Inhalation of NO during myocardial ischemia reduces infarct size and improves cardiac function.
OBJECTIVE
Bioactive NO carriers in circulating blood formed during NO inhalation selectively distribute blood flow to areas in need, and may thus improve collateral perfusion to the area-at-risk in acute myocardial infarction (AMI). Here, we tested the hypothesis that NO inhalation during the ischemic phase of AMI may improve left ventricular function and reduce infarct size in rats.


METHODS
Following left anterior descending coronary artery (LAD) occlusion, rats received 50 ppm NO for 2 h of ischemia, during subsequent 3 h of reperfusion, or for 5 h of ischemia and reperfusion. Effects of inhaled NO were compared to those of intravenous nitrite as a putative carrier formed during NO inhalation. Downstream signaling via soluble guanylate cyclase was tested by inhibition with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ).


RESULTS
NO inhalation during myocardial ischemia increased left ventricular systolic pressure, contractility, relaxation, and cardiac output, and reduced myocardial infarction size and area-at-risk as compared to untreated controls. NO inhalation during the reperfusion phase caused a comparable protective effect. Combined inhalation during ischemia and reperfusion did not further improve left ventricular hemodynamics, but had an additive protective effect on the myocardial area-at-risk. NO inhalation increased circulating nitrite levels, and mimicking of this effect by intravenous nitrite infusion achieved similar protection as NO inhalation during myocardial ischemia, while ODQ blocked the protective NO effect.


CONCLUSIONS
Inhalation of NO during myocardial ischemia improves left ventricular function and reduces infarct size by mechanisms that increase levels of circulating nitrite and involve soluble guanylate cyclase. NO inhalation may represent a promising early intervention in AMI.
Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Nils
N
Neye
Fabian
F
Enigk
Sruti
S
Shiva
Helmut
H
Habazettl
Nikolaus
N
Plesnila
Hermann
H
Kuppe
Mark T
MT
Gladwin
Wolfgang M
WM
Kuebler
D000280:Administration, Inhalation; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000502:physiology; D008297:Male; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009569:Nitric Oxide / Q000494:pharmacology*; D009573:Nitrites / Q000097:blood / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D013599:Systole; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D009573:Nitrites; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase