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(Circulation Research. 2000;87:431.)
© 2000 American Heart Association, Inc.

Editorials

Mitochondrial K_ATP Channels

Triggers or Distal Effectors of Ischemic or Pharmacological Preconditioning?

Garrett J. Gross, Ryan M. Fryer

From the Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, Wis.

Correspondence to Garrett J. Gross, PhD, Department of Pharmacology & Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail ggross{at}mcw.edu

Key Words: mitochondria • K_ATP channels • diazoxide • preconditioning

	Introduction

Top Introduction References

 
The ATP-sensitive potassium (K_ATP) channel has been shown by numerous investigations in whole animals, isolated hearts, and cardiac myocytes to be an important downstream mediator of ischemic preconditioning (IPC) or pharmacological preconditioning (PPC). However, in the present issue of Circulation Research, Pain et al¹ provide intriguing evidence suggesting that the K_ATP channel may not be the end effector of IPC or PPC. These authors suggest instead that the K_ATP channel, specifically the mitochondrial K_ATP channel, may function as a trigger that sets the myocardium into a preconditioned state via the generation of oxygen-derived free radicals.

Pain et al¹ demonstrate in an isolated buffer-perfused rabbit heart that IPC or the K_ATP channel openers pinacidil or diazoxide induce a reduction in infarct size (IS). 5-Hydroxydecanoate (5-HD), a mitochondrial selective K_ATP antagonist, and glibenclamide, a nonselective K_ATP channel blocker, were included in the buffer during an early or late protocol to additionally establish a role for the K_ATP channel. The early protocol included the antagonists in the buffer 5 minutes before, throughout, and 5 minutes after the preconditioning stimulus. The late protocol, however, included the antagonists in the perfusate only after the preconditioning stimulus, 5 minutes before, and throughout the prolonged ischemic insult. These investigators demonstrate that 5-HD and glibenclamide antagonize protection only when included during the early protocol, suggesting that the K_ATP channel is actually setting the heart into a preconditioned state. In the same laboratory, Baines et al² demonstrated that diazoxide, a mitochondrial K_ATP opener, protected the intact rabbit heart when administered before ischemia but not after the onset of occlusion. The results of these two studies seem to provide clear-cut evidence supporting the authors’ hypothesis. However, these observations are contradictory to many previous in vivo and in vitro studies performed in a variety of species in which the evidence is equally compelling to support the idea that the mitochondrial K_ATP channel is both a trigger and distal effector of IPC and PPC.

Gross and Auchampach³ first demonstrated the involvement of the K_ATP channel in IPC in the canine model and demonstrated that glibenclamide administered either before or after preconditioning could completely abolish cardioprotection. These data imply that the K_ATP channel may set the heart into a preconditioned state but clearly demonstrate that the K_ATP channel is a distal effector of IPC. In agreement, Yao et al⁴ found in dogs that 10 minutes of ischemia followed by 10 minutes of reperfusion induces a reduction in IS that is abolished by glibenclamide when administered 50 minutes after IPC. In intact rat hearts, Fryer et al⁵ recently showed that 5-HD given either 5 minutes before or 5 minutes after diazoxide completely blocked its cardioprotective effect. Additionally, in intact rabbit hearts, Ockaili et al⁶ found that pretreatment with diazoxide 30 minutes or 24 hours before 30 minutes of ischemia produced a reduction in IS. This was blocked by 5-HD if administered after diazoxide in both the early and late phases of cardioprotection. The present results of Pain et al¹ are at odds with these findings in the intact dog, rat, and rabbit hearts. This suggests that there is a possible difference in in vivo versus in vitro models of IPC or PPC that may contribute to these contradictory results.

Arguing against this hypothesis, however, are several studies by Liang,^{7 8} performed in cultured chick embryonic myocytes. Liang showed that chick cardiomyocytes could be preconditioned by a 5-minute period of hypoxia or phorbol ester administration followed by a 10-minute washout period before 90 minutes of hypoxia. This protective effect could be blocked by either administering glibenclamide or 5-HD during the preconditioning stimulus or during the 90-minute hypoxic period. These in vitro data provide evidence that the K_ATP channel is involved as both a trigger and mediator of IPC or PPC. Perhaps more important are the preliminary findings of Wang et al⁹ using a similar isolated perfused rabbit heart. In contrast to the findings of Pain et al,¹ these investigators found that diazoxide was cardioprotective when administered for 5 minutes followed by a 10-minute washout period before the 30-minute ischemic episode and when given 5 minutes before and throughout the 30-minute ischemic period. This early cardioprotective effect of diazoxide was blocked by concomitant administration of 5-HD; however, a higher concentration of 5-HD was necessary to block the late effect of diazoxide given during the 30-minute ischemic period. These results are at odds with those of the present study and suggest that diazoxide can trigger and mediate cardioprotection. It is difficult to understand why these two studies have opposing results, because they were performed in similar models. Differences in the timing of diazoxide administration and in the concentrations of 5-HD and diazoxide used in these two protocols may be factors that can help explain the different results.

IPC and PPC have also been shown to induce a second window of cardioprotection to reduce IS. Again, evidence for the involvement of the K_ATP channel as a mediator of delayed cardioprotection is abundant. Carroll and Yellon¹⁰ have demonstrated in a human cardiac cell line that delayed cardioprotection induced by either IPC or adenosine can be abolished by the administration of 5-HD 24 hours later, immediately before lethal simulated ischemia. Pell et al¹¹ and Joyeux et al¹² have demonstrated in rabbits and rats that preconditioning with heat stress is cardioprotective and can be abolished by glibenclamide or 5-HD administered immediately before a prolonged ischemic period 24 hours after heat stress. Like heat stress, the pharmacological agents CCPA (adenosine agonist) and TAN-67 (₁-opioid receptor agonist) have been shown to induce delayed cardioprotection that can be abolished when glibenclamide or 5-HD is administered immediately before sustained ischemia.^{13 14 15} Similarly, the K_ATP channel opener diazoxide induces both early and delayed cardioprotection that can be abolished when 5-HD is administered after diazoxide treatment.^{5 6} These data suggest that the K_ATP channel is a distal effector that mediates cardioprotection in models of delayed preconditioning. Although delayed preconditioning was not addressed in the present study, there is no reason to believe that the function of the K_ATP channel in early or late preconditioning would be different; however, this hypothesis has not been rigorously tested.

Two other important aspects of the present study by Pain et al¹ focus on the role of kinases, most notably protein kinase C (PKC) and tyrosine kinase (TK), as well as free radicals, in diazoxide-induced cardioprotection and where these important components of IPC or PPC come into play temporally. They demonstrate that diazoxide induces cardioprotection, which is abolished only when 5-HD is administered at the same time during the early protocol. This suggests that mitochondrial K_ATP channel activation triggers cardioprotection in a manner similar to IPC by first opening these channels. Furthermore, these authors demonstrate that the cardioprotection initiated by diazoxide is not abolished by the PKC inhibitor chelerythrine given in the early or late protocol but can be abolished by the TK inhibitor genistein if given immediately before the 30-minute occlusion period. These results are puzzling, because this group^{16 17 18 19 20 21} and others^{22 23 24 25 26} have clearly shown a role for PKC translocation and activation in preconditioning, and several investigators have shown that PKC activation enhances and is proximal to K_ATP channel opening. In this regard, Takashi et al²⁷ have recently shown in rats that chelerythrine and 5-HD administered immediately before diazoxide treatment or 10 minutes before ischemia on the second day abolished the reduction in IS induced if diazoxide was given 24 hours before regional ischemia. These data suggest that PKC and the mitochondrial K_ATP channel can serve both as a trigger and distal effector of PPC in the intact rat heart. Interestingly, Hu et al²⁸ have also demonstrated that PKC is likely to be proximal to K_ATP channel activation in both the rabbit and human heart, because the PKC activator phorbol 12,13-didecanoate elicited ATP-sensitive K⁺ channel (I_KATP) activation. Additionally, Liu et al²⁹ demonstrated that PKC activation can potentiate I_KATP current induced by pinacidil or metabolic inhibition in the presence of adenosine, suggesting PKC is an upstream regulator of the K_ATP channel, not vice versa. Furthermore, Ahmet et al³⁰ demonstrated that diadenosine tetraphosphate (AP4A) mimics the cardioprotective effect of IPC in the rat heart. This effect could be abolished when either glibenclamide or the PKC inhibitor GF 109203X was administered immediately before prolonged ischemia after AP4A or after 3 preconditioning cycles of ischemia and reperfusion.

The importance of TKs in IPC has been previously demonstrated.^{31 32} Indeed, the present study agrees with other groups, suggesting that a TK-sensitive mechanism may mediate IPC or PPC. However, a potential problem with the present study is the use of genistein as a selective antagonist of TK because of the many potential nonspecific targets of genistein, including the inhibition of voltage-gated Na⁺ channels³³ and protein histidine kinase³⁴ as well as the direct action of genistein to induce CFTR chloride current.³⁵ These alternative effects could confound the interpretation of the present results. Use of the inactive analog of genistein, daidzein, or a more selective TK inhibitor would have strengthened the argument in favor of TK-mediating effects initiated by opening of the mitochondrial K_ATP channel.

Finally, the present study explores the possible cellular mechanism that sets the heart in a preconditioned state after activation of the mitochondrial K_ATP channel. The authors suggest that potassium influx into the mitochondria induces a burst of free radicals that set the myocardium in a preconditioned state. Indeed, opening of the mitochondrial K_ATP channel would be thought to alter mitochondrial membrane potential and subsequently uncouple the electron transport chain. This may lead to free radical formation, which has been shown previously to induce a state of preconditioning after hypoxia or acetylcholine. Furthermore, buffer PO₂ exceeded 500 mm Hg in this preparation, and this amount of oxygen may have induced an excessive amount of free radical production independent of mitochondrial K_ATP channel function. Additionally, Vanden Hoek et al³⁶ have demonstrated that IPC in cardiomyocytes is cardioprotective by attenuating oxidant stress at reperfusion. However, they clearly demonstrate that hypoxic preconditioning induces an increase in reactive oxygen species (ROS) during preconditioning but attenuates oxidant generation at reperfusion. This reduction in ROS during the initial part of reperfusion could be abrogated by the PKC inhibitor Go-6976. Additionally, Vanden Hoek et al³⁶ demonstrated that 5-HD could abolish the reperfusion-induced reduction in oxidant burst but did not abolish ROS formation during the preconditioning stimulus. This suggests that ROS formation is not likely to be the result of K_ATP channel activation during IPC. On the other hand, several studies have clearly shown that ROS are capable of opening sarcolemmal K_ATP channels, and it is likely that this might also occur in the mitochondria. Thus, it is possible that ROS from a non–K_ATP channel source could open the channel, resulting in a cardioprotective effect by a yet to be determined mechanism.

In conclusion, the present study suggests a new scheme for the timing of the signaling pathway responsible for the early phase of IPC and PPC, where activation of the mitochondrial K_ATP channel is hypothesized to serve only as a trigger for cardioprotection. It is difficult to reconcile these findings with those previously published in several in vivo and in vitro models in which this channel has been clearly shown to be a distal effector of IPC and PPC. Obviously, additional studies are necessary to determine the critical juncture at which mitochondrial K_ATP channel activation elicits its important cardioprotective function.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

See related article, pages 460–466

	References

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gross, G. J. Articles by Fryer, R. M. Search for Related Content PubMed PubMed Citation Articles by Gross, G. J. Articles by Fryer, R. M. Related Collections Oxidant stress Cell signalling/signal transduction Ischemic biology - basic studies Ion channels/membrane transport