaldehyde measurements, because of the possibility of local formation from microflora inhabiting the upper airways and mouth. The concentration of acetaldehyde exhaled in breath after drinking alcohol demonstrates large inter-individual differences depending on various genetic (racial) and environmental factors. Moreover, acetaldehyde is an endogenous metabolite and even without drinking any alcohol the concentrations expelled in breath span from 0.2 to 0.6 nmol/l, with higher levels observed in smokers and abstinent alcoholics. Breath acetaldehyde concentration reached between 5 and 50 nmol/l in European subjects who drank a moderate dose of ethanol (0.4-0.8 g/kg), with the highest values seen in smokers. The concentration of breath acetaldehyde in Japanese subjects after drinking alcohol reached between 200 and 500 nmol/l at the peak. These much higher levels follow because a large proportion of Orientals (40-50%) inherit an inactive form of the low Km mitochondrial isoenzyme of aldehyde dehydrogenase (ALDH2). The highest concentration of breath acetaldehyde were seen in healthy Caucasians who drank a small dose of alcohol (0.25 g/kg) after taking the alcohol-sensitizing drug calcium carbimide, which blocks the action of ALDH isozymes. During the most intense acetaldehyde-flush reaction, breath acetaldehyde reached between 200 and 1300 nmol/l, but even these abnormally high concentrations did not interfere with the analysis of ethanol in breath by means of non-specific infrared analysers currently used in many countries for testing drinking drivers.

Acetaldehyde↗
PubMed1995

Phorbol ester-stimulated 6-keto-prostaglandin F1 alpha in aortas from control and aldosterone-salt rats.

OBJECTIVE: To assess the contribution of protein kinase C to the production of 6-keto-prostaglandin F1 alpha by stimulating protein kinase C directly. RESULTS: Phorbol myristate acetate caused a time-dependent increase in 6-keto-prostaglandin F1 alpha and thromboxane B2. The time course was slower than for norepinephrine-stimulated production of these metabolites, but the pattern was similar, with thromboxane B2 appearing before 6-keto-prostaglandin F1 alpha. The phorbol myristate acetate concentration-response curves for 6-keto-prostaglandin F1 alpha production for control-salt and aldosterone-salt hypertensive rats were equivalent. Staurosporine inhibited phorbol myristate acetate-stimulated 6-keto-prostaglandin F1 alpha production in control-salt and aldosterone-salt hypertensive rats concentration-dependently. The staurosporine median inhibitory concentration for phorbol myristate acetate-stimulated 6-keto-prostaglandin F1 alpha production was twofold greater in aldosterone-salt hypertensive than in control-salt rats, but was similar for norepinephrine-stimulated 6-keto-prostaglandin F1 alpha. CONCLUSION: Activation of protein kinase C results in increases in arachidonic acid metabolites, but alterations in this pathway do not seem to be responsible for the differences observed with norepinephrine-stimulated 6-keto-prostaglandin F1 alpha production. The present data offer some support for the concept of direct coupling between the alpha 1-adrenoceptor and phospholipase A2.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Biotransformation of acetone to isopropanol observed in a motorist involved in a sobriety check.

We report the identification of acetone (0.45 mg/mL) and isopropanol (0.17 mg/mL) but without the presence of ethanol in a blood sample from a man suspected of driving under the influence of alcohol. A preliminary breath screening test with an electrochemical instrument (Alcolmeter S-L2) was positive and an evidential breath-test with a dual wavelength infrared analyzer (Intoxilyzer 5000), recognized the presence of an interferant in the subject's breath. The man admitted drinking moderate amounts of alcohol (vodka) the previous evening and was being treated by his doctor for hyperglycemia by special dietary control. This case scenario provides a good example of severe metabolic ketoacidosis in an ostensibly healthy man driving on the highway. Biotransformation of the abnormally high concentration of blood-acetone to isopropanol occurs through the alcohol dehydrogenase pathway.

1-Propanol↗
PubMed1994

Guidelines for estimating the amount of alcohol consumed from a single measurement of blood alcohol concentration: re-evaluation of Widmark's equation.

This article deals with the pharmacokinetics of ethanol and the reliability of estimating the amount of alcohol ingested from a single measurement of a person's blood alcohol concentration (BAC). Blood alcohol curves were plotted for 108 male subjects after they drank various doses of ethanol (0.51-0.85 g/kg body weight). The rate of disappearance of ethanol from the blood (beta-slope) and the apparent volume of distribution of ethanol (Widmark's rho factor, rho) were calculated for each subject; the mean beta-slope was 13.3 mg/dl/h (SD = 2.0), and the mean rho factor was 0.689 l/kg (SD = 0.061). The value of beta increased slightly with increasing dose of alcohol (P < 0.05). The blood alcohol parameters beta and rho were negatively correlated (r = -0.135). The BACs measured at 2 h and 5 h post-drinking were used to estimate the amount of alcohol each subject had consumed according to the method proposed by Widmark [1]. The mean differences (estimated-actual) and the +/- 95% limits of agreement were -0.72 g (+/- 12), and 2.2 (+/- 15), for the 2 h and 5 h BAC values, respectively. A method based on error propagation was used to derive the 95% limits of uncertainty in the amount of alcohol ingested. On the basis of a single measurement of BAC, we could estimate the amount of alcohol ingested within +/- 20%.

Adult↗
PubMed1994

Between-subject and within-subject variations in the pharmacokinetics of ethanol.

1. Twelve healthy men drank 0.80 g ethanol kg-1 body weight on four occasions spread over several weeks. Ethanol was given as 96% v/v solvent which was diluted with orange juice to make a cocktail (20-25% v/v). This drink was ingested in exactly 30 min at 08.00 h after an overnight (10 h) fast. 2. Samples of venous blood were obtained at exactly timed intervals of 0, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 min after the start of drinking. The concentrations of ethanol in whole blood were determined by headspace gas chromatography. 3. Summary measures were used to evaluate the concentration-time profiles of ethanol for each subject. The between-subject and within-subject components of variation for the pharmacokinetics of ethanol were derived by one-way analysis of variance (ANOVA). 4. The variation between different subjects dominated the total variance for all of the pharmacokinetic parameters studied except the rate of disappearance of ethanol from blood (ko). For this latter parameter, 42% and 58% of the total variation arose from variations between- and within-subjects respectively. These results might be important to consider when experiments on the clinical pharmacokinetics of ethanol are being planned.

Administration, Oral↗
PubMed1994

Increased barium influx and potassium current in stroke-prone spontaneously hypertensive rats.

Arterial potassium permeability is increased in hypertension. In this study we conducted voltage-clamp experiments to determine whether the whole-cell K+ current is increased in a Ca(2+)-dependent manner in aortic smooth muscle cells from stroke-prone spontaneously hypertensive rats (SHRSP). Aortic cells from Wistar-Kyoto (WKY) rats and SHRSP demonstrated an outward rectifying current elicited by depolarization. The current was carried primarily by K+, because intracellular Cs+ replacement eliminated more than 97% of the current. The current density was higher (P < .05) in SHRSP cells at positive potentials. In the presence of LaCl3 (200 mumol/L) or tetraethylammonium (10 mmol/L), the residual current was similar in WKY and SHRSP cells. Also, the current density did not differ between WKY and SHRSP cells in which the intracellular Ca2+ concentration was clamped at zero. Fura 2 ratio measurement showed similar resting myoplasmic Ca2+ concentration (Ca2+m) in WKY and SHRSP cells (100 +/- 10 versus 117 +/- 9 nmol/L, P = .2). Under low extracellular Na+ conditions, which had a minimal effect on Ca2+m, Ba2+ replacement of Ca2+ caused a continuous and approximately linear increase in the fura 2 ratio, which was twofold faster in SHRSP cells. Because Ca2+ pumps do not transport Ba2+ and Na(+)-Ca2+ exchange was inhibited by low extracellular Na+, this increase reflected unidirectional Ba2+ influx.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Are a blood alcohol concentration of 256mg/dl and minimal signs of impairment reliable indications of alcohol dependence?

This article describes a drunk-driving scenario where a woman was apprehended for driving under the influence (DUI) with a blood alcohol concentration (BAC) of 256mg/dl. The correctness of this result was vigorously challenged by a medical expert witness for the defence, who was actually a specialist in alcohol diseases. Despite reanalysis to confirm the BAC as well as a DNA profile to prove the identity of the blood specimen, the woman was acquitted of the charge of drunk driving by the lower court. However, she was subsequently found guilty in the High Court of Appeals with a unanimous decision and sentenced to four weeks imprisonment. This case report illustrates some of the problems surrounding the use of expert medical evidence by the defence to challenge the validity of the prosecution evidence based solely on a suspect's BAC. In situations such as these, an expert witness should be called by the prosecution to clarify and, if necessary, rebut medical and/or scientific opinions that might mislead the court and influence the outcome of the trial.

Adult↗
PubMed1994

Eating a meal increases the clearance of ethanol given by intravenous infusion.

We studied the effect of eating a meal on the rate of ethanol elimination (clearance) from the blood after giving 0.4 g/kg by intravenous infusion to six female and six male volunteers. Half of the subjects had eaten breakfast whereas the other half had fasted overnight. After the first infusion of alcohol, those who had fasted ate lunch, and all the volunteers received a second infusion with the same dose of ethanol. The blood ethanol concentration was measured repeatedly for up to 180-240 min after the start of each experiment. Intake of food (lunch or breakfast) increased the clearance of ethanol by about 60% (P < 0.001). Alcohol intoxication was less pronounced at the end of the ethanol infusions preceded by eating a meal (P < 0.01). Gender had no significant effect on the rate of ethanol elimination. We conclude that eating a meal increases the rate of ethanol elimination even when alcohol is given by intravenous infusion.

Adult↗
PubMed1994

Food-induced lowering of blood-ethanol profiles and increased rate of elimination immediately after a meal.

In a two-part crossover study, ten healthy men drank a moderate dose of ethanol (0.80 g/kg) in the morning after an overnight fast or immediately after breakfast. The breakfast consisted of orange juice (150 mL), fruit yogurt (250 mL), two cheese sandwiches, one boiled egg, and one cup of coffee with milk and sugar. Ethanol was determined in venous blood at various times after the start of drinking by headspace gas chromatography. All subjects felt less intoxicated when alcohol was ingested after breakfast compared with drinking on an empty stomach. The peak BAC (+/- SD) was 67 +/- 9.5 mg/dL (ethanol + food) compared with 104 +/- 16.5 mg/dL when the drinking occurred after an overnight fast (P < 0.001). The mean area under the alcohol concentration-time profile (0-->6h) was 398 +/- 56 mg/dL x h in the fasting state compared with 241 +/- 34 mg/dL x h when subjects drank alcohol after the meal (P < 0.001). The time required to metabolize the dose of ethanol was approximately two hours shorter after the subjects had eaten breakfast. These results suggest that food in the stomach before drinking not only leads to a lowering of the peak BAC and diminishes the feelings of intoxication, but also boosts the rate of ethanol metabolism. A food-induced increase in the rate of disposal of ethanol was also confirmed when subjects ate a meal 5 h after drinking, that is, when the postabsorptive phase of ethanol metabolism was well established. The mean rate of disappearance of alcohol from blood was increased by between 36 and 50%.

Adult↗