Attenuated PGI2 synthesis in obese Zucker rats.
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 PGI(2) due to a nitration of PGI(2) synthase (PGIS), which is associated with a decreased prostanoid receptor expression. PGI(2), PGE(2), and thromboxane A(2) (TXA(2)) release were determined in vitro using ELISA under basal conditions and in response to arachidonic acid (AA) administration (50 microM). Immunofluorescence of PGI(2) and TXA(2) 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, PGI(2) and PGE(2) release were attenuated in OZR compared with lean Zucker rats (LZR; controls). Basal and AA-induced TXA(2) 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 PGI(2) pathway (attenuated PGI(2) synthesis), and not the TXA(2) pathway (normal TXA(2) synthesis/no change in TP receptor expression), underlie the attenuated functional hyperemia in the OZR.
Hodnett
Benjamin L
BL
Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA.
Dearman
Jennifer A
JA
Carter
Cory B
CB
Hester
Robert L
RL
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015153:Blotting, Western; D002469:Cell Separation; D011464:Epoprostenol / Q000096:biosynthesis*; D005455:Fluorescent Antibody Technique; D066298:In Vitro Techniques; D008297:Male; D008833:Microcirculation / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker; D044006:Receptors, Epoprostenol / Q000096:biosynthesis; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000096:biosynthesis; D014443:Tyrosine / Q000378:metabolism
D009566:Nitrates; D044006:Receptors, Epoprostenol; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D016718:Arachidonic Acid; D014443:Tyrosine; D011464:Epoprostenol