Myocardial protection by adenosine triphosphate−sensitive potassium channel opener diazoxide involves sulfonylurea receptor 2 subunit

Figures

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  Components of a diazoxide-responsive KATP channel are unknown. This study implicates SUR2.

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  Figure 1. Components of a diazoxide-responsive cardioprotective KATP channel subunit remain unknown. Wild type (WT) and SUR2 knockout hearts were used to investigate the role of SUR2 in cardioprotection by diazoxide. Unlike WT hearts, hearts lacking SUR2 did not have improved LVDP and reduced EDP in response to DZX. Figure created using BioRender. KATP, Adenosine triphosphate-sensitive potassium; SUR, sulfonylurea receptor; LVDP, left ventricular developed pressure; EDP, end-diastolic pressure; DZX, diazoxide.

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  Figure 2. Isolated mouse heart (Langendorff) model of global ischemia. Isolated mouse hearts (SUR2 knockout, or wild-type SUR2 knockout littermates) underwent Langendorff baseline perfusion with Krebs-Henseleit buffer (KHB) solution for 30 minutes followed by arrest (red arrow), and global ischemia (90 minutes) with test solution (hypothermic hyperkalemic cardioplegia ± KATP channel opener diazoxide), and then reperfusion with KHB for 30 minutes. Left ventricular pressures were recorded during baseline (at 30 minutes) and after 30 minutes (time 150) of reperfusion at identical balloon volumes (yellow symbols). Permission obtained from Elsevier, license 5994820944601 (3/23/2025). SUR, Sulfonylurea receptor; KATP, adenosine triphosphate-sensitive potassium; CPG, cardioplegia; DZX, diazoxide.

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  Figure 3. Baseline left ventricular pressures taken via intracavitary balloon at a range of balloon volumes in SUR2 (KO) and WT hearts. Isolated hearts from SUR2 KO or WT mice were cannulated and perfused with Krebs-Henseleit buffer. After 30 minutes of perfusion, baseline left ventricular pressures were measured with increasing balloon volumes. A, SUR2 KO hearts had significantly lower baseline LVDPs compared with WT. B, There was no difference in baseline EDPs between groups. ∗Simple comparisons for baseline LVDP between WT and SUR2 KO hearts were significant (P < .05) at all balloon volumes beyond zero using independent-samples t tests. SUR, Sulfonylurea receptor; KO, knockout; WT, wild type; LVDP, left ventricular developed pressure; EDP, end-diastolic pressure.

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  Figure 4. Prolonged global ischemia with hyperkalemic CPG is associated with reduced left ventricular developed pressure that is prevented by KATP channel opener diazoxide in WT but not SUR2 KO mouse hearts. Isolated mouse hearts from WT (A) or SUR2 KO (B) were subjected to 90 minutes of global ischemia after hyperkalemic cardioplegia ± DZX. Mean ± SEM change in LVDP from baseline across all LV balloon volumes after ischemia was measured and compared between groups. “ME time” is the main effect of balloon volume (regardless of group). “ME group” is the main effect of mouse type groups (collapsed across balloon volumes). “Interaction” is the interaction of balloon volume and group to indicate if the pattern of results over different balloon volumes differed by group. ∗Simple comparisons between LVDP CPG versus CPG + DZX were significant (P < .05) at balloon volumes 2.8 and 4.2 in WT using independent-samples t tests. CPG, Cardioplegia; KATP, adenosine triphosphate-sensitive potassium; WT, wild type; SUR, sulfonylurea receptor; KO, knockout; DZX, diazoxide; SEM, standard error of the mean; LVDP, left ventricular developed pressure; ME, main effect; F, analysis of variance F test statistic.

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  Figure 5. Prolonged global ischemia with hyperkalemic CPG is associated with increased EDP that is prevented by KATP channel opener diazoxide in WT but not SUR2 KO mouse hearts. Isolated mouse hearts from WT (A) or SUR2 KO (B) were subjected to 90 minutes of global ischemia after hyperkalemic CPG ± DZX. Mean ± SEM change in EDP from baseline across all balloon volumes after ischemia was measured and compared between groups. “ME time” is the main effect of balloon volume (regardless of group). “ME group” is the main effect of mouse type groups (collapsed across balloon volumes). “Interaction” is the interaction of balloon volume and group to indicate if the pattern of results over different balloon volumes differed by group. ∗Simple comparisons between EDP CPG versus CPG + DZX were significant (P < .05) at balloon volumes 4.2 and 5.6 in WT using independent-samples t tests. CPG, Cardioplegia; EDP, end-diastolic pressure; KATP, adenosine triphosphate-sensitive potassium; WT, wild type; SUR, sulfonylurea receptor; KO, knockout; DZX, diazoxide; SEM, standard error of the mean; ME, main effect; DZX, diazoxide; F, analysis of variance F test statistic.

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  Figure 6. Inline coronary flow after prolonged global ischemia in SUR2 (KO) and WT mouse hearts. Isolated hearts from SUR2 KO or WT hearts were cannulated and perfused with Krebs-Henseleit buffer at 37 °C. Hearts were then subjected to 90 minutes of global ischemia after hyperkalemic cardioplegia ± DZX. Coronary flow (mL/min ± SEM) was measured by inline probe in the column. The main effect of group from the repeated measures analysis of variance was not significant (F = 0.93, P = .435), indicating no difference in coronary flow between groups regardless of time point (baseline and during reperfusion). SUR, Sulfonylurea receptor; KO, knockout; WT, wild type; DZX, diazoxide; SEM, standard error of the mean; F, analysis of variance F test statistic.