Yang Xi-Ming, Philipp Sebastian, Downey James M, Cohen Michael V
Department of Physiology, University of South Alabama College of Medicine, MSB 3050, Mobile, AL 36688, USA.
Basic Res Cardiol. 2006 Jul;101(4):311-8. doi: 10.1007/s00395-006-0587-2. Epub 2006 Apr 8.
We investigated whether atrial natriuretic peptide (ANP) given just prior to reperfusion reduces infarction in rabbit hearts and whether protection is related to activation of protein kinase G (PKG). Isolated rabbit hearts were subjected to a 30-min period of regional ischemia; treated hearts received a 20-min infusion of ANP (0.1 microM) starting 5 min before 2 h of reperfusion. ANP infusion decreased infarction from 31.5+/-2.4% of the risk zone in untreated hearts to 12.5+/-2.0% (P<0.001). To explore mechanisms of protection ischemic hearts were treated simultaneously with ANP and isatin, a blocker of the natriuretic peptide receptor, shortly before reperfusion. ANP's protective effect was aborted (36.8+/-2.9% infarction). There is no acceptable blocker of protein kinase G that can be used in intact organs. However, 8-(4-chlorophenylthio)-guanosine 3', 5'-cyclic monophosphate (10 microM), a cell-permeable cGMP analog that directly activates PKG, was infused from 5 min before to 15 min after reperfusion. The PKG activator mimicked ANP's protection with only 18.2+/-3.6% infarction (P<0.001). 5-Hydroxyde-canoate (5-HD), a putative mitochondrial KATP channel (mKATP) inhibitor, abrogated ANP's protection (34.4+/-2.6% infarction). Unexpectedly, 1H-[1,2,4]oxadiazole- [4,3-a]quinoxalin-1-one (ODQ), a blocker of soluble guanylyl cyclase also prevented ANP's infarct-sparing effect. It is unclear whether this observation implicated participation of soluble guanylyl cyclase in the mechanism or simply a lack of selectivity of ODQ. Finally the reperfusion injury salvage kinases (RISK), phosphatidylinositol 3-kinase and extracellular signal-regulated kinase, were implicated in ANP's mechanism since either wortmannin or PD98059 infused at reperfusion prevented ANP's infarct-sparing effect. ANP administered just prior to reperfusion protects hearts against infarction, likely by activation of PKG, opening of mKATP, and stimulation of downstream kinases.
我们研究了在再灌注前给予心房利钠肽（ANP）是否能减少兔心脏梗死面积，以及这种保护作用是否与蛋白激酶G（PKG）的激活有关。将离体兔心脏进行30分钟的局部缺血处理；处理组心脏在再灌注2小时前5分钟开始接受20分钟的ANP（0.1微摩尔）输注。ANP输注使梗死面积从未经处理心脏危险区域的31.5±2.4%降至12.5±2.0%（P<0.001）。为探究保护缺血心脏的机制，在再灌注前不久，将ANP与利钠肽受体阻滞剂异吲哚酮同时用于处理缺血心脏。ANP的保护作用被消除（梗死面积为36.8±2.9%）。目前尚无适用于完整器官的PKG阻滞剂。然而，8-（4-氯苯硫基）-鸟苷3'，5'-环一磷酸（10微摩尔），一种可通透细胞的环鸟苷酸类似物，能直接激活PKG，在再灌注前5分钟至再灌注后15分钟进行输注。PKG激活剂模拟了ANP的保护作用，梗死面积仅为18.2±3.6%（P<0.001）。5-羟基癸酸（5-HD），一种推测的线粒体ATP敏感性钾通道（mKATP）抑制剂，消除了ANP的保护作用（梗死面积为34.4±2.6%）。出乎意料的是，可溶性鸟苷酸环化酶阻滞剂1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮（ODQ）也阻止了ANP的梗死面积减少效应。尚不清楚这一观察结果是表明可溶性鸟苷酸环化酶参与了该机制，还是仅仅意味着ODQ缺乏选择性。最后，再灌注损伤挽救激酶（RISK），即磷脂酰肌醇3-激酶和细胞外信号调节激酶，参与了ANP的作用机制，因为在再灌注时输注渥曼青霉素或PD98059均可阻止ANP的梗死面积减少效应。再灌注前给予ANP可保护心脏免受梗死，可能是通过激活PKG、开放mKATP以及刺激下游激酶实现的。
