Myocardial impairment in chronic hypoxia is abolished by short aeration episodes: involvement of K+ATP channels.
In vivo exposure to chronic hypoxia is considered to be a cause of myocardial dysfunction, thereby representing a deleterious condition, but repeated aeration episodes may exert some cardioprotection. We investigated the possible role of ATP-sensitive potassium channels in these mechanisms. First, rats (n = 8/group) were exposed for 14 days to either chronic hypoxia (CH; 10% O(2)) or chronic hypoxia with one episode/day of 1-hr normoxic aeration (CH+A), with normoxia (N) as the control. Second, isolated hearts were Langendorff perfused under hypoxia (10% O(2), 30 min) and reoxygenated (94% O(2), 30 min) with or without 3 microM glibenclamide (nonselective K(+)(ATP) channel-blocker) or 100 microM diazoxide (selective mitochondrial K(+)(ATP) channel-opener). Blood gasses, hemoglobin concentration, and plasma malondialdehyde were similar in CH and CH+A and in both different from normoxic (P < 0.01), body weight gain and plasma nitrate/nitrite were higher in CH+A than CH (P < 0.01), whereas apoptosis (number of TUNEL-positive nuclei) was less in CH+A than CH (P < 0.05). During in vitro hypoxia, the efficiency (ratio of ATP production/pressure x rate product) was the same in all groups and diazoxide had no measurable effects on myocardial performance, whereas glibenclamide increased end-diastolic pressure more in N and CH than in CH+A hearts (P < 0.05). During reoxgenation, efficiency was markedly less in CH with respect to N and CH+A (P < 0.0001), and ratex pressure product remained lower in CH than N and CH+A hearts (P < 0.001), but glibenclamide or diazoxide abolished this difference. Glibenclamide, but not diazoxide, decreased vascular resistance in N and CH (P < 0.005 and < 0.001) without changes in CH+A. We hypothesize that cardioprotection in chronically hypoxic hearts derive from cell depolarization by sarcolemmal K(+)(ATP) blockade or from preservation of oxidative phosphorylation efficiency (ATP turnover/myocardial performance) by mitochondrial K(+)(ATP) opening. Therefore K(+)(ATP) channels are involved in the deleterious effects of chronic hypoxia and in the cardioprotection elicited when chronic hypoxia is interrupted with short normoxic aeration episodes.
Milano
Giuseppina
G
Centre Hospitalier universitaire Vaudois, CH-1011, Lausanne, Switzerland. guisim@hotmail.com
Bianciardi
Paola
P
Corno
Antonio F
AF
Raddatz
Eric
E
Morel
Sandrine
S
von Segesser
Ludwig K
LK
Samaja
Michele
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002908:Chronic Disease; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D008297:Male; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000473:pathology*; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D005905:Glyburide