Vasoconstrictor PGs activating the TP receptor (R) include PGH2, TxA2 and isoprostanes (Iso). NO or peroxynitrite (ONOO), its reaction product with superoxide anion (02""""""""'), can activate cyclooxygenase (COX) whereas O2""""""""""""""""and ONOO can inactivate prostacyclin synthase (PGIz-S), activate TxAz synthase and generate Iso, thereby promoting vasoconstrictor PG mechanisms. The specific roles of COX-1 vs. -2, and the diverse agonists of the TP-R and their role in the regulation of microvascular resistance, salt balance and BP remain unclear. This is the focus of this proposal.
Specific Aim I will utilize COX-1 and TP-R gene deleted mice, and specific COX-2 antagonists to investigate the hypothesis that these systems have discrete roles in normal homeostasis by adjusting salt excretion, renal microvascular resistance, tubuloglomerular feedback (TGF) and proximal NaCI reabsorption to stabilize BP and prevent salt sensitivity during changes in salt intake.
Specific Aim II will investigate the hypothesis that neuronal nitric oxide synthase (nNOS)- derived NO generated during macula densa (MD) solute reabsorption activates COX-2 dependent signaling pathway from the MD that regulates afferent arteriolar tone via release of PGH2. PGH2 can be metabolized to vasodilator PG's that limit vasoconstrictor TGF responses, but during Ang II action, PGI2-S is blocked, and PGH2, Iso and TxA2 activate TP-R-dependent enhancement of TGF, thereby assisting in salt and volume preservation.
Specific Aim III will investigate the hypothesis that a COX- and TP-R-dependent process enhances vasoconstriction to Ang II and diminishes vasodUation to acetylcholine of the renal afferent arteriole of mice undergoing an Ang II slow pressor response. These studies are focused on the roles of COX-1 vs. -2, and TP-R in mediating renal mechanism of homeostasis and their dysregulation during Ang II hypertension.
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