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APPETITE, OBESITY, AND DIGESTION

Attenuated PGI₂ synthesis in obese Zucker rats

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi

Submitted 31 March 2008 ; accepted in final form 23 December 2008

In obesity, skeletal muscle blood flow during exercise (functional hyperemia) is impaired. We have indirectly demonstrated that an altered arachidonic acid metabolism is responsible for the impaired functional vasodilation in the obese Zucker rat (OZR), a model of obesity. In this study, we tested the hypothesis that there is an impaired release of PGI₂ due to a nitration of PGI₂ synthase (PGIS), which is associated with a decreased prostanoid receptor expression. PGI₂, PGE₂, and thromboxane A₂ (TXA₂) release were determined in vitro using ELISA under basal conditions and in response to arachidonic acid (AA) administration (50 µM). Immunofluorescence of PGI₂ and TXA₂ receptors (IP and TP, respectively) was determined in dispersed vascular smooth muscle cells (VSMCs). Nitration of tyrosine residues of the PGIS enzyme was determined using immunoprecipitation and Western blot analysis. Following AA administration, PGI₂ and PGE₂ release were attenuated in OZR compared with lean Zucker rats (LZR; controls). Basal and AA-induced TXA₂ release were not significantly different between groups. IP and TP immunofluorescence were not significantly different between OZR and LZR groups. OZR exhibited elevated nitration of tyrosine residues of PGIS compared with LZR. These results suggest that alterations in the PGI₂ pathway (attenuated PGI₂ synthesis), and not the TXA₂ pathway (normal TXA₂ synthesis/no change in TP receptor expression), underlie the attenuated functional hyperemia in the OZR.

vasodilation; arachidonic acid; microcirculation; exercise