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(Circulation. 2003;107:682.)
© 2003 American Heart Association, Inc.

Brief Rapid Communications

Cardioprotective Effect of Diazoxide Is Mediated by Activation of Sarcolemmal but Not Mitochondrial ATP-Sensitive Potassium Channels in Mice

Masashi Suzuki, MD; Tomoaki Saito, MS; Toshiaki Sato, MD; Masaji Tamagawa, BS; Takashi Miki, MD; Susumu Seino, MD; Haruaki Nakaya, MD

From the Department of Pharmacology (M.S., T. Saito, T. Sato, M.T., H.N.) and the Department of Cellular and Molecular Medicine (T.M., S.S.), Graduate School of Medicine, Chiba University, Chiba, Japan.

Correspondence to Haruaki Nakaya, MD, Department of Pharmacology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8670, Japan. E-mail nakaya{at}med.m.chiba-u.ac.jp

	Abstract

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Background— We recently demonstrated that the sarcolemmal ATP-sensitive potassium (sarcK_ATP) channel plays a key role in cardioprotection against ischemia/reperfusion injuries in Kir6.2-knockout (KO) mice. In the present study, we evaluated the effects of diazoxide, a mitochondrial ATP-sensitive potassium (mitoK_ATP) channel opener, on ischemia-induced myocardial stunning in sarcK_ATP channel-deficient mice.

Methods and Results— Langendorff-perfused hearts of wild-type (WT) and KO mice were subjected to global ischemia/reperfusion. Diazoxide improved the recovery of contractile function in WT hearts but not in KO hearts. Treatment with HMR1098 (a sarcK_ATP channel blocker) but not 5-hydroxydecanoate (a mitoK_ATP channel blocker) abolished the cardioprotective effect of diazoxide in WT hearts. In coronary-perfused WT ventricular muscle preparations, action potential shortening during ischemia was accelerated in the presence of diazoxide.

Conclusions— Diazoxide enhances action potential shortening during ischemia by activating sarcK_ATP channels and provides cardioprotection in mouse hearts.

Key Words: potassium • ischemia • reperfusion • ion channels

	Introduction

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ATP-sensitive potassium (K_ATP) channels play an important role in cardiovascular system. Our recent study using Kir6.2-deficient (KO) mice revealed that Kir6.2 forms the pore region of the cardiac sarcolemmal K_ATP (sarcK_ATP) channel but not that of the vascular sarcK_ATP channel.^1,2 In addition, neither Kir6.2 nor Kir6.1 seems to be a constituent of the mitochondrial K_ATP (mitoK_ATP) channel in cardiomyocytes,^2,3 as assessed by flavoprotein oxidation assay. Recently, it was postulated that activation of mitoK_ATP channels rather than sarcK_ATP channels is important in cardioprotection against ischemia/reperfusion injuries, and that diazoxide and 5-hydroxydecanoate (5-HD) are a mitoK_ATP-specific opener and blocker, respectively.^4–9 This conclusion was based on pharmacological data, however, and the molecular identity of the mitoK_ATP channel has not been established.

We recently found that ischemic preconditioning is abolished in sarcK_ATP channel-deficient mice despite intact mitoK_ATP channel function.³ It is unclear whether diazoxide can exert cardioprotective effect, however, even if the sarcK_ATP channel is negated. In the present study, we performed functional analysis of wild-type (WT) and knockout (KO) mouse hearts subjected to ischemia/reperfusion, and we show that the activity of the sarcK_ATP channel is essential for diazoxide-induced anti-stunning effect, possibly caused by the reduced cardiac excitability when they are open.

	Methods

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Kir6.2^-/- Mice
All procedures complied with National Institutes of Health standards for the care and use of animal subjects. A mouse line deficient in K_ATP channels was generated by targeted disruption of the gene coding for Kir6.2, as described previously.¹⁰ C57BL/6 mice from our laboratory were used as controls because the knockout animals had been backcrossed to a C57BL/6 strain for 5 generations.

In Vitro Functional Study Using Langendorff-Perfused Hearts
Functional study using isolated mouse hearts was performed as previously described.^1,3 Retrograde perfusion was maintained at a constant flow (3 mL/min) with modified Krebs-Henseleit solution containing (in mmol/L): NaCl 119, KCl 4.8, KH₂PO₄ 1.2, MgSO₄ 1.2, CaCl₂ 1.0, glucose 10, and NaHCO₃ 24.9, and equilibrated with 95% O₂/5% CO₂ (pH 7.4, 37°C). A balloon was inserted into the cavity of the left ventricle, and left ventricular pressure and coronary perfusion pressure (CPP) were measured continuously. After stabilization, hearts were subjected to no-flow, global ischemia (20 minutes) and reperfusion (60 minutes). Drug treatment was initiated 15 minutes before the ischemic period and continued throughout the experiments.

Action Potential Recordings in Coronary-Perfused Ventricular Preparations
The heart was isolated and perfused at a constant flow (2 mL/min) with the Tyrode solution containing (in mmol/L): NaCl 125, KCl 4, NaH₂PO₄ 1.8, MgCl₂ 0.5, CaCl₂ 2.7, glucose 5.5, and NaHCO₃ 25, and gassed with 95% O₂/5% CO₂. The right and left atria, right ventricular free wall, and septum were removed. Coronary-perfused ventricular muscle preparations stimulated at 5 Hz were subjected to no-flow global ischemia. Action potentials (APs) were recorded with conventional microelectrode. Diazoxide was applied 10 minutes before the ischemic period.

Drugs
The drugs used were 5-HD, diazoxide (Sigma), and HMR1098 (1-[5-[2-(5-chloro-o-anisamide)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea, Aventis Pharma, Tokyo, Japan). Diazoxide was dissolved in DMSO, and the final concentration of solvent was 0.01%. HMR1098 and 5-HD were dissolved in the perfusate.

Statistics
All data are presented as mean±SEM. Statistical analyses of the data were performed using Student’s t test or ANOVA. Probability values less than 0.05 were considered significant.

	Results

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There were no significant differences in baseline values of heart rate, left ventricular developed pressure (LVDP), and CPP among the 6 experimental groups: control WT (WT-CON, n=9), diazoxide (100 µmol/L)-treated WT (WT-DZ, n=7), diazoxide (100 µmol/L) plus 5-HD (500 µmol/L)-treated WT (WT-DZ+5HD, n=6), diazoxide (100 µmol/L) plus HMR1098 (30 µmol/L)-treated WT (WT-DZ+HMR, n=7), control KO (KO-CON, n=9), and diazoxide (100 µmol/L)-treated KO hearts (KO-DZ, n=7). Treatment with diazoxide significantly decreased CPP in WT (107±5 mm Hg to 73±4 mm Hg) and KO hearts (108±7 mm Hg to 70±6 mm Hg). The drug concentration used in this study was reported to activate or block mitoK_ATP or sarcK_ATP channels.⁸

During global ischemia, left ventricular developed pressure gradually declined and the left ventricular end-diastolic pressure (EDP) increased (Figure 1a). It took significantly more time for KO-CON (7.7±1.2 minutes, P<0.05) and WT-DZ+HMR hearts (8.0±2.5 minutes, P<0.05) to cease contracting during ischemia compared with WT-CON hearts (3.5±0.5 minutes). Ischemic contracture appeared more rapidly in WT-DZ+HMR (4.9±0.5 minutes, P<0.05), KO-CON (6.2±0.8 minutes, P<0.05), and KO-DZ hearts (4.2±1.1 minutes, P<0.05) than in WT-CON hearts (9.8±1.0 minutes).³ The increase in EDP at 15 minutes of ischemia was significantly greater in KO than WT hearts (Figure 1b). Diazoxide slightly attenuated the increase in EDP in WT (WT-DZ, not significant) but not KO hearts (KO-DZ). Coadministration of HMR1098 abolished the lessening effect of diazoxide on the increase in EDP in WT hearts (P<0.05), whereas addition of 5-HD to diazoxide slightly and insignificantly enhanced the increase in EDP (Figure 1b).

View larger version (36K): [in this window] [in a new window]   Figure 1. Summarized data of mechanical function of isolated hearts during ischemia/reperfusion. a, Representative left ventricular pressure changes in control WT (WT-CON), diazoxide (100 µmol/L)-treated WT (WT-DZ), diazoxide (100 µmol/L) plus 5-HD (500 µmol/L)-treated WT (WT-DZ+5HD), diazoxide (100 µmol/L) plus HMR1098 (30 µmol/L)-treated WT (WT-DZ+HMR), control KO (KO-CON), and diazoxide (100 µmol/L)-treated KO hearts (KO-DZ) are shown. Arrows with full line and those with dashed line show the time points of cessation of contraction and onset of contracture, respectively. b, Left ventricular end-diastolic pressure (EDP) at 15 minutes after ischemia and c, recovery rate of left ventricular developed pressure at 30 minutes of reperfusion are summarized. Values are expressed as mean±SEM. *P<0.05 versus WT-CON; #P<0.05 versus WT-DZ.

After reperfusion, LV contractile function recovered gradually. Treatment with diazoxide significantly improved the recovery of LV function in WT hearts (Figure 1c). However, diazoxide did not improve the recovery of LV function in KO hearts. In addition, the recovery of LV function in WT-DZ+HMR hearts was similar to that in both KO groups (KO-CON, KO-DZ). Coadministration of 5-HD (WT-DZ+5HD) did not significantly affect the diazoxide-induced protective effect (Figure 1c). These findings indicate that activation of sarcK_ATP rather than mitoK_ATP channels is necessary for diazoxide-induced cardioprotection.

To determine if diazoxide activates sarcK_ATP channels during ischemia in WT hearts, we measured APs in coronary-perfused ventricular muscle preparations. The preischemic values of AP duration at 90% repolarization (APD₉₀) and resting membrane potential in control (untreated) WT hearts (n=5) and diazoxide-treated WT hearts (n=5) were 61.4±3.7 ms and -71.6±2.4 mV and 58.0±4.4 ms and -73.7±3.4 mV, respectively. There were no significant differences between the baseline values. After induction of global ischemia, APD gradually decreased in untreated WT hearts (Figure 2a). Treatment with diazoxide significantly accelerated the action potential shortening during ischemia (Figure 2b). APD₉₀ at 2 minutes after ischemia in untreated and diazoxide-treated WT hearts were 50.4±4.1 ms and 17.2±2.5 ms, respectively (P<0.05) (Figure 2c). These findings indicate that diazoxide activates sarcK_ATP channels and enhances AP shortening during ischemia.

View larger version (16K): [in this window] [in a new window]   Figure 2. APs recorded from left ventricular free wall preparations. a and b, Effects of no-flow global ischemia on AP in control (a) and diazoxide-treated WT heart preparations (b). Typical traces of AP at preischemia (left panel) and 2 minutes after ischemia (right panel) are shown. c, Ischemia-induced changes of action potential duration at 90% repolarization (APD90) are expressed as a percentage of the value at preischemia in control WT (WT-CON, open circle; n=5) and diazoxide-treated WT heart preparations (WT-DZ, closed circle; n=5). Values are expressed as mean±SEM. *P<0.05 versus WT-CON.

	Discussion

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Diazoxide is generally thought to be a mitoK_ATP channel-specific opener in cardiomyocytes. In addition, diazoxide induces no sarcolemmal K_ATP currents using nystatin-perforated patch-clamp techniques in isolated mouse ventricular cells (Suzuki et al, unpublished observations, 2001), as has been reported also in other species.^4,8,11 Because diazoxide produces a flavoprotein oxidation that reflects similar openings of mitoK_ATP channels in ventricular cells of both WT and Kir6.2-deficient mice,³ diazoxide should have a similar mitoK_ATP channel-mediated cardioprotective effect. However, diazoxide significantly improved the recovery of left ventricular function after ischemia/reperfusion in WT but not in KO hearts in this study. These diazoxide-induced cardioprotective effects were abolished by coadministration of HMR1098 but not 5-HD, further indicating that the cardioprotective effect is mediated by sarcK_ATP channels but not mitoK_ATP channels. In addition, diazoxide shortened APD during myocardial ischemia in coronary-perfused ventricular muscle preparations of WT mice. These findings strongly suggest that in mice hearts, diazoxide activates sarcK_ATP channels and shortens the action potential duration during ischemia, thereby blunting intracellular Ca²⁺ overload.

Recently, Matsuoka et al¹² and D’hahan et al¹³ reported that diazoxide activates sarcK_ATP channels during simulated ischemia or when ADP is added in reconstituted channels (Kir6.2/SUR2A) or guinea pig ventricular myocytes, in accord with our findings. During myocardial ischemia, the intracellular ADP level might increase sufficiently to allow diazoxide to activate the sarcK_ATP channels. Because ischemia-induced action potential shortening occurred more rapidly in the presence of diazoxide (Figure 2), intracellular Ca²⁺ overload might well be lessened and the recovery of left ventricular function after reperfusion improved.

It should be noted that in our studies contractile function but not infarct size was measured, we did not give any mitoK_ATP openers other than diazoxide, and direct assessment of mitoK_ATP channel activity was not performed, although our previous study showed that mitoK_ATP channel activity, indirectly assessed by flavoprotein fluorescence measurement, was preserved.³ These facts potentially limit the interpretation of our findings. In addition, role of sarcK_ATP against ischemia/reperfusion injuries might be exaggerated in mouse relative to larger animals, as mouse is a species in which the physiological heart rate is approximately 10-fold higher than in humans. In this context, it is noteworthy that in rat, cardioprotective doses of diazoxide did not shorten APD during ischemia, and the cardioprotection by diazoxide was blocked by 5-HD but not by HMR1098.^4,7 Therefore, the findings obtained from mouse hearts cannot be directly extrapolated to clinical settings.

In conclusion, diazoxide-induced protective effect on the ischemia-induced contractile dysfunction of mouse heart is mediated by accelerated activation of sarcK_ATP channels during ischemia, suggesting that activation of sarcK_ATP channels rather than of mitoK_ATP channels is important for diazoxide-induced anti-stunning effect.

	Acknowledgments

 
This work was supported by a Scientific Research Grant and a Grant-in-Aid for Creative Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Mitsui Life Insurance Research Foundation; and K. Watanabe Research Fund. HMR1098 was kindly provided by Aventis Pharma, Tokyo, Japan. We thank Drs H. Uemura and T. Ogura for helpful discussion. We are grateful to Y. Reien and I. Sakashita for excellent technical and secretarial assistance.

Received October 8, 2002; revision received December 13, 2002; accepted December 18, 2002.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 107/5/682    most recent 01.CIR.0000055187.67365.81v1 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 Suzuki, M. Articles by Nakaya, H. Search for Related Content PubMed PubMed Citation Articles by Suzuki, M. Articles by Nakaya, H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Cardiovascular Pharmacology