Involvement of p38-mitogen-activated protein kinase in adenosine receptor-mediated relaxation of coronary artery

Abstract

Teng, Bunyen, Weixi Qin, Habib R. Ansari, and S. Jamal Mustafa. Involvement of p38-mitogen-activated protein kinase in adenosine receptor-mediated relaxation of coronary artery. Am J Physiol Heart Circ Physiol 288: H2574 -H2580, 2005. First published January 14, 2005 doi:10.1152/ajpheart.00912.2004.-The purpose of this study was to explore the involvement of adenosine receptor(s) in porcine coronary artery (PCA) relaxation and to define the role of MAPK signaling pathways. Isometric tensions were recorded in denuded PCA rings. 5Ј-(N-ethylcarboxamido)adenosine (NECA), a nonselective adenosine receptor agonist, induced a concentrationdependent relaxation (EC 50 ϭ 16.8 nM) of PGF2␣ (10 M)-preconstricted arterial rings. NECA-induced relaxation was completely blocked by 0.1 M SCH-58261 (A 2A antagonist) at lower doses (1-40 nM) but not at higher doses (80 -1,000 nM). MRS-1706 (1 M, A 2B antagonist) was able to shift the NECA concentration-response curve to the right. CGS-21680 (selective A2A agonist) induced responses similarly to NECA, whereas N 6 -cyclopentyladenosine (A1 agonist) and Cl-IB-MECA (A3 agonist) did not. Furthermore, the effect of NECA was attenuated by the addition of SB-203580 (10 M, p38 MAPK inhibitor) but not by PD-98059 (10 M, MEK inhibitor). Interestingly, SB-203580 had no effect on CGS-21680-induced relaxation. Western blot analysis demonstrated that PGF 2␣ and adenosine agonists stimulated p38 MAPK at a concentration of 40 nM in PCA smooth muscle cells. MRS-1706 (1 M) significantly reduced NECAinduced p38 MAPK phosphorylation. Addition of NECA and SB-203580 alone or in combination inhibited PGF 2␣-induced p38 MAPK. Western blot data were further confirmed by p38 MAPK activity measurement using activating transcription factor-2 assay. Our results suggest that the adenosine receptor subtype involved in causing relaxation of porcine coronary smooth muscle is mainly A 2A subtype, although A2B also may play a role, possibly through p38 MAPK pathway. adenosine receptors; vascular smooth muscle; p42/44; c-Jun NH2-terminal kinase; prostaglandin F2␣ ADENOSINE IS KNOWN TO CAUSE dilation of coronary artery. Four adenosine receptor subtypes, A 1 , A 2A , A 2B , and A 3 , have been identified and cloned (14). It has been suggested that both A 2A and A 2B adenosine receptors mediate hyperpolarization and nitric oxide (NO) release from coronary artery endothelium (2, 30, 47). The adenosine receptor subtypes responsible for endothelium-independent vasodilation in coronary artery smooth muscle are still not fully understood; however, both A 2A and A 2B adenosine receptors have been implicated (28,40,41).Upon activation, both A 2A and A 2B receptors, which are coupled to G s protein and subsequently activate adenylyl cyclase, cause an activation of various second messenger systems, including mitogen-activated protein kinases (MAPKs). There are three well-characterized MAPKs: extracellular signal-regulated kinases (ERKs, or p42/44), p38, and c-Jun NH 2 -terminal kinase (JNK). These MAPKs have been linked to isch...

Characterization of the Relaxant Response to N,N′-Dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine in Porcine Coronary Arteries

“…It should be mentioned that recent studies on porcine coronary arterial smooth muscle cells have demonstrated an activation of p38 MAPK by PGF 2␣ . PGF 2␣ -induced p38 MAPK phosphorylation occurred rapidly (within minutes), reached a peak at 10 min, and decreased within 60 min (Teng et al, 2005). The ineffectiveness of PGF 2␣ to show an activation of p38 MAPK after 120 min in the present study is consistent with this observation.…”

“…To examine a possible role of p38 MAPK in the vasorelaxant response to 8, arterial rings with or without endothelium were precontracted with PGF 2␣ (3 M) following a 30-min incubation with SB 203580 (10 M), an inhibitor of p38 MAPK (Teng et al, 2005). Compound 8 (10 M) was administered when the contractile response to PGF 2␣ had reached a plateau.…”

Mechanisms involved in the adenosine-induced vasorelaxation to the pig prostatic small arteries

“…Whereas adenosine A 2A receptor plays a significant role in background NO release, thus affecting basal coronary tone [32], the role played by adenosine A 2B receptors in NO release remains to be determined. In addition, both adenosine A 2A and A 2B receptors have also been implicated in endotheliumindependent relaxation of coronary artery smooth muscle [37]. In our study, mechanical removal of the endothelium potently reduced the relaxations to NECA, thus indicating that adenosine relaxes pig prostatic arteries through adenosine receptors located on endothelial cells.…”

Up-regulation of A2B adenosine receptor in A2A adenosine receptor knockout mouse coronary artery

“…A 2A AR involvement with exogenous application of adenosine mediated coronary vasodilation is well established [2,27,33]. A 2A AR mediated NO release is also well recognized in various endothelial cell culture studies, including human, rat and porcine [4,34,35].…”