Adenosine (A), acting on 4 G-protein linked receptors (A1, A2A, A2B and A3), plays a critical role in the regulation of renal vascular tone and tubular function. The A2A receptor (A2AR) mediates endothelial-dependent vasodilation and natriuresis by stimulation of Gs( activity and increased adenylyl cyclase (AC) and protein kinase A (PKA) activity. We have shown that the A2AR selective agonist, CGS 21680, stimulates cytochrome P450 (CYP) epoxyeicosatrienoic acids (EETs) release from rat preglomerular microvessels (PGMV) and that the vasodilator action of CGS 21680 in arcuate arteries is inhibited by a selective epoxygenase inhibitor, MS-PPOH. As EETs are vasodilators and natriuretic and can account for the biological actions of adenosine acting on A2AR, we propose 1) that the EETs are mediators of the biological functions of adenosine acting via A2AR and 2) this signaling pathway via A2AR/EETs is involved in the adaptive response to increased dietary salt intake. To test our hypothesis, we propose the following Specific Aims: 1. To study the biochemical events and functional consequences of the signal transduction pathway responsible for A2A receptor-induced EET stimulation and dilation of rat arcuate/interlobular arteries. 2. To determine the physiological role of adenosine and EETs by studying their contribution to the adaptive natriuretic response to high salt (HS) intake after modifying, in vivo, either adenosine or EET levels with receptor antagonists or epoxygenase inhibition. 3. To determine the role of adenosine and EETs in the DAHL salt-sensitive model of hypertension by studying the effect of modifying either adenosine or EET levels in salt-sensitive (DAHL S), salt-resistant Brown-Norway (BN) and SS-BN13 rats, in response to HS intake by monitoring sodium excretion, blood pressure and renal function. To also compare changes in vasoreactivity in BN, SS-BN13 vs. DAHL S rats in their responses to A2AR agonists and EETs. Stimulation of EET synthesis in response to adenosine activation of A2AR may represent a mechanism that participates in the regulation of PGMV tone and, thereby, GFR and salt and water excretion. Selective A2AR agonists may provide a therapeutic approach to controlling blood pressure.
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