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Biomedical subjects

R A Lawrence

Publications and source records attributed to R A Lawrence.

At least 19 recordsLinked to original sources
PubMed1992

Investigation of the prostaglandin E (EP-) receptor subtype mediating relaxation of the rabbit jugular vein.

1. Prostaglandin E2 (PGE2) relaxes circular smooth muscle of the rabbit isolated jugular vein at very low concentrations (mean pIC50 against histamine-induced contraction = 9.34). This effect is not blocked by the EP1-receptor antagonist, AH 6809 (2 microM). 2. From a group of prostaglandin E analogues examined, 16,16-dimethyl PGE2, misoprostol, 11-deoxy PGE2-1-alcohol and 11-deoxy PGE1 were highly potent relaxant agents, whereas 17-phenyl-omega-trinor PGE2, MB 28767 and butaprost had low potency and sulprostone and oxoprostol were virtually inactive. 3. Comparison of the jugular vein data with published data for inhibitory agonist potencies on the cat trachea (EP2 preparation) and the field-stimulated guinea-pig vas deferens (EP3) indicates that the EP-receptor in the rabbit jugular vein is closest to the EP2 subtype. However, the correlation is not entirely convincing. For example, butaprost, 16,16-dimethyl PGE2 and 11-deoxy PGE1 are of similar potency on the cat trachea, whereas butaprost is about 300 times less potent than the other two analogues on the jugular vein. The existence of more than one EP2-receptor appears possible. 4. It was felt that the activity of butaprost required further investigation in view of the claim that it is a specific EP2-receptor agonist. We have shown that butaprost has very low inhibitory activity on the guinea-pig vas deferens, a very sensitive EP3-receptor containing preparation. However, on the chick ileum, the original EP3 preparation, butaprost showed potent contractile activity (pEC25 approximately 8.0).In addition, its maximum response was lower than that of PGE2; lower maxima were also found for sulprostone, MB 28767 and oxoprostol, but not for ICI 80205, 16,16-dimethyl PGE2 and 17-phenyl-omega-trinor PGE2. The maximal response to a combination of either sulprostone and butaprost or sulprostone and PGE2 was similar to that achieved by PGE2 alone. Analysis of the interaction between sulprostone and PGE2 appears to exclude a partial agonist action for sulprostone. Furthermore neither sulprostone nor butaprost appear to have inhibitory activity on the ileum. AH 6809 at 2 pM produced only a small shift of the PGE2 log concentration-response curve.5. It is likely that contraction of the longitudinal smooth muscle of the chick ileum is mediated by (at least) two EP-receptor subtypes; activation of only one receptor system does not induce the maximum response (i.e. the acetylcholine maximum) of the preparation. One receptor could be an EP3 subtype, at which sulprostone exerts a selective agonist action. The other receptor is unlikely to be an EP, subtype, because of the high agonist potency of butaprost, the low agonist potency of iloprost, and the low antagonist potency of AH 6809. An alternative hypothesis is that the chick ileum contains a novel EP-receptor subtype in addition to an EP3-receptor.

Animals↗
PubMed1992

Characterization of receptors involved in the direct and indirect actions of prostaglandins E and I on the guinea-pig ileum.

1. A study of the effects of prostaglandin E2 (PGE2) and eleven synthetic analogues on the guinea-pig isolated ileum preparation has revealed three distinct contractile actions, each associated with a different prostaglandin E (EP-) receptor subtype. In addition, PGI2 (prostacyclin) and its stable analogues can activate prostaglandin I (IP-) receptors to elicit both contraction and relaxation of the ileum. 2. Two of the PGE actions involve direct stimulation of the smooth muscle, being unaffected by 1 microM morphine treatment. One action is blocked by AH 6809 at micromolar concentrations and ICI 80205 and 16,16-dimethyl PGE2 are particularly potent agonists. Activation of EP1-receptors appears to be involved. The second action is unaffected by AH 6809; sulprostone and MB 28767 are potent agonists. Comparison with agonist potency rankings on the guinea-pig vas deferens indicates that EP3-receptors may be involved. 3. The third PGE effect and the stimulant PGI effect are blocked by morphine, indicating enteric neurones and/or sensory nerve terminals as sites of action. EP2-receptors may be involved in the PGE action, in view of the marked effect of morphine on the contractile actions of misoprostol, 11-deoxy PGE2-1-alcohol, 11-deoxy PGE1 and butaprost, all of which show some selectivity for EP2-receptors. The PGI action is most easily studied with cicaprost (EC25 = 1.3 nM), since iloprost, carbacyclin and to a lesser extent PGI2 also have agonist activity at EP1-receptors. 4. The contractile action of 17-phenyl-omega-trinor PGE2 on the ileum is unaffected by morphine. Since this analogue shows only weak agonist activity on the rabbit jugular vein (EP2 preparation) and guinea-pig vas deferens (EP3), it may be a more useful standard agonist than PGE2 in EPl1-receptor studies.5. In the presence of morphine and AH 6809, cicaprost inhibits histamine-induced contractions (IC25 = 22 nM). PGI2 and iloprost show mixed inhibitory/potentiating actions, whereas carbacyclin only potentiates histamine contractions. This IP-receptor-mediated inhibition may account for the bell-shaped log concentration-response curve of cicaprost (no inhibitors present) and the very marked block of iloprostinduced contractions by AH 6809.6. We have found no evidence for either IP-receptors mediating direct contraction or EP-receptors mediating inhibition of the ileum longitudinal smooth muscle, as has been suggested in the literature.7. In view of the complexity of prostanoid action on the guinea-pig ileum we feel that the preparation must be used with caution to ascertain the EPl agonist or antagonist potencies of novel compounds.

Animals↗
PubMed1992

Endothelial cell cystine uptake and glutathione increase with N,N-bis(2-chloroethyl)-N-nitrosourea exposure.

Glutathione (gamma-glutamylcysteinylglycine, GSH) is an important cellular antioxidant. In typical cultured cell preparations GSH synthesis is limited by the availability of intracellular cysteine. Because extracellular cystine is the chief source of intracellular cysteine in cultured cells, increasing cystine transport can result in increased intracellular GSH. Depletion of GSH or exposure to oxidants has been shown to stimulate cystine transport in bovine pulmonary endothelial cells and other cell types. BCNU [N,N-bis(2-chloroethyl)-N-nitrosourea] is a potent inhibitor of glutathione reductase (GSSG-Red). We examined the effects of BCNU on cystine uptake by bovine pulmonary artery endothelial cells (BPAEC). We hypothesized that blocking GSSG-Red could result in increased cellular uptake of cystine to replenish decreases in GSH caused by oxidation. Levels of BCNU between 0.005 and 0.05 mM added to the cell culture medium inhibited GSSG-Red at 2, 4, and 24 h after addition. BCNU treatment resulted in concentration-dependent increases in both cystine uptake and GSH levels after 24 h of exposure. The increases in uptake were specific for cystine and glutamate and were sodium independent, suggesting induction of a xc(-)-like transport system. No intracellular accumulation of GSSG was measured nor was any significant depletion of GSH noted at any time of BCNU exposure.

Animals↗
PubMed1992

Resistive breathing activates the glutathione redox cycle and impairs performance of rat diaphragm.

Free radical activation and lipid peroxidation have been described in skeletal muscle during strenuous exercise. We hypothesized that oxygen radicals could also be formed in the diaphragm muscle during strenuous resistive breathing and that these radicals might affect diaphragm function. Seven control and 12 experimental male Sprague-Dawley rats were studied. Six experimental animals were subjected to resistive breathing (RB) alone and six animals received 15 min of mechanical ventilatory support (MV) after the resistive breathing period. Inspiratory resistance was adjusted to maintain airway opening pressure at 70% maximum in both groups until exhaustion. Diaphragm samples were obtained for analysis of thiobarbituric acid-reactive substances (TBAR), reduced glutathione (GSH), and glutathione disulfide (GSSG). In vitro isometric contraction times, twitch (Pt) tension and maximum tetanic (Po) tension, force-frequency curves, fatigue index, and recovery index were measured. In RB and MV compared with controls, there were significant decreases in Pt and Po. Diaphragm TBAR concentrations were increased in MV compared with controls or RB. GSSG-to-total glutathione ratio was increased in RB and MV compared with controls. Production of free radicals during RB and MV may represent an important mechanism of diaphragmatic injury that could contribute to the decline in contractility.

Airway Resistance↗
PubMed1992

The medico-legal, social and ethical implications of surrogate parenthood.

Infertility has existed for thousands of years and treatment has evolved with the advance of medical science. Surrogate parenthood was effected previously by sexual intercourse, but AIH, AID and GIFT have rendered this practice obsolete. The terms surrogate mother, partial and full surrogacy are defined. Medico-legal, social and ethical arguments for and against surrogacy are discussed. References are made to varying national attitudes as to the desirability of legalizing surrogate parenthood and the implications for commissioning parents, the surrogate mother and adequate counselling are considered.

Contracts↗
PubMed1992

Diphosphoryl lipid A protects rats from lethal hyperoxia.

Bacterial endotoxin has been shown to protect rats from lethal hyperoxia. The structure of endotoxin contains diphosphoryl lipid A (DPL) as the lipid backbone stripped of protein and polysaccharides. DPL is the component of the endotoxin molecule that has been demonstrated (in previous studies) to be responsible for the immunologic, mitogenic, pyrogenic, and lethal properties of endotoxin. Monophosphoryl lipid A (MPL) is a nonpyrogenic, nontoxic modification of the DPL molecule that retains its immunostimulatory and mitogenic properties. We hypothesized that DPL may be the actual active component of endotoxin that protects rats from lethal hyperoxia. We also hypothesized that the protection from hyperoxia that is afforded by the DPL component may be related to endogenous release of tumor necrosis factor alpha which should allow MPL to also be protective. To test these hypotheses, we performed a series of experiments in which rats were treated with endotoxin, DPL, MPL or vehicle and exposed to room air or hyperoxia. We found that DPL and endotoxin both protected rats from lethal hyperoxia, but MPL alone was not protective. Even though MPL was not protective, DPL and MPL both increased endogenous release of tumor necrosis factor alpha early after injection (peak DPL level, 3619 +/- 1500 pg/ml, peak MPL level, 4038 +/- 500 pg/ml). Protection in both the endotoxin- and DPL-treated animals was associated with increases in lung antioxidant enzyme activities. We concluded that DPL protect rats from hyperoxia but that MPL is not protective in spite of its immunostimulatory and mitogenic effects.

Animals↗
PubMed1991

Effects of age on rat glutathione metabolism.

The authors hypothesized that rat plasma or tissue glutathione metabolism could change with age due to possible decreases in glutathione-related enzyme activities. To test this hypothesis, the authors measured plasma and tissue concentrations of glutathione and glutathione-related enzymes. Animals were 3 months, 12 months, or 24 months old at the time of experiments. Plasma glutathione was found to be significantly increased in both the 12-month-old and 24-month-old groups compared to the 3-month-old rats. Tissue enzyme measurements showed no significant differences between the groups in lung or liver glutathione peroxidase or glutathione S-transferase. gamma-Glutamyl transpeptidase activity was significantly decreased in kidney and lung with aging. Decreases in tissue gamma-glutamyl transpeptidase activity occur with age; this may contribute to increases in plasma glutathione concentrations.

Age Factors↗
PubMed1991

Allopurinol-induced effects in premature baboons with respiratory distress syndrome.

To test the hypothesis that administration of allopurinol could modify the response to prolonged hyperoxia in premature baboons (140 days gestation) with respiratory distress syndrome, we evaluated physiological, pathological, and lung biochemical parameters in groups of premature baboons treated with mechanical ventilation and exposed to various amounts of oxygen for 6 days. Three groups of experimental animals were studied, including animals that received oxygen as needed to maintain arterial oxygen between 60 and 80 Torr [inspiratory O2 concentration- (FIO2) PRN], animals that received 100% oxygen continuously but also received allopurinol intravenously at a dose of 10 mg.kg-1.day-1 (FIO2-1.0 + allopurinol), and animals that received 100% oxygen continuously and the vehicle for allopurinol administration (FIO2-1.0). Pathological examinations of the experimental animals showed evidence of lung injury in both 100% oxygen-exposed groups, but the allopurinol-treated animals had findings more compatible with the FIO2-PRN group, with relatively few macrophages or polymorphonuclear lymphocytes being present in lung tissue. Lungs of animals treated with allopurinol were also more distensible and had a trend toward decreased lung water compared with the FIO2-1.0 group. Allopurinol-treated animals were able to induce lung glutathione concentrations and glutathione-related and antioxidant enzyme activities compared with the normoxic control (FIO2-PRN) group. Ventilator pressure requirements were also decreased in the allopurinol-treated animals compared with the FIO2-1.0 controls after 42 h. These data suggest that treatment of hyperoxia-exposed premature baboons with allopurinol for the first 6 days of life results in significant changes in lung responses and antioxidant defenses compared with vehicle-treated baboons exposed to 100% oxygen for the same time period.

Allopurinol↗
PubMed1991

Dental needs assessment survey: three Florida counties.

Dental needs assessment surveys were completed in three Florida counties (1987 - Lee County), (1988 - Pasco County) and (1989 - St. Lucie County). The data collected were then compared with the results from the national caries prevalence surveys in 1979-80 and 1986-87, by individual county and with the combined three-county total. Visual tactile examinations were done using the Radlike criteria for the DMFS index and the WHO Treatment Needs Index. Schools were selected based on the percent of students enrolled in the free or reduced lunch program and by geographic distribution. Although there were age group differences within individual counties, the combined data showed every age group except the seven year olds at a lower DMFS mean level than the data from the 1986-87 national survey for Region IV. The differences range from -.20 surfaces in 8-year-olds to -.57 surfaces in 13-year-olds. None of the differences were statistically significant from the national surveys. This indicates that these small scale surveys are a reliable method for needs assessment.

Adolescent↗
PubMed1989

Breastfeeding and medical disease.

Breastfeeding is an important opportunity for both mother and infant. There are nutritional, immunologic, infection protection, and psychological reasons to preserve lactation when illness intervenes. The internist will have patients with acute self-limited disease who are breastfeeding and patients with chronic long-term illness who wish to breastfeed their infants. The internist will need to consider the breastfeeding and the infant when planning treatment. The risk of treatment to the infant versus the great benefits of breastfeeding in most cases will support continuing breastfeeding. This article discusses the key considerations in managing the lactating woman with an illness.

Bacterial Infections↗
PubMed1989

EP 171: a high affinity thromboxane A2-mimetic, the actions of which are slowly reversed by receptor blockade.

1. Replacement of the four-carbon omega-terminus in 9,11-endoxy-10a-homo prostaglandin H2 with a p-fluorophenoxy group produces a compound (EP 171) with very high agonist potency at TP-receptors. 2. On six isolated smooth muscle preparations EP 171 was 33-167 times more potent as a TP-receptor agonist than U-46619 (11,9-epoxymethano PGH2); EC50 values ranged from 45 to 138 pM. The actions of EP 171 were difficult to study because of their slow onset and offset. For example, on the guinea-pig trachea the time required for 50% reversal of EP 171-induced contractions during washout was about 3 h. 3. On the pig pulmonary artery, a more rapidly responding preparation, it was possible to show that the TP-receptor antagonist EP 092 blocked the contractile actions of EP 171 and U-46619 to similar extents: pA2 = 8.09 and 8.15 respectively. 4. EP 171 was also a very potent activator of human blood platelets, being about 90 times more potent than U-46619. Both shape change (0.1 nM) and aggregation (1 nM) were slow in onset, a profile not previously observed for a thromboxane A2-mimetic. 5. When potencies at TP-, EP1-(guinea-pig fundus) and FP-(dog iris sphincter) receptors were compared, EP 171 showed a higher specificity as a TP-receptor agonist than either STA2 or U-46619. These studies also showed that contrary to earlier reports, the guinea-pig fundus does contain TP-receptors mediating muscle contraction. However, the maximal response due to activation of TP-receptors was only about 35% of the PGE2 maximum. 6. Established responses to EP 171 were slowly reversed following addition of a high concentration of a TP-receptor antagonist (EP 092, GR 32191 or BM 13177). Faster reversals of three less potent 16-p-halophenoxy prostanoids and U-46619 were obtained. Half-times for offset (and onset) of agonist action appeared to correlate with potency rather than with lipophilicity. 7. Competition between the agonists and a radio iodinated PTA2 derivative ([125I]-PTA-OH) for binding to TP-receptors on intact human platelets was studied. IC50 values correlated well with aggregating potency, EP 171 having the lowest IC50 of 2.9 nM. The true Ki for EP 171 may be about 1 nM if both its racemic nature and reduction of initial free ligand concentration due to TP-receptor binding are taken into account. 8. It is concluded from a comparison of agonist potency rankings that subclassification of the TP-receptor is not warranted at this time. The factors that may be responsible for the slow kinetics of EP 171 action are discussed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Functional and ligand binding studies suggest heterogeneity of platelet prostacyclin receptors.

1. This study describes attempts to compare prostacyclin (IP-) receptors in human, pig, horse, rabbit and rat platelets and in circular muscle of human, rabbit and dog mesenteric and pig gastroepiploic arteries. Three stable prostacyclin analogues, iloprost, cicaprost and 6a-carba-prostacyclin (6a-carba-PGI2) and a prostaglandin endoperoxide analogue EP 157 (previously shown to mimic prostacyclin on human platelets) were used. 2. Our main conclusion is that prostacyclin receptors on human, pig and horse platelets are similar in nature, but distinct from those on rabbit and rat platelets. Functional studies (inhibition of aggregation) showed that iloprost and cicaprost always had similar potencies whereas 6a-carba PGI2 was much more potent than EP 157 on rabbit and rat platelets (300 and 1000 fold on a molar basis) compared with human, pig and horse platelets (2, 7 and 7 fold respectively). Measurement of initial rates of cyclic AMP production confirmed these orders of potency. 3. Although pig platelets were quite sensitive to inhibition by EP 157 (threshold = 10 nM in some experiments), maximal inhibition of aggregation was not always achieved (20 microM). EP 157 also produced only small elevations of cyclic AMP and inhibited rises in cyclic AMP induced by iloprost. It is possible that EP 157 has a lower efficacy than iloprost at the IP-receptor and on pig platelets it can sometimes act as a partial agonist. 4. Human, pig and horse platelet membranes bound [3H]-iloprost at 30 degrees C and this binding was inhibited by the four prostanoids. On human and pig membranes the order of potency was cicaprost = iloprost greater than 6a-carba PGI2 greater than EP 157. The order of potency may be similar on horse platelet membranes, but the analysis is complicated by the presence of a second component of [3H]-iloprost binding that is inhibited by iloprost and 6a-carba PGI2 but not by cicaprost. This binding may be due to the presence of an EP1-receptor, since iloprost and 6a-carba PGI2 but not cicaprost are known to have potent EP1-receptor agonist actions on smooth muscle preparations. IC50 values for cicaprost inhibition on human, pig and horse membranes were 110, 90 and 165 nM respectively. The need for IP-receptor radioligands of greater specificity is apparent from these studies. 5. Minimal binding of [3H]-iloprost to rabbit and rat platelet membranes was obtained at 30 degrees C. Lowering the incubation temperature to 4 degrees C and ensuring that the temperature did not rise during the filtration process increased binding and allowed inhibition curves to be obtained. The results suggest a lower binding affinity for [3H]-iloprost, associated with a higher dissociation rate for the radioligand-receptor complex. IC50 values for cicaprost were 900nm for rabbit and 640nm for rat platelets. In a similar manner to horse platelet membranes, the presence of a second binding site for [3H]-iloprost was detected on rabbit platelet membranes. 6. Sensitivity to the relaxant action of iloprost on the arterial smooth muscle preparations decreased in the order: human mesenteric, dog mesenteric, rabbit mesenteric, pig gastro-epiploic. Cicaprost was always slightly more potent than iloprost (1.2-2.8 fold). On the pig vessel preparation 6a-carba PGI2 did not produce complete relaxation. The possibility that this is due to an opposing contractile action mediated via EP1 or EP3 receptors is discussed. 7. EP 157 relaxed the human, pig and rabbit arterial preparations at concentrations 100-200 times those of iloprost. This correlates well with its IP-receptor agonist potency on human, pig and horse platelets. The results obtained with EP 157 further demonstrate the potential difficulties in separating platelet inhibitory and vasodilator properties of prostacyclin mimetics in man.

Animals↗