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Ann Thorac Surg 2006;81:1408-1416
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Diazoxide Provides Maximal K_ATP Channels Independent Protection if Present Throughout Hypoxia

Marek A. Deja, MD ^{a , _*} , Krzysztof S. Golba, MD, PhD ^b , Marcin Malinowski, MD ^a , Kazimierz Widenka, MD ^a , Jolanta Biernat, MD ^b , Dariusz Szurlej, MD, PhD ^c , Stanislaw Wo, MD, PhD ^a

^a Second Department of Cardiac Surgery, Medical University of Silesia, Katowice, Poland
^b Department of Cardiology, Medical University of Silesia, Katowice, Poland
^c Department of Anesthesiology, Medical University of Silesia, Katowice, Poland

Accepted for publication November 28, 2005.

^_* Address correspondence to Dr Deja, Second Department of Cardiac Surgery, Medical University of Silesia, Ul. Ziolowa 47, Katowice 40-635, Poland (Email: narizol{at}slam.katowice.pl).

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
BACKGROUND: It is not clear what the optimal timing of diazoxide administration for cardioprotection in human myocardium is. We aimed to establish it. We next checked whether protection depended on adenosine triphosphate (ATP)–inhibited potassium (K_ATP) channels.

METHODS: Isolated human right atrial trabeculae were subjected to 90-minute hypoxia and 120-minute reoxygenation in vitro, followed by adding 10^-4 M norepinephrine. Diazoxide (100 µM) was added (1) as a 10-minute preconditioning signal with 10-minute washout before hypoxia or (2) 10-minute pretreatment without washout before hypoxia or (3) throughout hypoxia or (4) 10 minutes before and throughout hypoxia or (5) during the first 20 minutes of reoxygenation only. In the control, no diazoxide was added. In another set of experiments, diazoxide (100 µM) was present throughout hypoxia in control, while we tried to inhibit its protective effect with glibenclamide (1, 10, 100 µM) or 5-hydroxydecanoate (100 µM).

RESULTS: The presence of diazoxide throughout hypoxia improved recovery of contractility during reoxygenation, allowed for significant response to norepinephrine at the end of reoxygenation, prevented "ischemic contracture" development, and reduced release of troponin I to tissue bath during hypoxia. Adding diazoxide 10 minutes before hypoxia conferred significantly weaker protective effects in all the above respects. We failed to show a protective effect of diazoxide used as a preconditioning signal or during reoxygenation. Neither 5-hydroxydecanoate nor glibenclamide significantly influenced protective effects of diazoxide added during hypoxia.

CONCLUSIONS: Administration of diazoxide throughout hypoxia provided maximal protective effect, suggesting that diazoxide may be an important adjunct to cardioplegic solution. The protection offered by diazoxide used during hypoxia appears independent of its influence on K_ATP channels.

	Introduction

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We have previously shown that using a relatively high concentration of diazoxide, 100 µM, may be appropriate to achieve significant myocardial protection and should be thought of as a possible supplement to cardioplegia[1]. As diazoxide is purported to open mitochondrial adenosine triphosphate (ATP)–inhibited potassium (K_ATP) channels (mK_ATP), it might be enough to use it as a signal before ischemia to trigger the state of "pharmacologic preconditioning." That would imitate ischemic preconditioning in which a short period of ischemia is followed by an obligatory short period of reperfusion necessary to induce protection. Diazoxide used this way has been shown to provide protection to human myocardium in vitro [2]. On the other hand, as mK_ATP channels are downstream the ischemic stimulus in classic preconditioning, their direct stimulation may not have to be followed by reperfusion, and administration of diazoxide immediately before ischemia should suffice. This could be achieved in surgical settings with supplementing only the first dose of cardioplegia with diazoxide.

This protocol has been shown to confer protection on top of what can be achieved with K/Mg cardioplegia in an isolated heart model [3]. The same group used diazoxide in cardioplegia at induction in pigs and suggested that avoiding diazoxide in maintenance doses of cardioplegia prevented a significant decrease in mean arterial pressure upon reperfusion[4]. Therefore, one would need firm evidence of additional benefit to administer diazoxide during ischemia. Moreover, Pomerantz and colleagues [5] suggested that exposing the myocardial tissue to diazoxide for the entire hypoxia period may actually abolish the protective effect. Last but not least, one might expect diazoxide to confer some protection even if given only during reperfusion. Diazoxide has been reported to inhibit the mitochondrial permeability transition, a fundamental event in the pathway of reperfusion–induced cell death [6].

No study has compared and decided on the optimal timing of diazoxide exposure. Should we use diazoxide for preconditioning, as a pretreatment, as an "ischemia" treatment, or shall we use it in reperfusion? The present study was designed to establish the optimal timing of diazoxide administration to achieve maximal cardioprotective effect in human myocardium in vitro.

Our results unexpectedly showed the superiority of adding diazoxide during hypoxia over its use for pharmacologic preconditioning. This finding might have suggested other than a mK_ATP-channel–dependent mode of protection. To test the hypothesis that observed protection is mK_ATP-channel independent and to check whether it depends on sarcolemmal K_ATP channel, we tried to inhibit the protection conferred by diazoxide treatment in hypoxia with both K_ATP-channel inhibitors.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment References

 
The experiments were performed on right atrial trabeculae obtained from patients undergoing elective coronary artery surgery (Table 1). Specimens acquired from diabetic patients were excluded. The Local Bioethics Committee approval for the use of human tissue was obtained and individual patient consent was waived.

The trabecula was gradually stretched to 90% of optimal tension according to the Frank-Starling relationship and left for 30 minutes of stabilization and washout (Fig 1).

View larger version (16K): [in this window] [in a new window]   Fig 1. Experimental set-up. (Ar = argon; CO2 = carbon dioxide; O2 = oxygen.)

We observed decline of muscle inotropism during reoxygenation. At the end, we used 10^-4M norepinephrine ([-]-arterenol bitartrate) to test for stunning [7]. All substances used were supplied by Sigma Chemical (St Louis, Missouri).

Contraction force was recorded continuously (Fig 2). Contractility was expressed in percent of the initial contraction force for given preparation. We compared the 10-minute recovered contraction force, the contraction force after 30, 60, and 120 minutes of reoxygenation, and that produced by adding 10^-4 M norepinephrine at the end of reoxygenation.

View larger version (23K): [in this window] [in a new window]   Fig 2. Example of the original recording of contractility from the first experiment. The drawing shows the contractility throughout the whole experiment. (Top) The control preparation. (Bottom) The preparation with diazoxide present throughout the hypoxia. Arrows point to the application time of substances. (Ar = argon; Diaz = diazoxide; min = minutes; NE = norepinephrine; O2 = oxygen.)

Experimental Protocol
Two trabeculae from one atrial appendage were always studied simultaneously, one serving as a control.

Experiment 1
In the first set of experiments, the optimal time of application of diazoxide to achieve cardioprotective effect was studied. The experimental protocol for this experiment is shown in Figure 3. In brief, diazoxide (100 µM) was added either as (1) a 10-minute signal with subsequent 10-minute washout before hypoxia (preconditioning; n = 12); (2) 10 minutes before hypoxia with no washout (pretreatment; n = 11); (3) throughout hypoxia (n = 10); (4) 10 minutes before and throughout hypoxia (n = 10); or (5) during the first 20 minutes of reoxygenation (n = 10). The control preparations were subjected to the same protocol of hypoxia-reoxygenation but the solvent dimethyl sulfoxide (DMSO) was added instead of diazoxide.

View larger version (32K): [in this window] [in a new window]   Fig 3. Experimental protocol for the first experiment. Open bars indicate 95% oxygen plus 5% carbon dioxide; shaded bars indicate 95% argon plus 5% carbon dioxide. Down arrows indicate time points of taking sample of tissue bath to measure troponin I concentration. For details see text. (min = minutes; NE = norepinephrine; Trop I = troponin I.)

View larger version (28K): [in this window] [in a new window]   Fig 4. Experimental protocol for the second experiment. Open bars indicate 95% oxygen plus 5% carbon dioxide; shaded bars indicate 95% argon plus 5% carbon dioxide. For details see text. (Glyb = glibenclamide; 5-HD = 5-hydroxydecanoate; min = minutes; NE = norepinephrine; Trop I = troponin I.)

	Results

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The recovery of contraction force at 10 minutes of reoxygenation after 90-minute hypoxia was on average 30% ± 2.7% in control. It was significantly enhanced by adding 100 µM diazoxide to the tissue bath. When diazoxide was present throughout hypoxia, the 10-minute recovery was 65% ± 4.3% (p < 0.001); and when it was added 10 minutes before and present throughout hypoxia, it reached 82% ± 10.5% (p < 0.001). Diazoxide pretreatment also conferred some protective effect with the contraction force recovery of 50% ± 8% at 10 minutes of reoxygenation (p = 0.009). Neither adding diazoxide to the tissue bath as a signal before hypoxia (with washout) nor adding it for the initial reoxygenation period improved postischemic recovery (Table 2).

View larger version (24K): [in this window] [in a new window]   Fig 5. Development of ischemic contracture. The drawing shows an increase in basal tension of atrial trabeculae, in mN/mg wet tissue mass, that occurred during 90-minute hypoxia. Bars depict mean ± SEM. (A) The abscissa labels indicate the time when 100 µM diazoxide (open bars) was present in the tissue bath. Control (solid bar) means no diazoxide was added. The p values on the drawing come from post-hoc testing. The p values in boxes are for the differences against control group. The p values above bars are given only if less than 0.1. (B) The influence of KATP channel inhibitors (hatched bars) on myocardial protection provided with 100 µM diazoxide (open bar) present throughout hypoxia is shown. (Diaz = diazoxide; Glyb = glibenclamide; 5-HD = 5-hydroxydecanoate; RM ANOVA = repeated measures analysis of variance.)

View larger version (28K): [in this window] [in a new window]   Fig 6. Relationship between ischemic contracture developed over 90-minute hypoxia and recovery of contractility at 10 minutes of reoxygenation. The data are pulled from both experiments (see text). Solid circles indicate no diazoxide added or diazoxide added in reoxygenation; triangles indicate 100 µM diazoxide added before hypoxia with or without washout; open circles indicate 100 µM diazoxide present throughout hypoxia with or without KATP channel inhibitor. The second-order polynomial regression line (solid line) with 95% confidence interval (dotted lines) is shown.

View larger version (21K): [in this window] [in a new window]   Fig 7. Troponin I release to tissue bath over 90-minute hypoxia, in ng/mg wet tissue mass. (A) The abscissa labels indicate the time when 100 µM diazoxide (open bars) was present in the tissue bath. Control (solid bar) means no diazoxide was added. The p values on the drawing come from post-hoc testing. The p values in boxes are for the differences against control group. The p values above bars are given only if less than 0.1. (B) The influence of KATP channel inhibitors (hatched bars) on myocardial protection provided with 100 µM diazoxide (open bar) present throughout hypoxia is shown. (5-HD = 5-hydroxydecanoate; Diaz = diazoxide; Glyb = glibenclamide.)

	Comment

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As mK_ATP channels act as triggers of ischemic preconditioning [6, 8], we were disappointed to see no improvement in functional recovery of atrial trabecula after pharmacologic preconditioning with diazoxide in our study. It seems contrary to other reports [2, 5, 6]. Straight comparisons with other studies are difficult to perform as models used differ. For instance, Pomerantz and associates [2, 5] use substrates-free solution for the period of hypoxia, whereas Forbes and collegues [9] and Lim and colleagues [10] create models with glucose present throughout ischemia. That might influence redox state and alter diazoxide action. Our data and those of Pomerantz and colleagues [2, 5] are based on isolated atrium, whereas the results of Forbes and associates [9] and Lim and coworkers [10] come from Langendorff preparation.

The closest to our study experiments, by Pomerantz and coworkers, in a very similar model of isolated human atrial trabeculae, uses two [5] or even three times [2] shorter hypoxia periods. Our 90-minute hypoxia might have injured the myocardium to the extent that did not allow pharmacologic preconditioning with diazoxide to show its effect. We chose this long hypoxia based on our previous study to be able to assess the amount of troponin I leakage from the myocardium [1] For the same reason, we did not replace tissue bath solution throughout hypoxia and reoxygenation, which might have resulted in stronger reoxygenation injury. When we use in our laboratory another protocol (60-minute hypoxia and repetitive tissue washout during reoxygenation), the protective effect of pharmacologic preconditioning with 100 µM diazoxide is clearly visible (data not shown). The latter protocol does not allow for measurement of troponin I release.

Leaving diazoxide in the tissue bath for the entire hypoxia period provided the strong myocardial protection. It significantly improved the recovery of contractility, allowed for significant response to 10^-4 M norepinephrine added 120 minutes after hypoxia, and attenuated troponin I release. Clearly, the protection provided by diazoxide acting in hypoxia is superior to what can be achieved by its use as pharmacologic preconditioning signal. It suggests different mechanisms are involved in those two settings. As shown by Wang and associates [11], diazoxide given before hypoxia acts through protein kinase C (PKC) whereas diazoxide used in hypoxia provides PKC-independent protection. Whereas the first involves the stimulation of mK_ATP channels acting as trigger of preconditioning, the latter suggests their role as end effectors [11].

Diazoxide added as 10-minute pretreatment afforded significant improvement in the recovery of contractility; however, this protection was inferior to that obtained with diazoxide given in hypoxia. Particularly, trabeculae failed to augment its contractility in response to 10^-4 M norepinephrine as opposed to the significant and considerable inotropic response of tissue protected with diazoxide throughout hypoxia. It shows, in our opinion, that the loss of contractile function during reoxygenation was the effect of stunning and could be overridden with inotropic stimulation when diazoxide was present throughout hypoxia, whereas the loss of contractility in other groups depended on more structural changes and could not be reversed with inotropes.

Still, the protection provided by diazoxide pretreatment is superior to that obtained with its use as a pharmacologic preconditioning signal. If diazoxide-stimulated mK_ATP channels acting as a trigger of preconditioning cascade, the observed protection should be similar in both situations. For instance, 100 µM diazoxide added 10 minutes before ischemia with or without 10-minute washout in rabbit isolated heart conferred similar decrease of infarction area [12]. We believe that the intermediate level of protection observed in our study with diazoxide pretreatment results from the action of this part of diazoxide, which managed to bind to the tissue and actually acts in hypoxia. Indeed, Ohnuma and colleagues [13] found that 100 µM diazoxide administered for 10 minutes before ischemia decreased the infarction zone in rabbit hearts independent of PKC-; thus, according to Wang and associates [11], in the effector phase of preconditioning. Similarly to our concept, Wei and associates [14] achieved superior protection with diazoxide used in cardioplegia for 5 minutes before ischemia than with its use as a preconditioning signal.

In the experiments of the McCully group [3, 15], diazoxide favorably modified infarct size and apoptosis in the area that it could apparently reach only during reperfusion, as admitted by one of the authors in the European Association for Cardiothoracic Surgery (EACTS) 15th Meeting discussion [15]. In our study, diazoxide used during reoxygenation failed to provide any visible myocardioprotective effect. It is consistent with other studies assessing the protective effect of diazoxide [12]. We think that diazoxide reaching myocardium by collateral circulation and acting during ischemia rather than in reperfusion might explain the results of McCully's group, particularly that they appeared at the border zone of the area at risk [3, 15].

The above considerations, in our opinion, might suggest that adding diazoxide to cardioplegia, rather than using it as a pretreatment or preconditioning, is the way of getting the most from its protective properties in a clinical setting. The obvious limitation of our study is that it is an in-vitro experiment with no perfusion, and thus no true ischemia and reperfusion. To stress this, we use the words "hypoxia" and "reoxygenation" throughout the manuscript even though we used substrate-free Krebs-Henseleit solution during hypoxia and replenished substrates during reoxygenation to simulate ischemia and reperfusion as closely as possible. In isolated heart in which perfusion was used, both pretreatment [16] and cardioplegia supplementation [3] were shown to be effective. Whether one has an advantage over the other requires further verification.

The level of protection assessed with infarct size reduction and left ventricular function recovery was shown to be similar irrespective of whether diazoxide was used to act on mK_ATP channel as a trigger or as an effector [11]. As our results unexpectedly showed the superiority of adding diazoxide during hypoxia over its use for pharmacologic preconditioning, we tried to assess whether the protective effect observed when adding diazoxide during hypoxia depended on opening K_ATP channels. We showed that the protection observed with adding 100 µM diazoxide to the tissue bath throughout hypoxia could neither be inhibited by 5-hydroxydecanoate, a selective mK_ATP-channel inhibitor, nor by glibenclamide, a nonselective K_ATP-channel blocker.

It seems an obvious discrepancy with what has been a generally accepted view of diazoxide providing myocardial protection through mitochondrial and possibly sarcolemmal K_ATP channels. However, Lim and colleagues [10] reported similar findings in Langendorff-perfused rat heart. The hearts were treated with 50 µM diazoxide for 10 minutes before ischemia. Because the ischemia was achieved by stopping the perfusion, diazoxide most probably remained in their model in coronary vessels for at least some period of 30-minute ischemia, just as cardioplegia would if it were infused at the induction of ischemia. Characteristically, 100 µM 5-hydroxydecaonate added 30 minutes before ischemia failed to significantly affect the improvement of left ventricular function provided by diazoxide treatment [10].

Our work provides, therefore, one more argument to the growing evidence that diazoxide may mediate some of its myocardioprotective effects through pathways other than the mK_ATP channel or the K_ATP channel in general [6, 10, 17, 18]. One of the suggested targets is succinate dehydrogenase. It has been known for many years, that diazoxide at a concentration range that overlaps with the high end of cardioprotective dose range—as used in our experiments—inhibits succinate dehydrogenase [10, 17] and therefore state-3 mitochondrial respiration. This effect is neither inhibited by 5-hydroxydecaonate nor by glibenclamide [10]. However, to draw firm conclusions on diazoxide action, a more sophisticated model going into the level of mitochondria and the exact status of K_ATP channels (open or closed) is needed. This is a deficiency of our experiment.

We showed that diazoxide used during hypoxia inhibited development of ischemic contracture. This effect was neither affected by 5-hydroxydecaonate nor by glibenclamide treatment. The significant negative correlation of the degree of contracture with recovery of contractility at 10 minutes of reoxygenation may give some additional clue to the mechanism of cardioprotection provided by diazoxide in our experiment.

Diazoxide might prevent development of contracture by an influence on calcium handling in myocytes. The increased level of cytosolic calcium or the problems with its clearance from cytoplasm in diastole may lead to impaired relaxation and increase basal tone of the atrial trabeculae in ischemia. On the other hand, if diazoxide acted this way, it would provide some protective effect when added at the beginning of reoxygenation, as reperfusion induces more calcium overload than ischemia alone.

Another possibility is that we observed the development of ischemic rigor contracture. It results from the formation of stable, low-energy, Ca²⁺-independent cross-bridges between actin and myosin as a consequence of low ATP availability [19]. The rigor contracture development was considered a signal of ATP depletion in other studies of myocardial protection [6]. Our results might therefore support the concept of diazoxide providing its protective action through influence on cell energy handling [6]. If this is the case, further studies are required.

In summary, the results of our study suggest that diazoxide is a potent cardioprotective agent, which to develop its maximal effect needs to be delivered throughout the whole hypoxia. This finding may be the key information to propose the use of diazoxide as an adjunct to cardioplegic solution, enabling the achievement of better myocardial protection during cardiac surgery. This way of using diazoxide may allow taking advantage also of its protective mechanism of action that seems to be independent of its influence on K_ATP channels.

	References

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This Article Abstract 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 Add to Personal Folders Download to citation manager Author home page(s): Marek A. Deja Kazimierz Widenka Stanislaw Wos Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deja, M. A. Articles by Wos, S. Search for Related Content PubMed PubMed Citation Articles by Deja, M. A. Articles by Wos, S. Related Collections Myocardial protection