Sevoflurane-induced preconditioning: impact of protocol and aprotinin administration on infarct size and endothelial nitric-oxide synthase phosphorylation in the rat heart in vivo.
BACKGROUND
Sevoflurane induces preconditioning (SevoPC). The effect of aprotinin and the involvement of endothelial nitric-oxide synthase (NOS) on SevoPC are unknown. We investigated (1) whether SevoPC is strengthened by multiple preconditioning cycles, (2) whether SevoPC is blocked by aprotinin, and (3) whether endothelial NOS plays a crucial role in SevoPC.


METHODS
Anesthetized male Wistar rats were randomized to 15 groups (each n = 6) and underwent 25-min regional myocardial ischemia and 2-h reperfusion. Controls were not treated further. Preconditioning groups inhaled 1 minimum alveolar concentration of sevoflurane for 5 min (SEVO-I), twice for 5 min each (SEVO-II), three times for 5 min each (SEVO-III), or six times for 5 min each (SEVO-VI). Aprotinin was administered with and without sevoflurane. Involvement of endothelial NOS was determined with the nonspecific NOS blocker N-nitro-l-arginine-methyl-ester, the specific neuronal NOS blocker 7-nitroindazole, and the specific inducible NOS blocker aminoguanidine.


RESULTS
SevoPC reduced infarct size in all protocols (SEVO-I, 42 ± 6%; SEVO-II, 33 ± 4%; SEVO-III, 11 ± 5%; SEVO-VI, 16 ± 4%; all P < 0.001 vs. control, 67 ± 3%) and was least after three and six cycles of sevoflurane (P < 0.001 vs. SEVO-II and -I, respectively). Aprotinin alone had no effect on infarct size but blocked SevoPC. N-nitro-l-arginine-methyl-ester abolished SevoPC (67 ± 4%; P < 0.05 vs. SEVO-III). Aminoguanidine and 7-nitroindazole blocked SevoPC only partially (25 ± 6 and 31 ± 6%, respectively; P < 0.05 vs. SEVO-III and control). SevoPC induced endothelial NOS phosphorylation, which was abrogated by aprotinin.


CONCLUSIONS
SevoPC is strengthened by multiple preconditioning cycles, and phosphorylation of endothelial NOS is a crucial step in mediating SevoPC. These effects are abolished by aprotinin.
Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Jan
J
Frädorf
Ragnar
R
Huhn
Nina C
NC
Weber
Dirk
D
Ebel
Nadja
N
Wingert
Benedikt
B
Preckel
Octavian
O
Toma
Wolfgang
W
Schlack
Markus W
MW
Hollmann
D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D007611:Aprotinin / Q000494:pharmacology*; D015153:Blotting, Western; D002316:Cardiotonic Agents; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006490:Hemostatics / Q000494:pharmacology*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011650:Pulmonary Alveoli / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D000077149:Sevoflurane
D018685:Anesthetics, Inhalation; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D006490:Hemostatics; D008738:Methyl Ethers; D000077149:Sevoflurane; D007611:Aprotinin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester