Post-conditioning reduces infarct size in the isolated rat heart: role of coronary flow and pressure and the nitric oxide/cGMP pathway.
We aimed to assess the role of the nitric oxide (NO)-cGMP pathway in cardioprotection by brief intermittent ischemias at the onset of reperfusion (i.e., post-conditioning (Post-con)). We also evaluated the role of coronary flow and pressure in Post-con. Rat isolated hearts perfused at constant- flow or -pressure underwent 30 min global ischemia and 120 min reperfusion. Post-con obtained with brief ischemias of different duration (modified, MPost-con) was compared with Post-con obtained with ischemias of identical duration (classical, C-Post-con) and with ischemic preconditioning (IP). Infarct size was evaluated using nitro-blue tetrazolium staining and lactate dehydrogenase (LDH) release. In the groups, NO synthase (NOS) or guanylyl-cyclase (GC) was inhibited with LNAME and ODQ, respectively. In the subgroups, the enzyme immunoassay technique was used to quantify cGMP release. In the constant-flow model, M-Post-con and C-Post-con were equally effective, but more effective than IP in reducing infarct size. The cardioprotection by M-Post-con was only blunted by the NOS-inhibitor, but was abolished by the GC-antagonist. Post-ischemic cGMP release was enhanced by MPost-con. In the constant-pressure model IP, M-Post-con and C-Post-con were equally effective in reducing infarct size. Post-con protocols were more effective in the constant-flow than in the constant-pressure model. In all groups, LDH release during reperfusion was proportional to infarct size. In conclusion, Post-con depends upon GC activation, which can be achieved by NOS-dependent and NOS-independent pathways. The benefits of M- and CPost-con are similar. However, protection by Post-con is greater in the constant-flow than in the constant-pressure model.
Penna
Claudia
C
Dipartimento di Scienze Cliniche e Biologiche dell'Università di Torino, Orbassano, TO, Italy.
Cappello
Sandra
S
Mancardi
Daniele
D
Raimondo
Stefania
S
Rastaldo
Raffaella
R
Gattullo
Donatella
D
Losano
Gianni
G
Pagliaro
Pasquale
P
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP