Adenosine is known to cause relaxation of coronary artery both in an endothelium-dependent and independent manner. The purpose of this study was to explore the adenosine receptor subtype(s) involved in porcine coronary artery relaxation and define the involvement of MAPKs. Porcine coronary arterial rings (endothelium denuded) were incubated in tissue baths. Changes in isometric tension were recorded and analyzed. NECA, a non-selective adenosine receptor agonist, induced a concentration-dependent relaxation (EC₅₀=16.8 nM) of PGF₂ (10 µM)-preconstricted arterial rings. NECA-induced relaxation was completely blocked by 0.1 µM SCH-58261 (an A_2A antagonist) at lower doses (1-40 nM), but not at higher doses (80-1000 nM). Although not being able to completely block the NECA-induced relaxation, MRS-1706, an A_2B antagonist, was able to shift the NECA concentration curve to the right at a concentration of 1 µM. CGS-21680, an A_2A selective agonist, induced responses similar to NECA, while CPA, an A₁ agonist, and Cl-IBMECA, an A₃ agonist, did not. Furthermore, the relaxing effect of NECA was attenuated by the addition of SB-203580 (10 µM), a p38 MAPK inhibitor, but not by PD-98059 (10 µM), a MEK inhibitor. Interestingly, SB-203580 was without an effect on CGS-21680-induced relaxation. Western blot experiments using cultured porcine coronary smooth muscle cells, PGF₂ and all the adenosine agonists stimulated p38 MAPK at a concentration of 40 nM. MRS-1706 (1 µM) significantly reduced NECA-induced p38 MAPK phosphorylation. The addition of NECA and SB-203580 alone or in combination inhibited PGF₂ induced p38 MAPK. Western blot data were further confirmed by p38 MAPK activity measurements using ATF-2 assay. Our results suggest that the adenosine receptor subtypes involved in causing relaxation of porcine coronary smooth muscle is mainly A_2A subtype while A_2B may also play a role possibly through p38 MAPK pathway.