Effects of mitochondrial K(ATP) modulators on cardioprotection induced by chronic high altitude hypoxia in rats.
OBJECTIVE
Adaptation of rats to intermittent high altitude hypoxia increases the tolerance of their hearts to acute ischemia/reperfusion injury. Our aim was to examine the role of mitochondrial ATP-sensitive potassium channels (K(ATP)) in this form of protection.


METHODS
Adult male Wistar rats were exposed to hypoxia of 5000 m in a barochamber for 8 h/day, 5 days a week; the total number of exposures was 24-32. A control group was kept under normoxic conditions (200 m). Infarct size (tetrazolium staining) was measured in anesthetized open-chest animals subjected to 20-min regional ischemia (coronary artery occlusion) and 4-h reperfusion. Isolated perfused hearts were used to assess the recovery of contractile function following 20-min global ischemia and 40-min reperfusion. In the open-chest study, a selective mitochondrial K(ATP) blocker, 5-hydroxydecanoate (5 mg/kg), or openers, diazoxide (10 mg/kg) or BMS-191095 (10 mg/kg), were administered into the jugular vein 5 and 10 min before occlusion, respectively. In the isolated heart study, 5-hydroxydecanoate (250 micromol/l) or diazoxide (50 micromol/l) were added to the perfusion medium 5 or 10 min before ischemia, respectively.


RESULTS
In the control normoxic group, infarct size occupied 62.2+/-2.0% of the area at risk as compared with 52.7+/-2.5% in the chronically hypoxic group (P<0.05). Post-ischemic recovery of contractile function (dP/dt) reached 60.0+/-3.9% of the pre-ischemic value and it was improved to 72.4+/-1.2% by adaptation to hypoxia (P<0.05). While 5-hydroxydecanoate completely abolished these protective effects of chronic hypoxia, it had no appreciable influence in normoxic groups. In contrast, diazoxide significantly increased the recovery of contractile function and reduced infarct size in normoxic groups only. The later effect was also observed following treatment with BMS-191095.


CONCLUSIONS
The results suggest that opening of mitochondrial K(ATP) channels is involved in the cardioprotective mechanism conferred by long-term adaptation to intermittent high altitude hypoxia.
Neckár
Jan
J
Institute of Physiology, Academy of Sciences of the Czech Republic and Centre for Experimental Cardiovascular Research, Vídenská 1083, 142 20 Prague 4, Czech Republic.
Szárszoi
Ondrej
O
Koten
Lukás
L
Papousek
Frantisek
F
Ost'ádal
Bohuslav
B
Grover
Gary J
GJ
Kolár
Frantisek
F
D000531:Altitude; D000704:Analysis of Variance; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002908:Chronic Disease; D003652:Decanoic Acids / Q000494:pharmacology*; D003981:Diazoxide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D023421:Models, Animal; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010477:Perfusion; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D013997:Time Factors
C428117:BMS 191095; D001578:Benzopyrans; D003652:Decanoic Acids; D006880:Hydroxy Acids; D007093:Imidazoles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C052853:5-hydroxydecanoic acid; D003981:Diazoxide