Date of Award

8-2005

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Food and Nutrition Sciences

Advisor

Dorothy J. Klimis-Zacas

Second Committee Member

Rodney J. Bushway

Third Committee Member

Patrick D. Harris

Abstract

Dietary manganese affects the structure and integrity of blood vessels, as well as vessel predisposition to endothelial dysfunction and cardiovascular disease. In this thesis, we studied the role of manganese on the functional properties of rat aorta as defined by the endothelial and vascular smooth muscle cell pathways for adrenergic-mediated vasoconstriction and cholinergic-mediated vasodilation. Weanling Sprague-Dawley rats were fed a manganese deficient (MnD), adequate (MnA-control group) or supplemented (MnS) diet (<1, 10-15 and 45-50ppm Mn respectively). After 14 weeks on the diet the aorta was excised and four aortic rings of three mm length were prepared from each animal. Alterations in vasoconstriction among diet groups were detected by dose-response curves to the ^-adrenergic agonist LPhenylephrine in endothelium-intact and endothelium-disrupted rings. Alterations in endothelium-dependent vasodilation among diet groups were determined by doseresponse curves to Acetylcholine. We studied the mechanism by which dietary manganese affects two different endothelium-dependent vasodilation pathways: the Larginine/ nitric oxide (NO) and the cyclooxygenase (COX) pathways. Inhibition of the enzymes for NO synthesis (NOS) with L-NMMA, and of prostanoids (COX I and II) with Mefenamic acid, determination of NOS expression, and in vitro addition of L-Arginine (substrate for NO formation) to vessel rings revealed the effect of manganese on the regulation of endothelium-mediated vasodilation and vasoconstriction. Dose-response curves to sodium nitroprusside provided data for the dietary effect on endotheliumindependent vasodilation. Supplementary dietary manganese increased adrenoreceptor-mediated vascular smooth muscle contraction, which was significantly reduced in the presence of functional endothelium. Absence of dietary manganese increased endothelial cell sensitivity to the (Xi-adrenergic vasoconstrictor agent. Manganese had a small effect on the cGMP-pathway for dilation of vascular smooth muscle but affected vasodilation primarily through an endothelium-mediated pathway, probably by preserving NO bioavailability. Inhibition of vasodilation in Mn deficiency appears to occur through an endothelium-derived vasoconstrictor, possibly thromboxane with a concomitant decrease in the synthesis of endothelium-mediated vasodilator prostanoids. Our results demonstrate that dietary manganese influences the contractile machinery of vascular smooth muscle cells and regulates the bioactivity of endothelium-mediated vasodilators to affect agonist-induced signaling pathways that participate in the regulation of vasomotor tone. This suggests possibilities for dietary intervention in blood pressure regulation.

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