Brief femoral artery ischaemia provides protection against myocardial ischaemia–reperfusion injury in rats: the possible mechanisms

Abstract

The present study was conducted to examine the role of nitric oxide (NO), mitochondrial ATP-sensitive K + channels (mito K + ATP channels) and reactive oxygen species (ROS) and their interdependence in brief femoral artery ischaemia-induced myocardial preconditioning. To assess myocardial injury, myocardial infarction was induced by occlusion followed by reperfusion of the left anterior descending (LAD) coronary artery in anaesthetized rats and was assessed by triphenyl tetrazolium chloride (TTC) staining. Left ventricular function was assessed by left ventricular end-diastolic pressure (LVEDP) and the maximal rate of rise of left ventricular pressure [LV(dP/dt) max ]. Serum creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were determined by colorimetric kits. Remote preconditioning (RPC) was induced by 15 min occlusion of femoral arteries followed by 10 min of reperfusion just before LAD coronary artery occlusion. Brief femoral artery ischaemia led to a 61% reduction in myocardial infarct size, 57% reduction in elevated serum LDH and 72% reduction in elevated CK-MB activities, and a significant improvement in LVEDP and LV(dP/dt) max compared with control animals. Pretreatment with 5-hydroxydecanoate (5-HD) or L-NAME or N -acetylcystein (NAC) blocked this protective effect of femoral artery ischaemia. Moreover, infusion of L-arginine or diazoxide before coronary artery occlusion markedly reduced the myocardial infarction and improved the left ventricular function. This effect of L-arginine was found to be abolished by the blockade of mito K + ATP channels with 5-HD and, similarly, the effect of diazoxide was blocked in the presence of a ROS scavenger, NAC. The results suggest that brief femoral artery ischaemia-induced RPC is mediated by a combination of increased NO synthesis, opening of mito K + ATP channels and increased ROS production. Moreover, it appears that NO is working upstream and acts via activation of mito K + ATP channels, which subsequently increases the production of ROS. Ischaemic preconditioning (IPC) is the phenomenon whereby brief episodes of myocardial ischaemia render the ischaemic territory tolerant to subsequent, sustained insult and limit myocardial necrosis (Murry et al. 1986). Remote preconditioning (RPC) is a process in which brief ischaemia in a remote organ or vascular bed may render the heart resistant to subsequent sustained ischaemia (Przyklenk et al. 1993) and has been demonstrated in many models, such as brief occlusion of the mesentric/renal arteries or hindlimb/skeletal muscle ischaemia (Oxman et al. 1997;Pell et al. 1998;Kharbanda et al. 2002;Wang et al. 2002;Weinbrenner et al. 2002;Wolfrum et al. 2002).The benefits observed were a decrease in myocardial infarct size, correction of biochemical markers and endothelial dysfunction, and an anti-arrhythmic effect. To the best of our knowledge, however, the effect of transient femoral artery occlusion-reperfusion in rats on myocardial infarct size and left ventricular function and the post-infarct elevation in serum CK-...

The role of gasotransmitters NO, H2S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

“…Similarly, in rabbits preconditioned by pulmonary ischaemia, the NOS inhibitor L-NAME did not affect cardioprotection (Tang et al, 2014). However, in rats with brief femoral artery ischaemia-induced myocardial PC, cardioprotection was mediated by a combination of increased NO synthesis, opening of mitoKATP channels and increased ROS production (Shahid et al, 2008). In a rabbit renal ischaemia-induced remote PC, cardioprotection was associated with a PPARmediated increase in iNOS expression (Lotz et al, 2011).…”

Redox balance and cardioprotection

“…At least three hypotheses have been proposed to explain the occurrence of remote ischemic preconditioning reperfusion of an organ provokes a systemic protective response, which suppresses inflammation and apoptosis [82]. A role for ROS signaling in the remote organ and a reduction of redox stress in the target organ has been also proposed [93,194]. In particular, it appears that remote ischemic preconditioning is triggered by a combination of increased NO • synthesis, opening of mK ATP channels and increased ROS production in remote tissue.…”

“…In particular, it appears that remote ischemic preconditioning is triggered by a combination of increased NO • synthesis, opening of mK ATP channels and increased ROS production in remote tissue. Moreover, it seems that NO • is working upstream and acts via activation of mK ATP channels, which subsequently increases the production of ROS [93,194]. Of note, it has been suggested that in man the activation of a single cell surface receptor may be sufficient to trigger preconditioning, while blockade of multiple pathways may be required to abolish the protective effect of remote preconditioning [156].…”

Remote ischaemic conditioning: cardiac protection from afar

“…Interestingly, production of NO, via activation of NO synthase, is seemingly not required for production of the cardioprotective factor, but is required for induction of the protective phenotype 54.…”