The p38 MAPK Inhibitor SB203580 Blocks Adenosine A1 Receptor-Induced Attenuation of In Vivo Myocardial Stunning

Abstract

There is considerable evidence implicating a key role for p38 mitogen-activated protein kinase (MAPK) in ischemic and pharmacological preconditioning against myocardial infarction. However, there have been few, if any, studies examining the role of p38 MAPK in the protection of stunned myocardium. The purpose of this study was to determine whether p38 MAPK plays a role in the adenosine A(1) receptor anti-stunning effect in in vivo porcine myocardium. Regional myocardial stunning in anesthetized, open-chest pigs was induced by 15 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion (RP). Animals were treated with either vehicle (n = 5), AMP579 (70 microg/kg i.v.; 25 microg/kg bolus + 1.5 microg/kg/min for 30 min prior to ischemia, n = 5), the p38 MAPK inhibitor SB203580 (0.25 mg/kg i.v. bolus, n = 4) or a combination of SB203580 plus AMP579 (n = 5). Regional ventricular function was monitored by measurements of segment shortening and load insensitive parameters including preload recruitable stroke work (PRSW) and PRSW area (PRSWA). The ischemic area at risk was similar in all groups and there was no necrosis in any heart. Treatment with AMP579 significantly improved reperfusion regional PRSW and PRSWA compared to vehicle controls. The p38 inhibitor SB203580 alone did not alter the extent of myocardial stunning, but it abolished the beneficial effect of AMP579 pretreatment. These results provide the first evidence that p38 MAPK activation may play an important role in the mechanism by which adenosine agonists attenuate myocardial stunning.

Pretreatment with adenosine and adenosine A1 receptor agonist protects against intestinal ischemia-reperfusion injury in rat

“…The endogenous adenosine or selective pharmacological agonists activate A1ARs. Preischemic activation of A1ARs has been demonstrated to prevent from I/R damage in various organs including heart [15][16][17][18]25] , kidney [26,27] and brain [28,29] . In these studies, the activation of A1ARs has been strongly implicated in the mediation of IPC.…”

“…Activated PKC then induces an increase in opening of ATP-sensitive K + channels in heart [11,12] . Stimulation of A1ARs also precedes the early activation of some other kinases such as tyrosine kinases, p38, MAPK [11,19,25,31,33] , ERK [32] , and Akt [20] . Additionally, in protection obtained by agonist-induced stimulation of A1AR, elevated content or activity of many proteins have been demonstrated such as HSP 27 [11] and Mn-SOD [15] .…”

“…Administration of adenosine either prior to ischemia or during reperfusion has been shown to attenuate myocardial injury [23,24] . Treatment with adenosine A1AR agonist initiates preconditioning not only in heart [15][16][17][18]25] but also in tissues such as kidney [26,27] and brain [28,29] , resulting in attenuation of ischemic injury. One of the underlying mechanisms suggested for adenosine receptor-mediated preconditioning in the heard is through involvement of protein kinase C (PKC) in heart [11,12,30] .…”

“…Activation of PKC induces opening of ATP-sensitive K + channels [11,12,31] . Among other effectors that most likely contribute to the cytoprotection by adenosine are mitogen activated protein (MAP) kinases [25,[31][32][33] , heat shock proteins (HSPs) [11][12][13][14][15]34] , antioxidant enzymes [15,34] and inducible nitric oxide synthase (iNOS) [11,12] . Moreover, induction and activation of manganese superoxide dismutase (Mn-SOD) is also believed to be a significant factor in mediating myocardial adaptation in response to activation of A1AR [15] .…”

“…Intensive investigation has been focused on explaining how adenosine accomplishes the beneficial effect of preconditioning. For instance, currently published studies suggest important anti-ischemic roles of the A1 [18,25,30] , A3 [17,21] or A2a [44,45] adenosine receptors in heart. On the other hand, relatively little data are available on the role of the different adenosine receptors in mediating cytoprotection in intestinal tissue which is exposed to I/R.…”