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Atrial natriuretic peptide administered just prior to reperfusion limits infarction in rabbit hearts

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Abstract

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 μM) 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 μM), 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.

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Acknowledgment

This study was supported in part by grants HL-20648 and HL-50688 from the Heart, Lung and Blood Institute of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Physiology , University of South Alabama College of Medicine , MSB 3050, Mobile, AL, 36688, USA

    Xi-Ming Yang, Sebastian Philipp, James M. Downey & Michael V. Cohen

  2. Department of Medicine , University of South Alabama College of Medicine, Mobile, AL, USA

    Michael V. Cohen

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  1. Xi-Ming Yang
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  2. Sebastian Philipp
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  4. Michael V. Cohen
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Correspondence to Michael V. Cohen.

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X.-M. Yang and S. Philipp contributed equally to this work.

Returned for revision: 4 January 2006

Revision received: 11 January 2006

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Yang, XM., Philipp, S., Downey, J.M. et al. Atrial natriuretic peptide administered just prior to reperfusion limits infarction in rabbit hearts. Basic Res Cardiol 101, 311–318 (2006). https://doi.org/10.1007/s00395-006-0587-2

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