Date of Award

5-2012

Level of Access Assigned by Author

Campus-Only Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Food and Nutrition Sciences

Advisor

Dorothy J. Klimis-Zacas

Second Committee Member

Anastasia Z. Kalea

Third Committee Member

Dale A. Schuschke

Abstract

This study examined the mechanism of action of wild blueberries (WB) on key signaling steps of the nitric oxide (NO) and cyclooxygenase (COX) pathways of vascular tone upon stimulation of aortic rings with the α1-adrenergic agonist phenylephrine (Phe) in adult Spontaneously Hypertensive rats (SHR) with endothelial dysfunction. Adult SHRs were sacrificed at the age of 20 weeks after eight weeks on a control diet (C) or a WB-enriched diet. Phenylephrine-induced vasoconstriction was examined in the absence or presence of inhibitors targeting NO synthase (NOS), soluble guanylyl cyclase (sGC) and phosphodiesterase-5 (PDE5), enzymes of the NO pathway or inhibitors targeting COX, prostaglandin I2 (PGI2) synthase and thromboxane A2 (TXA2) synthase, enzymes of the COX pathway. The maximum response (Fmax) and the vessel sensitivity (pD2) to the agonist were estimated. Concentration of NO, cyclic guanosine monophosphate (cGMP) and the prostanoids PGI2 and TXA2 were measured in plasma, aortic tissue and aortic medium, respectively, to further assess the effect of the WB diet on the NO and COX pathways. The reduced response of aortic rings to the Phe-induced vasoconstriction observed in the SHRs that consumed the WB diet, was abolished when NOS was inhibited, suggesting the involvement of the NO pathway in the lower response to the α1-adrenergic agonist. Additionally, the higher Fmax observed in the WB rings when sGC activity was blocked reflects a critical role of sGC in the reduced adrenergic constriction of the WB group. Phosphodiesterase-5 may also play a role in the WB response, and finally an increased concentration of the vasorelaxant cGMP in the WB aorta represents further evidence of the role of the NO-cGMP signaling in the lower tension elicited by the WB diet. Functional studies with inhibitors of COX, PGI2 and TXA2 synthase do not point to a major effect of wild blueberries on the COX pathway, despite an increased concentration of PGI2 in aortic media. This is the first study to document that a WB diet reduces vascular tone in response to an α1-adrenergic adrenergic agonist via enhancing NO-sGC-cGMP signaling in the adult SHR model of endothelial dysfunction with implications for cardiovascular protection.

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