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In the present work we studied the effect of adenosine and various adenosine analogues on cAMP level in guinea pig coronary endothelial cells of microvascular origin. The tested adenosine agonist mediate a concentration-dependent increase in cAMP level. The rank order of potency was 5'-N-ethylcarboxamidoadenosine (NECA)CGS 21680N6-phenylisopropyladenosine (R-PIA)2-chloro-N6-cyclopentyladenosine (CCPA) which is typical for an adenosine A2 receptor. Their respective concentrations for half maximal stimulation of cAMP formation were 0.36 microM, 0.82 microM, 4.7 microM and 9.8 microM. The tested agonists showed differences in efficacy, NECA being the most efficacious. R-PIA, CCPA and adenosine were less efficacious, suggesting partial agonism. The efficacy of adenosine was unchanged by the addition of the nucleoside transport inhibitor S(4-nitrobenzyl)-6-thioinosine (NBTI, 10 microM) suggesting that inhibition of adenylyl cyclase through P-site activation is not responsible for the observed low efficacy of adenosine. We could demonstrate CGS 21680 activation of adenylyl cyclase in a peripheral receptor. We therefore suggest that the endothelial adenosine receptor resembles the striatal adenosine A2a receptor.