© 2000 American Heart Association, Inc.
Editorials |
Mitochondrial KATP Channels
Triggers or Distal Effectors of Ischemic or Pharmacological Preconditioning?
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 • KATP channels • diazoxide • preconditioning
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Introduction |
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 Top Introduction References |
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The ATP-sensitive potassium (KATP) 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 KATP channel may not be the end effector of IPC or PPC. These authors suggest instead that the KATP channel, specifically the mitochondrial KATP 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 KATP channel openers pinacidil or diazoxide induce a reduction in infarct size (IS). 5-Hydroxydecanoate (5-HD), a mitochondrial selective KATP antagonist, and glibenclamide, a nonselective KATP channel blocker, were included in the buffer during an early or late protocol to additionally establish a role for the KATP 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 KATP channel is actually setting the heart into a preconditioned state. In the same laboratory, Baines et al2 demonstrated that diazoxide, a mitochondrial KATP 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 KATP channel is both a trigger and distal effector of IPC and PPC.
Gross and Auchampach3 first demonstrated the involvement of the KATP 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 KATP channel may set the heart into a preconditioned state but clearly demonstrate that the KATP 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 KATP 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 KATP 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
KATP 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 KATP 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 KATP 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 KATP 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 group16 17 18 19 20 21 and others22 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 KATP 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 KATP 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 KATP channel activation in both the rabbit and human heart, because the PKC activator phorbol 12,13-didecanoate elicited ATP-sensitive K+ channel (IKATP) activation. Additionally, Liu et al29 demonstrated that PKC activation can potentiate IKATP current induced by pinacidil or metabolic inhibition in the presence of adenosine, suggesting PKC is an upstream regulator of the KATP 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 KATP channel.
Finally, the present study explores the possible cellular mechanism that sets the heart in a preconditioned state after activation of the mitochondrial KATP 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 KATP 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 KATP 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 KATP channel activation during IPC. On the other hand, several studies have clearly shown that ROS are capable of opening sarcolemmal KATP channels, and it is likely that this might also occur in the mitochondria. Thus, it is possible that ROS from a non–KATP 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 KATP 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 KATP channel activation elicits its important cardioprotective function.
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Footnotes |
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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
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References |
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