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Adenosine_2A receptor vasodilation of rat preglomerular microvessels is mediated by EETs that activate the cAMP/PKA pathway

¹Department of Pharmacology, New York Medical College, Valhalla, New York; and ²Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 3 June 2005 ; accepted in final form 6 February 2006

Dilation of rat preglomerular microvessels (PGMV) by activation of adenosine A_2A receptors (A_2AR) is coupled to epoxyeicosatrienoic acid (EET) release. We have investigated the commonality of this signal transduction pathway, i.e., sequential inhibition of G_s, adenylyl cyclase, PKA, and Ca²⁺-activated K⁺ (K_Ca) channel activity, to the vasoactive responses to A_2AR activation by a selective A_2A agonist, CGS-21680, compared with those of 11,12-EET. Male Sprague-Dawley rats were anesthetized, and microdissected arcuate arteries (110–130 µm) were cannulated and pressurized to 80 mmHg. Vessels were superfused with Krebs solution containing N^G-nitro-L-arginine methyl ester (L-NAME) and indomethacin and preconstricted with phenylephrine. We assessed the effect of 3-aminobenzamide (10 µM), an inhibitor of mono-ADP-ribosyltranferases, on responses to 11,12-EET (3 nM) and CGS-21680 (10 µM) and found that both were inhibited by 70% (P < 0.05), whereas the response to SNP (10 µM) was unaffected. Furthermore, 11,12-EET (100 nM), like cholera toxin (100 ng/ml), stimulated ADP-ribose formation in homogenates of arcuate arteries compared with control. SQ-22536 (10 µM), an inhibitor of adenylyl cyclase activity, and myristolated PKI (14–22) amide (5 µM), an inhibitor of PKA, decreased activity of 11,12-EET and CGS-21680. Incubation of 11,12-EET (3 nM-3 µM) with PGMV resulted in an increase in cAMP levels (P < 0.05). The responses to both 11,12-EET and CGS-21680 were significantly reduced by superfusion of iberiotoxin (100 nM), an inhibitor of K_Ca channel activity. Thus in rat PGMV activation of A_2AR is coupled to EET release upstream of adenylyl cyclase activation and EETs stimulate mono-ADP-ribosyltransferase, resulting in Gs protein activation.

cytochrome P-450; rat arcuate artery

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