The role of nitric oxide, K(+)(ATP) channels, and cGMP in the preconditioning response of the rabbit.
BACKGROUND
The role of nitric oxide (NO), K(+)(ATP) channels, and cyclic GMP (cGMP) in preconditioning is unknown.


METHODS
Isolated rabbit hearts were pretreated with the NO precursor L-arginine (L-Arg), both alone and after infusion of the NO synthetase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Guanylate cyclase inhibitor methylene blue (MB) was infused prior to L-Arg in a separate group of hearts. To contrast the mechanisms of NO preconditioning and potassium channel opener (PCO) preconditioning, we infused the PCO pinacidil after L-NAME and the PCO blocker glibenclamide before L-Arg. Control hearts had no drug infused. The LAD coronary artery was occluded for 1 h and reperfused for 1 h in all hearts. Action potential duration (APD(50)), coronary flow (CF), and left ventricular developed pressure (DP) were measured, and infarct size (IS) was determined and expressed as a percentage of the area at risk.


RESULTS
L-Arg prolonged APD(50) at 60 min of reperfusion (94 +/- 6 ms vs 69 +/- 2 ms (control) vs 70 +/- 2 ms (L-NAME) vs 74 +/- 3 ms (MB), P < 0.05). L-Arg reduced IS compared with control (24 +/- 2% vs 49 +/- 3%, P < 0.05); this was reversed by either L-NAME (53 +/- 4%, P < 0.05) or MB (43 +/- 3%, P < 0.05), but not by glibenclamide (20 +/- 4%), unlike the increase in CF during L-Arg infusion, which was blocked by glibenclamide. Pinacidil infusion decreased IS (26 +/- 2%), but this effect was blocked by L-NAME (53 +/- 7%, P < 0.05 vs pinacidil), although L-NAME did not blunt the increase in CF. There were no significant differences in DP among groups.


CONCLUSIONS
L-Arginine preconditions the heart through NO generation, and this response is mediated through a cGMP-dependent mechanism, but is independent of the K(+)(ATP) channels. Coronary vasodilation is mediated through a mechanism different from that responsible for cardiomyocyte preconditioning.
Horimoto
H
H
Division of Cardiothoracic Surgery and The Institute for Molecular Cardiology, State University of New York at Stony Brook, Stony Brook, New York 11794, USA.
Gaudette
G R
GR
Saltman
A E
AE
Krukenkamp
I B
IB
D000200:Action Potentials / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D019194:Ischemic Preconditioning; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009203:Myocardial Infarction / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D011817:Rabbits
D004791:Enzyme Inhibitors; D015221:Potassium Channels; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D001120:Arginine; D006152:Cyclic GMP; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester