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Biomedical subjects

G D Williams

Publications and source records attributed to G D Williams.

At least 55 records · Page 3Linked to original sources
PubMed1995

Amrinone loading during cardiopulmonary bypass in neonates, infants, and children.

OBJECTIVES: To determine whether amrinone is bound to cardiopulmonary bypass circuits. When amrinone is administered to children during cardiopulmonary bypass, determine whether measured amrinone concentrations differ from those predicted based on a reported volume of distribution of 1.6 L/kg. DESIGN: In vitro study: Uptake of amrinone by cardiopulmonary bypass circuits was determined. Clinical study: Prospective, open label investigation. SETTING: University-affiliated tertiary children's hospital. PARTICIPANTS: Clinical study: 27 children participated, including 5 neonates and 9 infants. INTERVENTIONS: In vitro study: Waste blood was circulated within seven pediatric cardiopulmonary circuits. Amrinone was administered, and blood was serially assayed for amrinone levels. Clinical study: Amrinone (mean dose 4.9 mg/kg) was loaded during cardiopulmonary bypass and amrinone concentrations in pump blood were determined at termination of bypass. Amrinone measured by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Cardiopulmonary bypass circuit uptake reduced amrinone concentrations to 79% of predicted. After correcting for circuit uptake, serum amrinone levels in patients were significantly higher than predicted. The levels, expressed in the ratio of measured: predicted amrinone concentration, did not differ among neonates, infants, and children older than 1 year of age. CONCLUSIONS: When amrinone is administered to children during cardiopulmonary bypass, about 20% of the dose becomes bound to the circuit. Available drug is distributed within a smaller volume than predicted. This may be the consequence of the physiologic perturbations of hypothermic cardiopulmonary bypass.

Amrinone↗
PubMed1994

Cerebral energy metabolism during hypoxia-ischemia correlates with brain damage: a 31P NMR study in unanesthetized immature rats.

The association between the ultimate brain damage resulting from unilateral hypoxic-ischemic insult (HI) and the changes in high-energy metabolites, measured by noninvasive phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy during the insult, was evaluated in 7-day postnatal rats. When the NMR metabolite levels were integrated over the last 1.5 h out of 2.5 h of HI, there was a significant correlation of both the estimator of phosphorylation potential (P < 0.001) and ATP levels (P < 0.01) with histologic score of damage and area morphometry. In particular, the development of cerebral infarction could be predicted from the NMR evaluation (P < 0.005). These findings suggest that a large disturbance in cellular energy metabolism is a prerequisite for the subsequent neuropathological alterations in this model.

Adenosine Triphosphate↗
PubMed1994

Variations in quantity-frequency measures of alcohol consumption from a general population survey.

This paper examines differences in quantity-frequency (QF) measures of alcohol consumption from the 1988 US National Health Interview Survey. Three methods--global QF, beverage-specific QF, and beverage-specific QF with drink size (QFS)--were used to estimate the average daily ethanol consumption (ADC) of current drinkers. These ADC estimates then were used to categorize drinkers into light, moderate or heavier drinking levels. Total prevalence estimates of heavier drinking were not significantly different among men, but were significantly higher with the QFS measure among women. All mean ADC scores were significantly different for both sexes. The global QF showed the lowest mean consumption, followed by the higher beverage-specific QF and QFS measures. Adding beverage type and drink size to the QF measures increased mean ADC scores for both men and women. However, moderately high correlations (0.84 for men and 0.88 for women) were found with ADC scores from the beverage-specific QF and QFS measures.

Alcohol Drinking↗
PubMed1993

Simultaneous determination of intracellular magnesium and pH from the three 31P NMR Chemical shifts of ATP.

The simultaneous determination of intracellular [MgT]/[ATPT] and pH from the three 31P NMR chemical shifts of ATP has been demonstrated using two-dimensional calibrations. The resulting pH will more accurately represent that of healthy tissue than by using the standard NMR technique. As a result of other possible complexes of MgATP and uncertainties in intracellular pH, errors in the values of KMgATPD (pH), the MgATP NMR shift limits, and thus intracellular magnesium levels are reduced by using this self-consistent analytical method. Direct determination of free magnesium from the (gamma-beta) shifts of ATP may be more sensitive in the alkaline pH range than with the commonly used (alpha-beta) shifts. In addition, the calibration data sets allow for a graphical representation of the uncertainty in magnesium due to the uncertainty in the measured chemical shifts and pH. Our results indicate that KMgATPD is consistent with the literature and favors a value near 50 microM at pH 7.2, but that free magnesium levels will be lower than most prior estimates.

Adenosine Triphosphate↗
PubMed1993

Hemodynamic effects of amrinone and colloid administration in children following cardiac surgery.

Amrinone was used as the sole vasoactive medication in 9 of 14 children (aged 5 months to 8.25 years) given the drug following open repair of congenital cardiac lesions. Four children received a concomitant dopamine infusion and one infant had the infusion stopped after 5 hours for low mean arterial pressure (49 mmHg). In the 10 children receiving only amrinone, cardiac index increased 21% (range, 0 to 94%) after a total loading dose of 4.5 mg/kg given over 1 hour. Four of 14 patients (29%) required dopamine infusions to maintain mean arterial pressure over 55 mmHg and in these children cardiac index increased from baseline and was maintained during the amrinone infusion. Preload was held constant by administration of whole blood or plasmanate during amrinone loading; a decrease in systemic vascular resistance index was seen resulting in a stable arterial blood pressure. Minimal chronotropic effect was seen and no arrhythmias occurred. The sole child with postoperative pulmonary hypertension had a beneficial decrease in pulmonary artery pressure, increase in cardiac index, and stable systemic blood pressure during amrinone use. Cardiac index changes during amrinone loading in these children were variable and less clearly related to serum levels than reported in adults. Pharmacokinetic analysis in 12 children showed a clearance of 3.4 mL/min/kg, a volume of distribution of 1.65 L/kg, and an elimination half-life of 5.75 hours. Decreases in platelet counts were seen in 6 children and platelet transfusion was needed in 1; thus, serial platelet counts should be monitored.(ABSTRACT TRUNCATED AT 250 WORDS)

Amrinone↗
PubMed1992

Allopurinol preserves cerebral energy metabolism during perinatal hypoxia-ischemia: a 31P NMR study in unanesthetized immature rats.

The effects of high dose allopurinol (ALLOP) pretreatment on the cerebral energy metabolism of unanesthetized 7-day-postnatal rats during exposure to 3 h of cerebral hypoxia-ischemia were serially quantitated using non-invasive 31P NMR spectroscopy. Adenosine triphosphate, integrated over the last 2 h of hypoxia and expressed as a fraction of baseline, was 0.73 +/- 0.16 with ALLOP pretreatment (200 mg/kg s.c.) compared to 0.52 +/- 0.05 for saline pretreatment (P = 0.001). Inorganic phosphate/phosphocreatine (Pi/PCr), integrated over the same time interval, was 2.63 +/- 1.23 relative to baseline with ALLOP versus 5.13 +/- 1.45 for saline-treated pups (P less than 0.0005). We suggest that the neuroprotection achieved with high dose ALLOP pretreatment may be attributed in part to preservation of energy metabolites.

Adenosine Triphosphate↗
PubMed1992

A 31P NMR study of mitochondrial inorganic phosphate visibility: effects of Ca2+, Mn2+, and the pH gradient.

The effects of external pH, temperature, and Ca2+ and Mn2+ concentrations on the compartmentation and NMR visibility of inorganic phosphate (Pi) were studied in isolated rat liver mitochondria respiring on succinate and glutamate. Mitochondrial matrix Pi is totally visible by NMR at 8 degrees C and at low external concentrations of Pi. However, when the external Pi concentration is increased above 7 mM, the pH gradient decreases, the amount of matrix Pi increases, and the fraction not observed by NMR increases. Raising the temperature to 25 degrees C also decreases the pH gradient and the Pi fraction observed by NMR. At physiologically relevant concentrations, Ca2+ and Mn2+ do not seem to play a major role in matrix Pi NMR invisibility. For Ca2+ concentrations above 30 nmol/mg of protein, formation of insoluble complexes will cause loss of Pi signal intensity. For Mn2+ concentrations above 2 nmol/mg of protein, the Pi peak can be broadened sufficiently to preclude detection of a high-resolution signal. The results indicate that mitochondrial matrix Pi should be mostly observable up to 25 degrees C by high-resolution NMR. While the exact nature of the NMR-invisible phosphate in perfused or in vivo liver is yet to be determined, better success at detecting and resolving both Pi pools by NMR is indicated at high field, low temperature, and optimized pulsing conditions.

Animals↗
PubMed1992

Error in the calibration of the MgATP chemical-shift limit: effects on the determination of free magnesium by 31P NMR spectroscopy.

The measurement of free intracellular magnesium (Mg2+) using the 31P chemical shifts of ATP requires the use of appropriate calibration solutions to determine the chemical-shift limits delta ATP alpha beta and delta MgATP alpha beta. Solutions containing excess Mg2+ contain significant amounts of Mg2ATP and yield positive errors in the value of delta MgATP alpha beta. For physiological applications this may overestimate free intracellular Mg2+ by as much as 300%. This error may be minimized if appropriate mole ratios of Mg2+/ATP are used to calibrate delta MgATP alpha beta.

Adenosine Triphosphate↗
PubMed1992

Changes in levels of alcohol consumption: United States, 1983-1988.

Using data from the 1983 and 1988 National Health Interview Surveys, this note examines changes both in the prevalence of abstention and the prevalence of heavier drinking among drinkers in the United States. Changes are examined separately by gender and according to other sociodemographic characteristics often associated with different levels of alcohol consumption. Results suggest an increase in abstention and a decrease in heavier drinking between 1983 and 1988. For women, decreases in heavier drinking were found among those 18-44 years of age, among those employed, and among those divorced/separated or never married. For men, decreases in heavier drinking were found among those employed, among those with family income of $25,000 or more, and among those married or divorced/separated. Changes both in abstention and heavier drinking were found to vary considerably by geographical region. These findings do not support results from other general population survey studies on alcohol use that suggest a stability in drinking levels, or even a slight increase in heavier drinking among men.

Adolescent↗
PubMed1992

Effect of pH and inorganic phosphate on creatine kinase inactivation: an in vitro 31P NMR saturation-transfer study.

The pseudo-first-order rate constant of rabbit muscle creatine kinase (CK), in the direction of ATP synthesis (kf), was determined by saturation-transfer 31P NMR. When pH was varied between 6.0 and 7.4, kf increased linearly at both 20 degrees C and 37 degrees c. The corresponding flux is very small between pH 6.0 and 6.5, in contrast to previous studies. Up to 50 h exposure of the CK enzyme to high concentrations of inorganic phosphate (Pi), a known inhibitor in certain situations, had negligible effect on enzymatic flux in the physiological pH range. Thus under in vivo conditions, such as in stroke, where pH falls as low as 6.2 and Pi rises to high levels, the rate of the CK reaction may be severely reduced due to pH but not due to high Pi concentrations.

Adenosine Triphosphate↗
PubMed1991

31P NMR saturation-transfer study of the in situ kinetics of the mitochondrial adenine nucleotide translocase.

The exchange of intramitochondrial ATP (ATP(in)) for extramitochondrial ATP (ATP(out)) was measured by using 31P NMR spectroscopy over a range of temperatures in isolated rat liver mitochondria oxidizing glutamate and succinate in the presence of external ATP but no added ADP (state 4). The rate of this exchange is more than an order of magnitude faster than rates reported previously that were determined by using isotopic techniques in the presence of oligomycin, the potent ATPase inhibitor. Differences are ascribed in part to the low levels of matrix ATP present in oligomycin-treated mitochondria. The addition of oligomycin to mitochondrial suspensions decreases intramitochondrial ATP levels from 17 +/- 3 (SEM) nmol/mg of protein in state 4 to 1.51 +/- 0.1 nmol/mg of protein in the presence of inhibitor at 8 degrees C. Simultaneously, transporter flux falls from 960 +/- 55 nmol/min.mg to undetectable levels (less than 300 nmol/min.mg). Although transport rates are much faster when measured by saturation-transfer than by conventional isotopic methods, the enthalpy values obtained by determining the effect of temperature on flux are very similar to those reported in the past that were determined by using isotopic techniques. Intramitochondrial ATP content regulates the rate of the ATP(in)/ATP(out) exchange. At 18 degrees C, the concentration of internal ATP that produces half-maximal transport rate is 6.6 +/- 0.12 nmol/mg of mitochondrial protein. The relationship between substrate concentration and flux is sigmoidal and is 90% saturated at 11.3 +/- 0.18 nmol/mg of mitochondrial protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1991

Rates of various reactions catalyzed by ATP synthase as related to the mechanism of ATP synthesis.

The forward and reverse rates of the overall reaction catalyzed by the ATP synthase in intact rat heart mitochondria, as measured with 32P, were compared with the rates of two partial steps, as measured with 18O. Such rates have been measured previously, but their relationship to one another has not been determined, nor have the partial reactions been measured in intact mitochondria. The partial steps measured were the rate of medium Pi formation from bound ATP (in state 4 this also equals the rate of medium Pi into bound ATP) and the rate of formation of bound ATP from bound Pi within the catalytic site. The rates of both partial reactions can be measured by 31P NMR analysis of the 18O distribution in Pi and ATP released from the enzyme during incubation of intact mitochondria with highly labeled [18O]Pi. Data were obtained in state 3 and 4 conditions with variation in substrate concentrations, temperature, and mitochondrial membrane electrical potential gradient (delta psi m). Although neither binding nor release of ATP is necessary for phosphate/H2O exchange, in state 4 the rate of incorporation of at least one water oxygen atom into phosphate is approximately twice the rate of the overall reaction rate under a variety of conditions. This can be explained if the release of Pi or ATP at one catalytic site does not occur, unless ATP or Pi is bound at another catalytic site. Such coupling provides strong support for the previously proposed alternating site mechanism. In state 3 slow reversal of ATP synthesis occurs within the mitochondrial matrix and can be detected as incorporation of water oxygen atoms into medium Pi even though medium [32P]ATP does not give rise to 32Pi in state 3. These data can be explained by lack of translocation of ATP from the medium to the mitochondrial matrix. The rate of bound ATP formation from bound Pi at catalytic sites was over twice the rate of the overall reaction in both states 4 and 3. The rate of reaction at the catalytic site is considerably less sensitive to the decrease in membrane potential and the concentration of medium ADP than is the rate of medium ATP formation. This supports the view that the active catalytic site is occluded and proceeds at a rapid rate which is relatively independent of delta psi m and of media substrates.

Adenosine Triphosphate↗
PubMed1991

Relationship between in vitro relaxation of the costo-uterine smooth muscle and mesovarial leiomyoma formation in vivo by beta-receptor agonists.

The three beta-agonists, salbutamol, ritodrine, and terbutaline have been shown to possess differing potentials to induce leiomyomas in rat costo-uterine muscle following chronic exposure (salbutamol greater than terbutaline greater than ritodrine). It has been suggested that the potential to induce leiomyomas is related to the relaxant properties of these agonists in the costo-uterine muscle. In order to test this hypothesis, the potencies of salbutamol, terbutaline, and ritodrine were compared to isoproterenol and norepinephrine in vitro in the rat costo-uterine smooth muscle, a beta 2-adrenergic receptor rich tissue. All compounds produced relaxation of potassium chloride (KCl) contracted costo-uterine smooth muscle. Significant differences in potency were observed, with isoproterenol being the most potent, followed in rank order by salbutamol, terbutaline and ritodrine. The relative potency of the non-selective beta-blocker propranolol in inhibiting the agonist mediated relaxant activity was similar for all agonists examined, indicative of interactions at the same receptor site (Tallarida and Jacob 1979). When tested for beta-agonist activity in the guinea pig atria, salbutamol and ritodrine were less potent in these tissues compared to the costo-uterine muscle. In summary, the in vitro pharmacological potency of salbutamol, terbutaline and ritodrine correlated with the potential to induce leiomyoma formation in rat costo-uterine muscle following chronic exposure to the respective beta-agonists. These results indicate that the isolated rat costo-uterine muscle is a sensitive model for comparing the potency of beta-agonists, and may assist in establishing the risk of costo-uterine leiomyoma formation in chronic rat studies relative to agents such as salbutamol.

Adrenergic beta-Agonists↗
PubMed1991

A23187-induced pulmonary gas trapping and inflammation in the guinea pig.

A brief A23187 aerosol exposure produced prolonged airway obstruction with granulocyte accumulation in conscious guinea pigs. Aminophylline, atropine, pyrilamine, salbutamol, SC-41930 (a leukotriene B4 antagonist) and WEB 2086 (a platelet activating factor antagonist) were administered intravenously (i.v.) to evaluate their ability to prevent these changes. Inhaled salbutamol was also assessed. Aminophylline, atropine, and salbutamol (i.v. and aerosol) inhibited A23187-induced gas trapping (p less than 0.01). However, pyrilamine, SC-41930 and WEB 2086 did not influence this airway obstructive effect. Only atropine, inhaled salbutamol and SC-41930 inhibited the cell influx (p less than 0.01), while pyrilamine potentiated the inflammation (p less than 0.05). We conclude that A23187 produces a sustained bronchospasm and an intense granulocyte accumulation. The treatment agents tested differ considerably in their ability to alter A23187-induced airway obstruction and inflammation.

Albuterol↗
PubMed1991

Beta-adrenoceptor profile of ractopamine HCl in isolated smooth and cardiac muscle tissues of rat and guinea-pig.

The investigational sympathomimetic amine, ractopamine hydrochloride, has been profiled for adrenergic activity in selected smooth and cardiac muscle preparations. There was no significant interaction of ractopamine with alpha-adrenergic receptors in the rat vas deferens at concentrations up to 10(-5) M. However, ractopamine produced a concentration-dependent increase in the force and rate of contractions of atria isolated from normal and reserpinized guinea-pigs (EC50 = 1 x 10(-7) M). These increases were submaximal compared with isoprenaline (70-85%), suggesting partial agonist activity at the beta 1-receptor site. Ractopamine completely relaxed the KCl-contracted guinea-pig trachea and rat costo-uterine smooth muscle to their resting tensions (EC50 = 3 x 10(-7) and 5.5 x 10(-8) M, respectively), indicative of full beta 2-agonist properties. Propranolol blocked the response of ractopamine in isolated tracheal and atrial tissues (pA2 = 7.70), demonstrating a beta-adrenergic mechanism of activity. Ractopamine also exhibited antagonism of the response of the guinea-pig trachea to the beta-agonist, isoprenaline. Relative to other beta-agonists, ractopamine was 100-fold more potent than the phenethanolamines, salbutamol and ritodrine, at the beta 1-adrenoceptor, and approximately 7- to 11-fold more potent than ritodrine, but only one-sixth to one-tenth as potent as salbutamol at the beta 2-adrenoceptor. Thus, ractopamine possesses significant beta 1- and beta 2-agonist properties. The submaximal stimulation of the force and rate of atrial contractions is indicative of a partial beta 1-agonist, while the maximal relaxation of the tracheal and costo-uterine smooth muscle is characteristic of a full beta 2-agonist.

Adrenergic beta-Agonists↗