Inhibition of peroxynitrite precursors, NO and O2, at the onset of reperfusion improves myocardial recovery.

Abstract

AIM OF STUDY:

Previous reports note an increase in both reactive oxygen species (ROS) and nitric oxide (*NO) at the onset of myocardial reperfusion. We tested the hypothesis that inhibition of *NO or ROS production at the time of reperfusion improves recovery of post-ischemic myocardial function.

METHODS AND MATERIALS:

Isolated rat hearts were perfused with temperature controlled (37.4 degrees C) modified Krebs Henseleit buffer solution at 85 mm Hg. Following 20 min of global ischemia, hearts were reperfused for the first 10 min with: (1) standard buffer (control), (2) buffer with a NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), (3) buffer with superoxide dismutase (SOD) or (4) buffer with N-morpholinosydnonimine hydrochloride (SIN-1), a peroxynitrite generator. Tissue O(2) and *NO were continuously measured with thin electrochemical probes embedded in the wall of the LV. ROS was measured with the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) (40 mM). LV contractile function was continuously monitored.

RESULTS:

Recovery of LV contractile function was significantly improved in hearts initially reperfused with L-NAME and SOD and significantly depressed in hearts reperfused with SIN-1 compared with control (p<0.01, n=5-8 per group). DMPO-adduct during reperfusion (measure of ROS) was significantly decreased with SOD (p<0.001 versus L-NAME and Control, n=4 per group) and unchanged with L-NAME and SIN-1 compared with Control. With L-NAME, tissue *NO and PO(2) were significantly decreased, independent of coronary flow, during reperfusion compared with control and SIN-1.

CONCLUSIONS:

Inhibition of O(2)*(-) or *NO at the time of reperfusion improves early reperfusion LV function and alters tissue oxygen tension. In contrast to pre-ischemic treatments, intervention to reduce peroxynitrite generation at the onset of reperfusion can effectively improve post-ischemic myocardial recovery.

• Authors: Jessica A Falk, Sverre E Aune, Vijay K Kutala, Periannan Kuppusamy, Mark G Angelos
• Journal: Resuscitation (Resuscitation) Vol. 74 Issue 3 Pg. 508-15 (Sep 2007) ISSN: 0300-9572 [Print] Ireland
• PMID: 17418932 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Free Radical Scavengers
• Reactive Oxygen Species
• Peroxynitrous Acid
• Nitric Oxide
• linsidomine
• Molsidomine
• Superoxide Dismutase
• Sodium-Potassium-Exchanging ATPase
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Free Radical Scavengers (therapeutic use)
• Male
• Molsidomine (analogs & derivatives, therapeutic use)
• Myocardial Contraction (drug effects)
• Myocardial Reperfusion Injury (drug therapy, metabolism, physiopathology)
• Myocardium (metabolism)
• NG-Nitroarginine Methyl Ester (therapeutic use)
• Nitric Oxide (antagonists & inhibitors)
• Oxygen Consumption (drug effects)
• Peroxynitrous Acid (antagonists & inhibitors, metabolism)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (antagonists & inhibitors)
• Recovery of Function
• Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors)
• Superoxide Dismutase (therapeutic use)
• Treatment Outcome
• Ventricular Function, Left (drug effects, physiology)