Ischemic tolerance in skeletal muscle: role of nitric oxide.
We tested the hypothesis that ischemic preconditioning (PC) of skeletal muscle provided tolerance to a subsequent ischemic event 24 h later, and that such protection was due to nitric oxide (NO). Male Wistar rats, anesthetized with halothane, were randomly assigned to groups: ischemic (no PC; n = 11), PC (n = 11), PC + N-nitro-L-arginine methyl ester (L-NAME; 100 micromol/l; n = 5), PC + N-nitro-D-arginine methyl ester (100 micromol/l; n= 4), PC + aminoguanidine (AMG; 100 micromol/l; n = 4), ischemic + L-NAME (n= 4), or ischemic + AMG (n = 4). PC consisted of 5x 10 min of ischemia and reperfusion, and, 24 h later, 2 h of ischemia were induced by a tourniquet applied to the limb. With the use of intravital microscopy, the number of perfused capillaries (Npc) in the extensor digitorum longus (EDL) muscle was measured over a 90-min reperfusion period. The ratio of ethidium bromide- to bisbenzimide-labeled nuclei was used to estimate tissue injury. PC preserved Npc (23.6 +/- 2.5) following 2 h of ischemia compared with sham muscles (11.5 +/- 5.1), significantly elevating inducible NO synthase (iNOS) activity (81% increase), but did not afford protection to the parenchyma. L-NAME and AMG prevented ischemia-reperfusion-induced reduction in Npc in muscles without PC. However, after 90 min of reperfusion, L-NAME (Npc = 15.0 +/- 1.7), but not AMG (Npc = 22.8 +/- 3.1), significantly reduced the microvascular protection afforded by PC. We conclude that PC of the EDL muscle resulted, 24 h later, in protection to microvascular perfusion only, and that such protection was due to NO from sources other than iNOS.
Pudupakkam
S
S
London Health Sciences Centre Research Incorporated, University of Western Ontario, London, Ontario, Canada N6A 4G5.
Harris
K A
KA
Jamieson
W G
WG
DeRose
G
G
Scott
J A
JA
Carson
M W
MW
Schlag
M G
MG
Kvietys
P R
PR
Potter
R F
RF
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007511:Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D019194:Ischemic Preconditioning; D007700:Kinetics; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D018715:Microscopy, Video; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013997:Time Factors
D004791:Enzyme Inhibitors; D006146:Guanidines; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester