Pharmacological & Physiological Characterisation of the Rat Mammary Artery at Different Stages of Reproduction: Final Report to the Scottish Government Rural and Environment Research and Analysis Directorate (RERAD).

The overarching-aim of the project was to assess the responsiveness of the rat mammary artery during different stages of the reproductive cycle. This has implications for not only normal physiology, but also heart disease, since women who undergo coronary artery bypass surgery using mammary arteries as the conduit and who have breastfed their offspring have a significantly better prognosis that those who have never breastfed.sch_diepub811pu

Effect of Oatmeal on Postprandial Vascular Compliance Following a High Fat Meal

Background and aim: Postprandial hyperlipidaemia has been associated with acute cardiovascular effects e.g. endothelial dysfunction and peripheral vasodilatation. Oats have known health benefits, and may reduce the transient, post-prandial endothelial dysfunction. The aim of this short study was to investigate if markers of endothelial function pulse wave velocity (PWV) and augmentation index corrected for heart rate (AIx@75) are affected by a meal with varying levels of saturated fat, with or without oatmeal. Methods and results: Fourteen subjects (aged between 22 and 51 years) were recruited. On their first visit, following baseline measurements of anthropometry, blood pressure (BP), heart rate (HR), PWV and AIx@75, they were given one of three meals (low fat, high fat, and high fat with 60g oatmeal) in a randomised order. Subjects returned three hours later for re-assessment of BP, PWV and AIx@75. Visits two and three followed the same protocol, but only BP, HR, PWV and AIx@75 were measured. There was a significant correlation between baseline PWV and systolic pressure (p<0.02), and AIx@75 and diastolic pressure (p<0.005). AIx@75 was positively related to BMI and waist circumference (p<0.01 and p<0.005 respectively). AIx@75 fell following the high fat meal (p<0.05), but not when oats were taken. Heart rate increased following the high fat meal with oats (p<0.05), but no differences were found between fasting and postprandial PWV after any of the meals. Conclusion: AIx@75 was correlated with BMI and waist circumference. The decrease in AIx@75 following the high fat meal requires further investigation, and AIx@75 is possibly a more sensitive marker of arterial compliance than PWV in a young healthy population.sch_die2pub4327pub

An investigation of the post-prandial effects of a meal rich in long-chain omega-3 fatty acids

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Post-prandial effects of a meal rich in long-chain omega-3 fatty acids on indicators of cardiovascular risk

Funding was provided through a joint funding initiative from the Institute for Health & Welfare Research at RGU and QMUIntroduction Evidence from epidemiological studies indicates that the regular consumption of oily fish may be protective against the risk of cardiovascular disease. The benefits appear to be related to the content of long-chain omega-3 fatty acids (LC n-3 PUFA), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Current UK dietary guidelines therefore recommend the consumption of two portions of fish per week, one of which should be oily (1), which equates to 0.45g LC n-3 PUFA per day. Although there is limited information about intakes of EPA and DHA in Scotland, recent studies show that they are consistently below recommendations (2). Further review of the dietary intake data indicates that the consumption of oily fish is sporadic and inconsistent (3) despite attempts to promote regular intake. Several of the mechanisms involved in the development of cardiovascular disease (CVD) involve endothelial function. Post-prandial hyperlipidaemia has been linked to an increased risk of CVD (4), which is largely attributed to the transient (2-6 hour) decrease in endothelial function (5). Changes in endothelial function have also been shown to be associated with superoxide production (6), implicating oxidative stress as a possible mechanism for endothelial dysfunction. The long-term effects of LC n-3 PUFA on oxidative stress and inflammation are well established, however little is known about their immediate post-prandial effects. Identifying the possible benefits of consumption of a single meal rich in LC n-3 PUFA may provide a new perspective on which to promote dietary changes. The aim of this pilot project was therefore to identify post-prandial changes in markers of cardiovascular risk, assessed by measurement of arterial compliance, whole blood fatty acid profile, plasma glucose and insulin, markers of endothelial dysfunction, oxidative stress and antioxidant status in response a test meal naturally rich LC n-3 PUFA compared with a control meal.sch_dieunpub2825unpu

Cumulative mutagenesis of the basic residues in the 201-218 region of insulin-like growth factor (IGF)-binding protein-5 results in progressive loss of both IGF-I binding and inhibition of IGF-I biological action

We have reported previously that mutation of two conserved nonbasic amino acids (G203 and Q209) within the highly basic 201–218 region in the C-terminal domain of IGF-binding protein-5 (IGFBP-5) decreases binding to IGFs. This study reveals that cumulative mutagenesis of the 10 basic residues in this region, to create the C-Term series of mutants, ultimately results in a 15-fold decrease in the affinity for IGF-I and a major loss in heparin binding. We examined the ability of mutants to inhibit IGF-mediated survival of MCF-7 cells and were able to demonstrate that this depended not only upon the affinity for IGF-I, but also the kinetics of this interaction, because IGFBP-5 mutants with similar affinity constants (KD) values, but with different association (Ka) and dissociation (Kd) rate values, had markedly different inhibitory properties. In contrast, the affinity for IGF-I provided no predictive value in terms of the ability of these mutants to enhance IGF action when bound to the substratum. Instead, these C-Term mutants appeared to enhance the actions of IGF-I by a combination of increased dissociation of IGF-IGFBP complexes from the substratum, together with dissociation of IGF-I from IGFBP-5 bound to the substratum. These effects of the IGFBPs were dependent upon binding to IGF-I, because a non-IGF binding mutant (N-Term) was unable to inhibit or enhance the actions of IGF-I. These results emphasize the importance of the kinetics of association/dissociation in determining the enhancing or inhibiting effects of IGFBP-5 and demonstrate the ability to generate an IGFBP-5 mutant with exclusively IGF-enhancing activity

Measurement of ionised magnesium in HEPES-buffered serum samples

The objective of the research is to develop a method of adjusting the pH of serum samples to 7.4, thus allowing measurement of ionised magnesium (Mg2+) at physiological pH without the need to maintain samples under anaerobic conditions. Levels of Mg2+ HEPES-buffered samples were compared with results obtained when serum samples were buffered with CO2, and the Mg2+ level at pH 7.4 calculated from the log form of the Siggaard-Andersen equation. The HEPES buffering technique was also used to measure Mg2+ in serum samples from sheep where circulating levels of Mg2+ were elevated by infusion of MgCl2. The mean Mg2+ values obtained when samples (n=6) were buffered with CO2 or 50 or 100 mM HEPES were not significantly different from each other (mean±S.E.M.; 0.675±0.019, 0.684±0.015, and 0.669±0.015, respectively). When MgCl2 was infused into sheep (n=6), a significant rise in serum Mg2+ was found (mean±S.E.M.; basal 0.613±0.045 mM; peak 1.450±0.095 mM) when using the HEPES-buffering method for sample pre-treatment (final HEPES concentration was 50 mM)

Project Report to the Society for Endocrinology - The effect of 17_-oestradiol on Na+/H+ exchange in human breast cancer cell lines

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Changes in ionised Mg2+ and Ca2+ in maternal serum during weaning in goats.

Ionised levels of serum magnesium (Mg2+) and calcium (Ca2+) were measured in HEPES-buffered serum from lactating goats before and during weaning. During this period, there was a significant rise in serum Ca2+, and a concomitant fall in Mg2+. These opposing changes can be explained by the known enhanced absorption of Ca relative to Mg by the gut during lactation coupled with a Ca-induced suppression of PTH-driven renal Ca and Mg reabsorption. A rise in the serum Ca2+/Mg2+ ratio during weaning suggests that this is a period of potential cardiovascular risk for the mother, and merits closer studyNO DIVISION15pub4389pub03-Ap

Response of isolated ruminant mammary arteries to the long R3 analogue of insulin-like growth factor I.

Isolated mammary arteries from ruminants were used in a conventional organ bath system. Acetylcholine relaxed bovine but not ovine mammary arteries; both types responded to sodium nitroprusside. Noradrenaline (NA) caused a dose-dependent increase in generated tension. An analogue of insulin-like growth factor I (long R3-IGF-I) caused a rightward shift in the NA response curve in bovine vessels with intact endothelium (P < 0.02), and also in sheep arteries (P < 0.01). In bovine vessels, this effect was abolished when the endothelium was removed. The effect of long R3-IGF-I in bovine vessels was abolished by N -nitro-L-arginine methyl ester (L-NAME) an inhibitor of nitric oxide synthase, suggesting the effect of IGF-I on mammary arteries in vitro requires NO generation.NO DIVISION85pub4392pub

Project report to Medical Research Scotland - The Effect of 17-_ Oestradiol, Resveratrol, and Genistein on Na+/H+ Exchange in Breast Cancer Cells Lines

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