Early pharmacological preconditioning by erythropoietin mediated by inducible NOS and mitochondrial ATP-dependent potassium channels in the rat heart.
Administration of recombinant human erythropoietin (rhEPO) is known to induce protection against cardiac ischaemia injury improving functional recovery and reducing apoptosis. But the underlying mechanisms are not elucidated. We determined the role of nitric oxide synthases (NOS) as well as ATP-dependent (K(ATP)) and calcium-activated (K(Ca)) potassium channels in the early cardioprotection induced by rhEPO. Wistar male rats were divided into two experimental groups treated by rhEPO (5,000 IU/kg, i.p.) or saline (control group). One hour later, rats were anaesthetized, hearts isolated, retrogradely perfused and submitted to a 30-min no-flow global ischaemia followed by 120 min of reperfusion sequence. Cardiac functional recovery (left ventricular developed pressure, LVDP) was significantly higher in the group treated by rhEPO (LVDP at 30 min reperfusion: 71.7 +/- 2.3 mmHg) compared with the control group (57.4 +/- 5.8 mmHg). We observed the same significant effect on its derivative (dP/dt). The rhEPO-induced improvement in ventricular function was abolished by perfusion prior to ischaemia with either N-nitro-l-arginine methyl ester (l-NAME, a nonspecific NOS inhibitor) or N-(3-(aminomethyl)benzyl)acetamidine (1,400W, a specific inducible NOS inhibitor) or 5-hydroxydecanoic acid (5HD, a mitochondrial K(ATP) channel blocker) but not with paxilline (a K(Ca) channel inhibitor). Thus, in vivo rhEPO administration provides early preconditioning against ischaemic injury in the isolated perfused rat heart that is dependent on iNOS and mitochondrial K(ATP) channels.
Joyeux-Faure
M
M
Laboratoire HP2, Hypoxie Physio-Pathologie Respiratoire et Cardiovasculaire, Faculté de Médecine-Pharmacie, Université Grenoble I, France, INSERM ERI 0017, EA 3745, France. marie.faure@ujf-grenoble.fr
Ramond
A
A
Béguin
P C
PC
Belaïdi
E
E
Godin-Ribuot
D
D
Ribuot
C
C
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
D000578:Amidines; D001596:Benzylamines; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D011994:Recombinant Proteins; D004921:Erythropoietin; C052853:5-hydroxydecanoic acid; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester