Atrial natriuretic peptide administered just prior to reperfusion limits infarction in rabbit hearts.
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.
Yang
Xi-Ming
XM
Department of Physiology, University of South Alabama College of Medicine, MSB 3050, Mobile, AL 36688, USA.
Philipp
Sebastian
S
Downey
James M
JM
Cohen
Michael V
MV
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D017869:Cyclic GMP-Dependent Protein Kinases / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects
D002316:Cardiotonic Agents; D009320:Atrial Natriuretic Factor; D017869:Cyclic GMP-Dependent Protein Kinases