Endothelin-1 exerts a preconditioning-like cardioprotective effect against ischaemia/reperfusion injury via the ET(A) receptor and the mitochondrial K(ATP) channel in the rat in vivo.
In vitro studies have demonstrated that endothelin-1 (ET-1) given before myocardial ischaemia may evoke a preconditioning (PC)-like cardioprotective effect. The first aim of this study was to investigate whether administration of ET-1 before ischaemia exerts cardioprotection against ischaemia/reperfusion injury in vivo and to determine involvement of the ET-1 receptor subtype. The second aim was to examine the role of mitochondrial ATP-sensitive K+ channels (mitoK(ATP)) as a mediator of this cardioprotection. Anaesthetised open-chest Wistar rats were subjected to 30 min of coronary artery occlusion followed by 2 h reperfusion (I/R). In protocol I, the first group was subjected to I/R only (control, n=10). In the second (n=10) group, PC was elicited by three 5 min cycles of coronary artery occlusion, separated by 5 min reperfusion before I/R. The third (n=6) and fourth (n=7) groups were given ET-1 intravenous (i.v.) during three 5 min infusion periods separated by 5 min before I/R. The fourth group was in addition given the ET(A) receptor antagonist LU 135252 5 min before the infusions of ET-1. In protocol II, the first group was I/R control as in protocol I (n=8). The second (n=6), third (n=7) and fourth (n=7) groups were given ET-1 as in protocol I. The third group was in addition given the nonselective K(ATP) channel antagonist glibenclamide (Glib) 30 min before the ET-1 infusions and the fourth group the selective mitoK(ATP) channel antagonist 5-hydroxydecanoic acid (5-HD) 5 min before I/R. There were no significant differences in MAP or heart rate between the groups during I/R. In protocol I, PC reduced IS compared to the control group (10+/-3 vs 35+/-5%, P<0.01). Infusion of ET-1 also reduced IS (to 14+/-3%, P<0.05 vs control). The ET(A) receptor antagonist blocked the reduction in IS induced by ET-1 (IS 47+/-8% after LU+ET-1; P< 0.05 vs ET-1). In protocol II, Glib and 5-HD abolished the cardioprotective effect induced by ET-1 (IS 48+/-7% after Glib+ET-1 and 42+/-5% after ET-1+5-HD vs 18+/-4% after ET-1 alone; P<0.05). In conclusion, administration of ET-1 before ischaemia resulted in a PC-like cardioprotective effect. This effect is mediated via the ET(A) receptor and activation of mitoK(ATP) channels.
Gourine
Audrey V
AV
Department of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden. agourine@hotmail.com
Molosh
Audrey I
AI
Poputnikov
Dmitry
D
Bulhak
Aliaksandr
A
Sjöquist
Per-Ove
PO
Pernow
John
J
D000818:Animals; D004562:Electrocardiography / Q000187:drug effects; D019332:Endothelin-1 / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects*; D009203:Myocardial Infarction / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010666:Phenylpropionates / Q000494:pharmacology; D015221:Potassium Channels; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000187:drug effects*; D015427:Reperfusion Injury / Q000517:prevention & control*
D019332:Endothelin-1; D008565:Membrane Proteins; D010666:Phenylpropionates; D015221:Potassium Channels; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C117780:mitochondrial K(ATP) channel; C107831:darusentan