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Cardiovascular Research 2001 51(4):633-636; doi:10.1016/S0008-6363(01)00396-0
© 2001 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Diazoxide induced cardioprotection: what comes first, KATP channels or reactive oxygen species?

Hemal H. Patel and Garrett J. Gross*

Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

* Corresponding author

Received 14 June 2001; accepted 15 June 2001

See article by Carroll et al. [32] (pages 691–700) in this issue.

Ischemic preconditioning (IPC) is a phenomenon in which a sublethal stress of short duration has proved to be protective against a subsequent lethal stress [1]. The protection is biphasic in that there is an immediate phase of protection that is transient and disappears a few hours after the conditioning stimulus [2], and a late phase that occurs 24 h after the conditioning stimulus and can last up to 72 h [3,4]. The conditioning stimuli can be variable and include ischemia, stimulation of adenosine receptors [5–7], opioid receptors [8–11], physical manipulation such as heat stress [12–15], or activation of the mitochondrial ATP-dependent K-channel (mitoKATP) [16,17]. Early events appear to be linked to protein modification and translocation through activation of signal transduction pathways that are already in place. Late events are most likely contingent upon de novo protein synthesis [3,18] with nitric oxide synthase [19–24], catalase [25], superoxide dismutase [5,26–28], and heat shock proteins [13–15,29] likely induced in the late phase to facilitate protection.

Recently, a flurry of investigations have focused on the involvement of reactive oxygen species (ROS) in the protective mechanism of IPC. There is considerable evidence that ROS are involved in IPC since the role of ROS in both the pathogenesis and adaptation to severe damage produced by ischemia has been demonstrated. Sun et al. [30] show that repeated exposure to cycles of sublethal ischemia over many days led to an adaptation in which contractile function returned more quickly on days 2 and 3 compared to day 1. Subsequently, when the animals were treated with antioxidants in conjunction with the repeated cycles of ischemia the protective response was blocked on days 2 and 3. Recently, Pain et al. [31] showed in isolated rabbit hearts that diazoxide administration markedly reduced infarct size and this protection could be blocked by pretreatment with ROS scavengers. These data suggest the involvement of ROS and mitoKATP channels as triggers in the protective response.

Carroll et al. in this issue of Cardiovascular Research [32] demonstrate that opening of the mitoKATP channel in a human atrial-derived cell line causes protection. They further show that this protection is mediated via a free radical mechanism. They demonstrate in their cell model that diazoxide produced an increase in the oxidation of the ROS probe, reduced mitotracker orange. This increased oxidation of mitotracker orange was attenuated by pretreatment with 5-hydroxydeconoate (5-HD, a selective mitoKATP inhibitor), 2-mercaptopropionyl glycine (2-MPG) and N-acetyl cysteine (NAC), both free radical scavengers. Furthermore, they showed that with diazoxide treatment there was no change in the JC-1 signal suggesting there was no decrease in mitochondrial membrane potential. However, there were changes in light scattering which indicated that changes in mitochondrial volume were occurring during diazoxide treatment. Therefore, they hypothesized that stimulation of the mitoKATP channel by the specific opener, diazoxide, causes mitochondrial matrix swelling which results in ‘functional uncoupling’. The uncoupled mitochondria are then prone to generate ROS from Complex III. They postulate that this could be a common pathway linking IPC and diazoxide-mediated cardioprotection.

Forbes et al. [33] recently made similar observations to those of Carroll et al. Their studies conducted in adult rat cardiomyocytes and in the isolated, perfused rat heart showed that diazoxide significantly increased ROS generation as measured by DCFH-DA. This increase was also abrogated by 5-HD, 2-MPG and NAC. They further showed that in the perfused heart, NAC could attenuate the protective effects of diazoxide to improve the recovery of contractile function. This conclusion was the same as that of Carroll et al. [32], in that diazoxide induced ROS formation which initiated a signal which resulted in cellular protection. The major differences in these two studies relates to the use of different models and indicators for measuring ROS. Furthermore, Carroll et al. [32] demonstrated that the mitochondria swell in response to diazoxide, suggesting a possible explanation for ROS generation.

In an isolated neonatal chick myocyte model, Van den Hoek et al. [34] showed that preconditioning generated a free radical burst from the mitochondria. This burst could be attenuated by treatment with 2-MPG, an inhibitor of Cu,Zn-superoxide dismutase, or an anion channel inhibitor. This attenuation of the initial ROS burst increased cell death suggesting that free radicals induced by preconditioning are important for mediating protection. This group [35] further showed that the burst of ROS generated during hypoxic preconditioning attenuated oxidant stress at reperfusion potentially leading to protection. In the same study they showed that both the protein kinase C (PKC) inhibitor G0-6976 or 5-HD abolished the protection due to preconditioning. In addition, treatment with Go-6976 or 5-HD abrogated the attenuation of the oxidant stress produced by preconditioning at reperfusion. However, treatment with 5-HD was unable to attenuate the free radical burst initiated during preconditioning. This suggests that the mitoKATP channel is not the source of the initial generation of free radicals during preconditioning but must act as a downstream mediator of preconditioning and ROS generation. In addition, it would appear that opening of the mitoKATP channel during reperfusion results in a decrease in the generation of ROS rather than increase their production. Based on these findings, it seems unlikely that the mitoKATP channel in one instance (preconditioning episode) generates ROS, and in another (reperfusion) decreases ROS production. It seems likely that ROS are generated from a nonmitochondrial site or a source in the mitochondria distinct from the KATP channel which may subsequently facilitate opening of mitoKATP channels and lead to cardioprotection. These findings are in opposition to those of both Carroll et al. [32] and Forbes et al. [33] who suggest that it is the opening of the mitoKATP channel that is producing the oxidant flux leading to protection.

Nevertheless, the majority of pharmacological evidence suggests that opening of the mitoKATP channel is protective and that blocking this channel can attenuate the protection. Several animal studies [16,17] have shown this to be the case. In addition, numerous in vitro and in vivo studies have also shown that the KATP channel is directly involved as both a mediator and trigger of ischemic preconditioning [36].

So then what is the source of the oxidant environment that is generated by treatment with diazoxide? It seems one must consider more closely the effects of diazoxide and the selectivity it has for the mitoKATP channel. Sato et al. [37] recently investigated the pharmacological selectivity of diazoxide. In their study, they looked at flavoprotein oxidation as an indicator of mitoKATP channel activity and whole-cell currents as indicators of sarcolemmal KATP channel activity. Specific treatment with diazoxide caused a change in flavoprotein oxidation without changing whole-cell currents. This suggests that diazoxide is selective for the mitochondrial vs. the sarcolemmal KATP channel. In addition, they showed that a potassium channel opener, P-1075, is selective for the sarcolemmal channel because it increased the whole-cell current but not flavoprotein oxidation. 5-HD was shown to block the flavoprotein oxidation produced by diazoxide but not the whole-cell currents produced by P-1075, which strongly suggests that 5-HD is a selective mitoKATP channel blocker. It appears as a result of this study that both diazoxide and 5-HD have selective effects on the mitoKATP channel. However, selectivity in the sense of flavoprotein oxidation and mitoKATP channel opening does not necessarily imply a role for ROS generation in producing cardioprotection or the specific site at which the ROS are generated.

Kowaltowski et al. [38] recently showed that diazoxide possessed various activities in isolated heart mitochondria depending on the concentration used. They determined that at high concentrations of diazoxide (<50 µM) there was a non-specific effect unrelated to mitoKATP channel opening that produced a decrease in mitochondrial membrane potential and calcium uptake. This was confirmed by observing the same outcome in diazoxide-treated mitochondria in the presence of Li+ which is not transported through the mitoKATP channel. They suggested that this effect of diazoxide might be a toxic effect on mitochondria related to uncoupling and respiratory inhibition. However, at lower concentrations of diazoxide (<50 µM) the effect appears to be an increase in matrix volume that is associated with mitoKATP channel opening but no change in mitochondrial membrane potential. Taken together, these different studies suggest that the effects of diazoxide and 5-HD on the mitochondria are selective and must be interpreted carefully based on the concentrations used. It appears that mitochondrial swelling due to mitoKATP opening may be related to ROS production, but the mechanistic link to cardioprotection is still unclear.

In the study by Carroll et al. [32] the concentration of diazoxide used (30 µM) is in the range clearly selective for mito KATP channels. They observed an increase in ROS production in the presence of diazoxide although the exact mechanism by which this occurs is still unclear. Previous work [35] suggests that the activation of mitoKATP may not be the source of ROS but rather a downstream effect of ROS generation. However, in the studies of Carroll et al. [32] and Forbes et al. [33] treatment with 5-HD attenuated the generation of ROS produced by diazoxide administration. These data suggest that the mitoKATP channel may in fact be the source of the ROS. However, the non-selectivity of the fluorescent probes cannot be overlooked. Mitotracker orange is known to be a non-specific indicator of ROS in the cell. The reduced dye gets into the cytosol, where it is oxidized allowing it to permeate into the mitochondria where it becomes sequestered. This leads to some important considerations. If diazoxide is acting on the mitoKATP channel to form ROS, that would presume that the mitochondria are the source of the ROS. However, in the studies of Carroll et al. [32] there is no attempt made to positively implicate the mitochondria as the source of the diazoxide-induced ROS. It is possible that the probe is oxidized by cytosolic sources of ROS unrelated to diazoxide treatment or diazoxide may be able to generate ROS by a mechanism unrelated to the mitochondria which causes the probe to be oxidized and subsequently sequestered in the mitochondria.

The problem with the specificity of the ROS source could easily be addressed by considering the work of Becker et al. [39]. Use of mitochondrial electron transport chain (ETC) inhibitors or specific inhibitors of other known sources of ROS generation could be administered along with diazoxide to determine what the fluorescence of the specific probe is attributed to. This would then suggest the potential source of diazoxide-induced ROS generation and shed more light on the sequence of events as they occur in the induction of cardioprotection. Treatment with an ETC inhibitor and diazoxide, when there is no limit to the oxygen concentration, may give a false negative since ETC inhibition would generate ROS. However, during preconditioning it appears that mitochondrial complex III is the source of ROS since the ROS signal is abolished by myxothiazol [39].

Along similar lines of thinking, it appears that basic and essential controls that could easily validate if in fact mitotracker orange is picking up ROS generation are lacking. Namely, it is essential to use a positive control in which a known source of ROS such as hydrogen peroxide is added to the system to determine that the probe is behaving as it should. Furthermore, it would be important to conduct studies on isolated mitochondria. If diazoxide were to generate free radicals in isolated mitochondria, this would suggest that opening of the mitoKATP channel produced by diazoxide generates free radicals. In an isolated system other cellular sites of diazoxide action would be eliminated, although an interaction of diazoxide with mitochondrial components other than the mitoKATP (i.e. ETC) could not be completely ruled out.

The nature of the effects of diazoxide and 5-HD on the mitochondria in terms of bioenergetics and volume vary [38,40]. It appears that an investigation of the exact role of these parameters will be the key to determining the link between ROS and mitoKATP channels in terms of cardioprotection.

As for the nature of ROS and their potential place in the signaling scheme leading to cardioprotection, much still remains a mystery. Recently, our laboratory [41] has shown in an intact, open-chested rat model of myocardial infarction that an opioid can produce a potent delayed cardioprotective effect. This effect is mediated by an early burst of free radicals since administration of 2-MPG at the same time as the opioid completely blocked the delayed protective effect 24 h later. Pretreatment with the opioid and acute treatment with 2-MPG before ischemia did nothing to the delayed protective effect. These observations suggest that something other than the mitoKATP channel, namely opioids, which have been shown in the past to induce cardioprotection in a KATP channel dependent fashion can generate ROS. It appears that at least in the delayed setting the free radicals come first with the mitoKATP channel being a potential downstream effector of protection. It is quite possible that diazoxide at lower concentrations has both specific (mitoKATP opening) and non-specific (ROS generation) effects. It is possible that an extramitochondrial source of ROS generation by diazoxide exists whose downstream effect is to prime mitoKATP channel opening beyond that of diazoxide alone creating a positive feedback loop that leads to protection. So it would seem in diazoxide-mediated cardioprotection that both ROS and mitoKATP channels are equivalent in the signaling scheme or that ROS, as shown in our opioid-treated rat model, come first in the signaling scheme.

Future studies must address more carefully the nature of the oxidant source in terms of diazoxide treatment. It appears, based on the observations of the current study and that of Forbes et al. [33], that opening the mitoKATP channel is generating ROS and closing it attenuates ROS generation. The question is how this is related to the generation of the ROS. It would be ideal to also identify the nature of the ROS, whether it be superoxide, hydroxyl, or even a reactive nitrogen species. This may shed light on the mechanism by which the channels generate ROS which results in cardioprotection. In addition, it is imperative that we step beyond the ROS and the mitoKATP issue. It appears that these two triggers or mediators are putting into place very potent signals that lead to cardioprotection. In the future, we must consider how this relates to a more detailed mechanism of cardioprotection that may become useful in the prevention or treatment of various acute or chronic coronary syndromes.


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