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Biomedical subjects

L Poston

Publications and source records attributed to L Poston.

At least 73 records · Page 4Linked to original sources
PubMed1999

Maternal diet high in fat reduces docosahexaenoic acid in liver lipids of newborn and sucking rat pups.

The effect of a maternal diet high in fat, similar to Western foods, and of diabetes on liver essential fatty acid composition of the mother and the newborn and sucking pups was investigated. Female Sprague-Dawley rats were fed on either a low-fat (42 g/kg) or a high-fat (329 g/kg) diet for 10 d before mating, throughout pregnancy and post-partum. On the first day of pregnancy, diabetes was induced by intravenous administration of streptozotocin in half the animals from the two diet groups. Half the pups were killed at birth, and the remaining pups and mothers at days 15 and 16 respectively. At birth, there was a significant reduction in the proportions of docosahexaenoic acid (DHA) in the liver phosphoglycerols and neutral lipids of the pups of both high-fat control and diabetic mothers compared with those of low-fat control and diabetic mothers. Diabetes decreased arachidonic (AA) and linoleic acid values in both the low- and high-fat groups at birth. The sucking pups of both the high-fat control and diabetic mothers exhibited a significant reduction in DHA and a concomitant compensatory increase in AA and a lowering in DHA-AA balance. In the mothers, the high-fat diet significantly increased the proportions of DHA in ethanolamine phosphoglycerols but had no observable effect in choline phosphoglycerols and neutral lipids. In the fetus the DHA level (g/100 g total fatty acids) was disproportionately reduced by the maternal high-fat diet. The adverse effect of the high-fat diet on the level of DHA (g/100 g total fatty acids) was greater in the neonate (and by implication the fetus) than in the sucking pups or mothers. It is concluded that a distortion of the biochemistry is induced in the offspring through a maternal high-fat diet, without genetic predisposition.

Animals↗
PubMed1998

Flow-induced dilatation in isolated resistance arteries from control and streptozotocin-diabetic rats.

Acetylcholine-induced vasodilatation is impaired in animal models of insulin-dependent diabetes mellitus (IDDM), and may result from altered nitric oxide synthesis or release. The response to intraluminal flow, a more physiologically relevant stimulus for nitric oxide release, is unknown. This study examined flow-induced responses in isolated resistance arteries from male Sprague-Dawley control and streptozotocin-diabetic (45 mg/kg i.v., 4 week duration) rats. Mesenteric arteries (4-5th order) were dissected and cannulated on a pressure myograph (mean internal diameter +/- SEM at 40 mmHg, control 223 +/- 8, n = 9 vs diabetic 239 +/- 12 microm, n = 8, NS). Arteries were preconstricted with noradrenaline (1 micromol/l) and intraluminal pressure raised and maintained at 80 mmHg. Luminal flow was raised in incremental steps (0-1.27 microl/s). Arteries from control animals dilated to flow while arteries from diabetic animals constricted (% change in internal diameter +/- SEM at 0.79 microl/s: control 13.46 +/- 6.52, n = 9 vs diabetic -7.44 +/- 3.38%, n = 8; p < 0.005). Incubation with N(omega)-nitro-L-arginine methyl ester (0.1 mmol/l) abolished flow responses in arteries from controls but not from diabetic rats. In conclusion, impaired flow-induced nitric oxide-mediated vasodilatation may contribute to vascular disease in IDDM.

Acetylcholine↗
PubMed1998

Dietary antioxidant supplementation reduces lipid peroxidation but impairs vascular function in small mesenteric arteries of the streptozotocin-diabetic rat.

Impaired endothelium-dependent relaxation could underlie many of the vascular complications associated with insulin-dependent diabetes mellitus, and may be mediated by increased oxidative stress. The effect of antioxidants on vascular endothelial function and oxidative stress of streptozotocin-diabetic rats was assessed by dietary supplementation with vitamins E and C. Diabetic (i.v. streptozotocin, 45 mg/kg) male Sprague-Dawley rats were fed one of six supplemented diets containing 75.9, 250, or 500 mg vitamin E/kg chow, 250 mg vitamin C/kg H2O, 250 mg vitamin E/kg chow plus 250 mg vitamin C/kg H2O, or chow deficient in vitamin E, and then compared to standard-fed control rats. After 4 weeks, small mesenteric arteries were dissected and mounted on a small vessel myograph, concentration response curves were then constructed to noradrenaline, acetylcholine and sodium nitroprusside. Acetylcholine-mediated relaxation was impaired in arteries from diabetic rats (pEC50 6.701+/-SEM 0.120, n = 8) compared to controls (7.386+/-0.078, n = 6; p < 0.05). The 500 mg/kg vitamin E diet further impaired maximum relaxation to acetylcholine (58.2+/-10.5 vitamin E, n = 7 vs 84.4+/-5.3 % standard, p < 0.05), and the combined vitamin E plus C diet impaired maximum relaxation to sodium nitroprusside (48.5+/-4.1 in vitamin E + C, n = 8 vs 75.6+/-3.9 % standard; p < 0.01). However, plasma 8-epi-prostaglandin (PG)F2alpha (measured as an estimate of oxidative stress) was dose-dependently decreased in rats on vitamin E supplemented diets. Dietary antioxidant supplementation did not reverse impaired endothelial function in this model of uncontrolled diabetes despite a concomitant decrease in oxidative stress.

Animals↗
PubMed1998

Endothelial dysfunction in streptozotocin-diabetic rats is not reversed by dietary probucol or simvastatin supplementation.

Oxidative stress and dyslipidaemia are key features of diabetes mellitus and may be involved in mediating the vascular endothelial dysfunction associated with this disease. The aim of this study was to examine the effect of dietary lipid-lowering and antioxidant agents on vascular endothelial function and oxidative stress. Diabetic male Sprague-Dawley rats (i.v. streptozotocin, 45 mg/kg) were fed for 4 weeks on a standard diet or on a diet supplemented with either the lipid-lowering antioxidant probucol (1% w/w in diet) or the 3-hydroxy 3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor simvastatin (0.01% w/w in diet). Responses to noradrenaline, acetylcholine, and sodium nitroprusside were assessed in small mesenteric arteries (mean internal diameter 300+/-5 microm, n = 80) mounted on a small vessel myograph. Plasma concentrations of total cholesterol and triglycerides were significantly raised in standard-fed diabetic rats and significantly reduced in probucol and simvastatin-fed diabetic rats 8-epi-prostaglandin (PG)F2alpha, an indicator of oxidative stress, was raised in liver and aorta from diabetic rats compared to controls. Probucol supplementation reduced 8-epi-PGF2alpha in aorta and liver of diabetic rats but increased 8-epi-PGF2alpha content in plasma and aorta from control animals. The abnormal relaxation to acetylcholine in arteries from the diabetic rats (pEC550 diabetic 6.763+/-0.172 vs control 7.541+/-0.175; p < 0.05) was not improved by probucol or simvastatin. These data, therefore, do not support a role for oxidative stress or dyslipidaemia in mediating the impaired ACh-induced endothelium-dependent relaxation of small mesenteric arteries from the streptozotocin-diabetic rat.

Animals↗
PubMed1998

Enhanced acetylcholine induced relaxation in small mesenteric arteries from pregnant rats: an important role for endothelium-derived hyperpolarizing factor (EDHF).

1. Small mesenteric arteries from pregnant rats demonstrated greater sensitivity (pEC50 : P<0.001) and maximum relaxation (P<0.01) to acetylcholine (ACh) than those of control non-pregnant animals. 2. Maximum relaxation, but not sensitivity, to ACh remained greater (P<0.01) in pregnant animals when evaluated in 25 mM KCl, which prevents relaxation dependent upon hyperpolarization. ACh induced relaxation in the presence of 25 mM KCl was completely inhibited in pregnant and non-pregnant groups by N(omega)-nitro L-arginine methyl ester (L-NAME, 100 microM), indomethacin (INDO, 10 microM) and oxadiazole quinoxalin (ODQ, 1 microM), suggesting pregnancy associated enhancement of dilator prostanoid and/or nitric oxide (NO) synthesis. 3. ACh induced relaxation in 5 mM KCI was only partially inhibited by a combination of N(omega)-nitro L-arginine methyl ester (L-NAME, 100 microM), indomethacin (INDO, 10 microM) and oxadiazole quinoxalin (ODQ, 1 microM). The residual relaxation, which was greater in arteries from pregnant rats (maximum relaxation: P<0.01), was prevented by 25 mM KCl, indicating pregnancy associated enhanced synthesis/ reduced degradation of a hyperpolarizing factor. Residual relaxation to ACh in 5 mM KCl was inhibited by the cytochrome P450 inhibitor, proadifen (1 microM) in the pregnant group (P<0.001). 4. Relaxation to spermine NONOate was similar in pregnant and non-pregnant groups and totally inhibited by ODQ (in the presence of L-NAME). 5. This study suggests that, in addition to enhanced endothelium dependent NO/dilator prostanoid synthesis, a hyperpolarizing factor may contribute to the vascular adaptation to pregnancy.

Acetylcholine↗
PubMed1998

Effect of nimesulide and indomethacin on contractility and the Ca2+ channel current in myometrial smooth muscle from pregnant women.

The non-steroidal anti-inflammatory drug (NSAID) indomethacin inhibits both constitutive and inducible forms of cyclo-oxygenase (COX-1 and COX-2, respectively), while nimesulide is a selective COX-2 inhibitor. Uterine COX-2 is upregulated before and during term and pre-term labour, and prostaglandins play a crucial role in parturition. We therefore evaluated the effects of these drugs on myometrial contractility and the voltage-gated Ca2+ channel current in tissue strips and isolated human myometrial smooth muscle cells (HMSMC) from myometrial biopsies taken with informed consent from women undergoing caesarean section at term (not in labour). Nimesulide and indomethacin caused almost complete inhibition of spontaneous myometrial contractions at concentrations of 100 and 300 microM, respectively. The Ca2+ channel current was inhibited in a concentration-dependent manner by both drugs, with a 40% reduction of the current at 100 microM nimesulide and 300 microM indomethacin. Nimesulide also accelerated the decay of the Ca2+ channel current. The inhibition of the Ca2+ channel current by 100 microM nimesulide and 300 microM indomethacin was unaffected by the presence of either PGF2alpha or PGE2 (30 microM), and was of similar magnitude whether 10 mM Ba2+ or 1.5 mM Ca2+ was used as the charge carrier. The concentrations of indomethacin and nimesulide required to suppress spontaneous contractility in human pregnant myometrium were much higher than those necessary to inhibit prostaglandin production. The results suggest that both nimesulide and indomethacin inhibit myometrial contractility via mechanisms independent of cyclo-oxygenase inhibition. Blockade of the Ca2+ current may contribute to this effect.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Role of nitric oxide in the regulation of vascular tone in pressurized and perfused resistance myometrial arteries from term pregnant women.

OBJECTIVE: Our purpose was to evaluate flow-induced responses, myogenic tone, and norepinephrine-induced constriction in myometrial resistance arteries from normal term pregnant women and the role that nitric oxide and prostanoids may play in these responses. STUDY DESIGN: Arteries (approximately 200 microns, n = 14, at 40 mm Hg) were dissected from myometrial biopsy specimens from women undergoing cesarean section and then were mounted in a pressure arteriograph. Responses to intraluminal flow, pressure, and a constrictor agonist (norepinephrine 10(-6) mol/L) were studied in the absence and presence of N omega-nitro-L-arginine methyl ester (n = 7) or indomethacin (n = 5). Myogenic and norepinephrine-induced tone were calculated after the determination of artery diameter in the absence of extracellular calcium. RESULTS: Arteries developed myogenic tone (80 mm Hg) that was not modulated by nitric oxide or prostanoid release, whereas norepinephrine-induced tone was significantly enhanced by the nitric oxide inhibitor. An increase in intraluminal flow led to dilatation in physiologic salt solution and indomethacin, but to constriction in the presence of N omega-nitro-L-arginine methyl ester (percent increase in diameter at flow rate of 184.6 microliters/min, 24% +/- 8% in physiologic salt solution and 20% +/- 4% in the presence of indomethacin versus -27% +/- 12% in N omega-nitro-L-arginine methyl ester alone and -21% +/- 10% in indomethacin and N omega-nitro-L-arginine methyl ester, respectively, analysis of variance, p < 0.05). CONCLUSIONS: Flow-induced shear stress is a physiologic modulator of vascular tone in myometrial arteries from pregnant women. Nitric oxide, but not prostanoids, mediates this response and also blunts norepinephrine constriction. Nitric oxide may play a fundamental role in the maintenance of adequate blood supply to the fetus during human pregnancy.

Arteries↗
PubMed1997

17Beta-estradiol stimulates flow-induced vasodilatation in isolated small mesenteric arteries from prepubertal femal rats.

OBJECTIVE: Flow-induced vasodilatation may contribute to lowering of peripheral resistance to pregnancy. This study investigated modulation of flow responses by 17beta-estradiol. STUDY DESIGN: Small mesenteric arteries from prepubertal female Wistar rats were pretreated for 3 hours with 17beta-estradiol (10(-7) mol/L) with 17alpha-estradiol (10(-7) mol/L) or vehicle (0.1% dimethylsulfoxide). Responses to intraluminal flow were evaluated with use of a pressure arteriograph. RESULTS: After pretreatment with 17beta-estradiol arteries relaxed to flow, whereas those treated with vehicle or 17alpha-estradiol did not (percent change in diameter at maximum flow rate after 17beta-estradiol 38.7% +/- 5.7%, n = 10, vs 1.1% +/- 4.3%, n = 10 after vehicle; p < 0.01). Endothelium removal or pretreatment with either a nitric oxide synthase inhibitor or a novel soluble guanylyl cyclase inhibitor diminished the response to 17beta-estradiol. CONCLUSION: 17Beta-estradiol stimulated nitric oxide-mediated flow-induced relaxation. Through this pathway 17beta-estradiol could play an important role in the control of vascular tone.

Animals↗
PubMed1997

Association of gestational diabetes with abnormal maternal vascular endothelial function.

OBJECTIVE: To evaluate vascular endothelial function in isolated small arteries from women with gestational diabetes. METHODS: Small subcutaneous arteries (mean luminal diameter approximately 250 microns) were dissected from biopsies obtained at caesarean section in 14 normotensive women with gestational diabetes and in 18 normotensive nondiabetic pregnant women. Vascular function was determined after mounting the arteries on a small vessel myograph. RESULTS: Pre-constricted arteries from gestational diabetic pregnant women demonstrated poor relaxation to acetylcholine, an endothelium-dependent vasodilator (pEC50, mean [SE], 6.98 [0.10] vs normal pregnant, 7.28 [0.08], P < 0.03; % maximum relaxation, median [range], 88.2 [42.4-99.4] vs normal pregnant 94.2 [71.8-100.0], P < 0.01). In the presence of indomethacin relaxation to acetylcholine was similar in both groups suggesting a deficiency in dilator prostaglandin synthesis in the arteries from the diabetic women. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine further reduced sensitivity of arteries to acetylcholine but to a similar degree in both normal pregnant and gestational diabetic women. Relaxation to sodium nitroprusside, an indicator of sensitivity of the vascular smooth muscle to nitric oxide, was similar in both groups. CONCLUSIONS: Maternal vascular endothelial dysfunction may contribute to the increased incidence of cardiovascular disorders in women with gestational diabetes.

Acetylcholine↗
PubMed1997

Human placental syncytiotrophoblast microvillous membranes impair maternal vascular endothelial function.

OBJECTIVE: To investigate the hypothesis that, should there be an increase in deported syncytiotrophoblast microvillous membrane fragments in pre-eclampsia, it may cause maternal vascular endothelial dysfunction. DESIGN: Syncytiotrophoblast microvillous membrane (STBM) vesicles, prepared from normal term placentae, were perfused through small subcutaneous arteries isolated from fat biopsies obtained at caesarean section. Endothelial function of these arteries was studied by determining acetylcholine-induced relaxation after preconstriction with noradrenaline. As controls, physiological buffer or red blood cell membranes in physiological buffer were used and endothelial function similarly estimated. Transmission electron microscopy was performed on arteries after perfusion. SAMPLE: STBM vesicles, isolated from the placentae of three healthy women undergoing elective caesarean section for reasons unrelated to pre-eclampsia, were suspended in physiological buffer. Subcutaneous fat arteries were obtained from a separate group of 13 normotensive pregnant women, also undergoing elective caesarean section at term. RESULTS: Perfusion with red blood cell membranes or physiological buffer had no significant effect on the concentration dependent relaxation in arteries preconstricted with noradrenaline. However, after 2 h perfusion with STBM vesicles, arteries showed a significant reduction in relaxation to acetylcholine, indicative of altered endothelial function. Transmission electron microscopy of arteries perfused with STBM vesicles confirmed endothelial disruption. CONCLUSIONS: STBM vesicle perfusion specifically altered the relaxation response of preconstricted maternal subcutaneous fat arteries to acetylcholine, suggesting an alteration in endothelial dependent relaxation. Deported microvilli may therefore be capable of producing endothelial cell damage and endothelial dysfunction observed in the maternal syndrome of pre-eclampsia.

Arteries↗
PubMed1997

The role of endogenous nitric oxide synthesis in contractility of term or preterm human myometrium.

OBJECTIVE: To assess in vitro the role of endogenous myometrial nitric oxide synthesis on human myometrial contraction. DESIGN: Strips of myometrium were mounted in a standard organ bath for assessment of isometric contraction and the response to modulators of nitric oxide synthesis determined. SETTING: A teaching hospital research laboratory. SAMPLE: Women undergoing elective nonlabour caesarean section under regional anaesthesia: 54 at term and seven preterm. RESULTS: Neither addition of L-arginine, the substrate for nitric oxide synthase, nor of an inhibitor of nitric oxide synthase led to any specific change in spontaneous myometrial contraction. CONCLUSION: Endogenous nitric oxide production does not play an important role in the control of human term of preterm nonlabouring uterine smooth muscle contractility.

Arginine↗
PubMed1997

The control of blood flow to the placenta.

The maintenance of adequate blood flow to the placenta is essential for the successful outcome of pregnancy. The placental vascular bed is often regarded as a low-resistance circulation in which blood flow is determined by the fetal cardiac output, but in pregnancies associated with growth retardation, and for reasons unknown, vascular resistance increases and blood flow is compromised. This review concentrates on recent advances in our understanding of the factors that may influence fetoplacental blood flow, with particular emphasis upon the circulation of the human placenta. The placenta has no neuronal input and vascular resistance is entirely determined by humoral and structural factors. In the absence of catecholamine sensitivity, constrictor prostanoids and endothelin may be important constrictor agonists, whereas nitric oxide is now considered to contribute to tonic reduction in vascular resistance. Little is known of the relative contributions of these vasoactive agents in the elevation of fetoplacental vascular resistance, but recent evidence points to an important role for altered vascular structure in growth-retarded pregnancies.

Animals↗
PubMed1997

Flow-mediated vasodilatation is enhanced in normal pregnancy but reduced in preeclampsia.

Endothelium-derived nitric oxide is proposed to play an important role in the lowering of peripheral vascular resistance in normal pregnancy. In women with preeclampsia, the function of the endothelium is compromised, and it is suggested that reduced nitric oxide synthesis may contribute to the elevation of blood pressure and activation of coagulation pathways. In this study, we have compared responses to increments of intraluminal flow, considered to be a physiological stimulus to nitric oxide release, in arteries from normotensive nonpregnant and pregnant women and women with preeclampsia. Small subcutaneous arteries from normotensive pregnant women showed substantial flow-induced relaxation, which was attenuated by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (mean relaxation, 48.3+/-8.0% [absence of L-NAME] versus 19.2+/-10.6% [presence of L-NAME]), whereas those from nonpregnant women and women with preeclampsia demonstrated modest constriction (mean constriction, 10.1+/-7.3% and 1.2+/-7.2%, respectively). Shear stress, the frictional force that is the stimulus for flow responses, was calculated from parameters of flow, viscosity, and artery diameter. Arteries from pregnant women showed greater relaxation to shear than those from nonpregnant women or those with preeclampsia. We conclude that flow-induced shear stress is a potent stimulus to vasodilatation in arteries from pregnant women and that this mechanism may lead to a fall in peripheral vascular resistance in normal pregnancy. Failure of this flow-induced dilatation may contribute to the gestational hypertension of preeclampsia.

Adult↗
PubMed1997

Adverse pregnancy outcome in the antiphospholipid syndrome: focus for future research.

Pregnant patients with antiphospholipid syndrome (APS) may suffer from recurrent pregnancy loss, pre-eclampsia, intrauterine growth restriction and placental abruption. These conditions inevitably result in a high incidence of premature delivery with all the neonatal complications that follow. The mechanism underlying these adverse pregnancy outcomes has not yet been established. This may be primarily a maternal disease process with secondary placental maldevelopment and/or malfunction. Alternatively, there may be primary placental damage mediated directly or indirectly by antiphospholipid antibodies. The safe and successful treatment of pregnant women with APS lies in the understanding of the aetiology of this condition and the mechanism by which complications in pregnancy may arise. In this article we highlight areas in which research may be targeted such that our understanding of the pathogenesis of adverse pregnancy outcome may be enhanced.

Abortion, Habitual↗