The mechanism of helium-induced preconditioning: a direct role for nitric oxide in rabbits.
BACKGROUND
Helium produces preconditioning against myocardial infarction by activating prosurvival signaling, but whether nitric oxide (NO) generated by endothelial NO synthase plays a role in this phenomenon is unknown. We tested the hypothesis that NO mediates helium-induced cardioprotection in vivo.


METHODS
Rabbits (n = 62) instrumented for hemodynamic measurement were subjected to a 30-min left anterior descending coronary artery occlusion and 3 h reperfusion, and received 0.9% saline (control) or three cycles of 70% helium-30% oxygen administered for 5 min interspersed with 5 min of an air-oxygen mixture before left anterior descending coronary artery occlusion in the absence or presence of pretreatment with the nonselective NOS inhibitor N-nitro-l-arginine methyl ester (L-NAME; 10 mg/kg), the selective inducible NOS inhibitor aminoguanidine hydrochloride (AG; 300 mg/kg), or selective neuronal NOS inhibitor 7-nitroindazole (7-NI; 50 mg/kg). In additional rabbits, the fluorescent probe 4,5-diaminofluroscein diacetate (DAF-2DA) and confocal laser microscopy were used to detect NO production in the absence or presence of helium with or without L-NAME pretreatment.


RESULTS
Helium reduced (P < 0.05) infarct size (24% +/- 4% of the left ventricular area at risk; mean +/- sd) compared with control (46% +/- 3%). L-NAME, AG, and 7-NI did not alter myocardial infarct size when administered alone. L-NAME, but not 7-NI or AG, abolished helium-induced cardioprotection. Helium enhanced DAF-2DA fluorescence compared with control (26 +/- 8 vs 15 +/- 5 U, respectively). Pretreatment with L-NAME abolished these helium-induced increases in DAF-2DA fluorescence.


CONCLUSIONS
The results indicate that cardioprotection by helium is mediated by NO that is probably generated by endothelial NOS in vivo.
Pagel
Paul S
PS
Department of Anesthesiology, Medical College of Wisconsin, Clement J. Zablocki Veterans Affairs Medical Center, Anesthesia Service, 5000 W. National Ave., Milwaukee, WI 53295, USA. pspagel@mcw.edu
Krolikowski
John G
JG
Pratt
Phillip F
PF
Shim
Yon Hee
YH
Amour
Julien
J
Warltier
David C
DC
Weihrauch
Dorothee
D
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019793:Fluorescein / Q000494:pharmacology; D006371:Helium / Q000494:pharmacology*; D006439:Hemodynamics; D007191:Indazoles / Q000494:pharmacology; D007202:Indicators and Reagents / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011817:Rabbits
C414689:4,5-diaminofluorescein diacetate; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007191:Indazoles; D007202:Indicators and Reagents; D006371:Helium; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019793:Fluorescein; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester