Adenosine and a nitric oxide donor enhances cardioprotection by preconditioning with isoflurane through mitochondrial adenosine triphosphate-sensitive K+ channel-dependent and -independent mechanisms.
BACKGROUND
Preconditioning with isoflurane has been shown to confer cardioprotection via activation of mitochondrial adenosine triphosphate-sensitive K+ (mito K(ATP)) channels. However, the relative contribution of mito K(ATP) channel and non-mito K(ATP) channel mechanisms to isoflurane-mediated cardioprotection has not been investigated.


METHODS
Isolated and buffer-perfused rat hearts were used. Flavoprotein fluorescence was monitored as an index for mito K(ATP) channel activity. Isovolumic left ventricular function and infarct size were measured as indices for cardioprotection.


RESULTS
Flavoprotein fluorescence, which was monitored as an index for mito K(ATP) channel activity, was increased by isoflurane and a known mito K(ATP) channel opener, diazoxide, in a 5-hydroxydecanoate-sensitive manner. Although flavoprotein oxidation induced by diazoxide was dissipated soon after its removal from the buffer, flavoprotein oxidation induced by isoflurane was sustained after cessation of the treatment. The sustained increase in flavoprotein oxidation was associated with a significant reduction in infarct size after 30 min of ischemia followed by 120 min of reperfusion. Although adenosine and S-nitroso-N-acetyl-penicillamine each alone did not increase flavoprotein fluorescence, nor did they confer significant cardioprotection, coadministration of adenosine and S-nitroso-N-acetyl-penicillamine with isoflurane conferred a highly significant reduction of infarct size and improvement of left ventricular function without increasing flavoprotein oxidation over isoflurane alone. The early treatment with 5-hydroxydecanoate before and during preconditioning completely reversed flavoprotein oxidation and inhibited the infarct-sparing effect of isoflurane and combined preconditioning with isoflurane, adenosine, and S-nitroso-N-acetyl-penicillamine. The late treatment with 5-hydroxydecanoate after preconditioning abolished flavoprotein oxidation and the infarct-sparing effect of isoflurane but only partially inhibited cardioprotection conferred by the combined preconditioning, despite complete abrogation of flavoprotein oxidation.


CONCLUSIONS
Mito K(ATP) channel activation is the essential trigger of both preconditioning with isoflurane and combined preconditioning with isoflurane, adenosine, and S-nitroso-N-acetyl-penicillamine. Mito K(ATP) channel activation is also a crucial mediator of cardioprotection afforded by preconditioning with isoflurane. However, enhanced cardioprotection conferred by combined preconditioning is mediated through both mito K(ATP) channel-dependent and -independent mechanisms.
Wakeno-Takahashi
Mayu
M
Department of Anesthesiology, Kansai Medical University, Moriguchi City, Japan.
Otani
Hajime
H
Nakao
Shinichi
S
Uchiyama
Yuka
Y
Imamura
Hiroji
H
Shingu
Koh
K
D000241:Adenosine / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005420:Flavoproteins / Q000378:metabolism; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010084:Oxidation-Reduction; D015221:Potassium Channels; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology
D018685:Anesthetics, Inhalation; D002317:Cardiovascular Agents; D005420:Flavoproteins; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D026423:S-Nitroso-N-Acetylpenicillamine; D007530:Isoflurane; D000241:Adenosine; D003981:Diazoxide