Postconditioning?s protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3?kinase and guanylyl cyclase activation

Abstract

Protection from postconditioning has been documented in in situ animal models and it has been proposed that it is targeting circulating leukocytes. We therefore tested whether postconditioning can protect leukocyte-free, buffer-perfused rabbit hearts. Infarct size was measured with triphenyltetrazolium staining. In control hearts undergoing 30 min of regional ischemia and 2 h of reperfusion, 33.3 +/- 2.2% of the risk zone infarcted. The protocol previously used in open-chest animals of four postconditioning cycles of 30 s reperfusion/30 s ischemia starting at the beginning of reperfusion decreased infarction to only 24.8 +/- 2.5% of the risk zone in these isolated hearts. Because of the meager protection induced by four 30 s postconditioning cycles, we evaluated the effect of postconditioning with 6 cycles of 10 s reperfusion/10 s ischemia starting at the beginning of reperfusion. Robust salvage was seen with only 10.4 +/- 3.4% of the risk zone infarcting (p < 0.001 vs control and p < 0.003 vs 4 cycles of 30 s ischemia). The 10s protocol was used in all studies of signal transduction. Wortmannin (100 nM), a phosphatidylinositol 3- (PI3-) kinase antagonist, infused for 20 min starting 5 min before reperfusion, blocked postconditioning's, protection (31.2 +/- 4.2% infarction) as did 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (2 microM) a guanylyl cyclase inhibitor (36.9 +/- 5.3%) and 8-p-(sulfophenyl) theophylline (SPT) (100 microM), a non-specific adenosine receptor blocker (34.2 +/- 2.8%). Thus, postconditioning's protection is not dependent on circulating blood factors or cells, and its anti-infarct effect appears to require PI3-kinase activation, stimulation of guanylyl cyclase and occupancy of adenosine receptors. These signaling steps have also been identified in preconditioning and during pharmacologic cardioprotection and suggest commonality of a protective mechanism.

Efeitos do pós-condicionamento isquêmico na função ventricular esquerda de corações isolados de ratos

“…Subsequent studies confirmed the presence of the same behavior in other in vivo animal models (rabbits [22], rats [23]) and in vitro (rabbit [24], rats [25], mice [26]). …”

Postconditioning ameliorates lipid peroxidation in liver ischemia-reperfusion injury in rats

“…Philipp et al 9 described that the protective effect of postconditioning in the rabbit heart is dependent on the occupancy of adenosine receptors 9 and requires PI3-K and guanylyl cyclase activation 10 . Two reports indicate that endogenous adenosine elicits the infarct-sparing effect of postconditioning by the activation of A2B receptor 9,11 .…”

Postconditioning against ischaemia-reperfusion injury: ready for wide application in patients?

“…Thus, the reduction in myocardial infarct size elicited by IPOC was abolished in the presence of 8-p-(sulphophenyl) theophylline, a non-specific adenosine receptor blocker. 9 A subsequent study showed that the IPOC stimulus delayed the washout of adenosine generated during ischaemia-reperfusion in mouse hearts, likely resulting in greater activation of adenosine receptors during reperfusion. 10 Survival signalling pathways A number of different signalling pathways have been reported to mediate the protective effects of IPOC, most notably the RISK pathway.…”