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1 Department of Pharmacology, New York Medical College, Valhalla, NY, USA
2 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: mairead_carroll{at}nymc.edu.
Dilation of rat preglomerular microvessels (PGMV) by activation of adenosine A2A receptors (A2A R) is coupled to epoxyeicosatrienoic acids (EET) release. We have investigated the commonality of this signal transduction pathway - sequential inhibition of GS
, adenylyl cyclase, protein kinase A (PKA) and K+Ca2+ channel activity - to the vasoactive responses to A2A R activation by a selective A2A agonist, CGS 21680, when compared to those of 11,12-EET. Male Sprague Dawley rats were anesthetized and microdissected arcuate arteries (110 to 130 µm) were cannulated and pressurized to 80mmHg. Vessels were superfused with Krebs' solution containing 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 ca 70% (p<0.05), while the response to sodium nitroprusside (SNP; 10 µM) was unaffected. Further, 11, 12-EET (100nM), like cholera toxin (100ng/ml), stimulated ADP ribose formation in homogenates of arcuate arteries, as compared to control. SQ22536 (10µM), an inhibitor of adenylyl cyclase activity, and myristolated PKI (14-22) amide (5µM), an inhibitor of PKA decreased activity of 11, 12-EET and CGS 21680. Incubation of 11, 12-EET (3nM to 3µM) 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+Ca2+ channels activity. Thus, in rat PGMV activation of A2A R is coupled to EET release upstream of adenylyl cyclase activation and that EETs stimulate mono-ADP ribosyltransferase resulting in GS protein activation.
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