p38 Mitogen-activated protein kinase (p38 MAPK) is activated by short episodes of ischaemia-reperfusion as well as by sustained ischemia followed by reperfusion, Whether activation of this kinase is beneficial or deleterious to the ischaemic heart is still a subject of controversy. Since transient beta-adrenergic stimulation (5 min) stimulates p38 MAPK activation and mimics the cardioprotection of ischaemic preconditioning, it was used as a tool to further evaluate the role of this kinase in cardioprotection. The isolated perfused working rat heart, subjected to 25 min ischaemia and 30 min reperfusion was used as experimental model. p38 MAPK and ATF2 activation was determined using Western blots. The results showed that isoproterenol stimulated p38 MAPK in a dose- and time-dependent manner. Ischaemia-induced activation of p38 MAPK could be partially abolished by beta- and alpha1-adrenergic receptor blockade. Isoproterenol activation of the kinase could be abolished by alprenolol and verapamil, but not by 8-cyclopentyladenosine. p38 MAPK activation induced by either a multi-episode preconditioning protocol or isoproterenol (10(-7) M for 5 min) was associated with a significant reduction in p38 MAPK activation at all time intervals studied during 25 min global ischaemia and at 20 and 30 min of reperfusion, compared with the marked activation observed in untreated non-preconditioned hearts. In each case attenuation of p38 MAPK activation during ischaemia and during reperfusion was associated with improved functional recovery during reperfusion. Cyclic elevations in tissue cAMP during an ischaemic preconditioning protocol acted as trigger of cardioprotection, since pretreatment of such hearts with alprenolol abolished cardioprotection. Mechanical failure in such hearts was characterized by a significant stimulation of p38 MAPK activity during ischaemia and reperfusion. However, p38 MAPK activation during an ischaemic preconditioning protocol did not act as trigger: inhibition of p38 MAPK activation by SB 203580 during the preconditioning phase did not abolish cardioprotection. In fact, functional recovery was significantly better than that of untreated preconditioned hearts. On the other hand, SB 203580, when administered before and during the isoproterenol-preconditioning protocol abolished cardioprotection, suggesting that p38 MAPK activation by a beta -adrenergic-induced preconditioning protocol does act as trigger of cardioprotection. In addition, attenuation of p38 MAPK activity during sustained ischaemia and reperfusion as occurs in ischaemic- or isoproterenol-preconditioned hearts, is beneficial.
Copyright 2001 Academic Press.