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Cardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive

Published version
Peer-reviewed

Type

Article

Change log

Authors

Ahmad, T 
Wang, J 
Velez, AK 
Suarez-Pierre, A 
Clement, KC 

Abstract

Background: Myocytes exposed to stress exhibit significant swelling and reduced contractility. These consequences are ameliorated by adenosine triphosphate–sensitive potassium (KATP) channel opener diazoxide (DZX) via an unknown mechanism. KATP channel openers also provide cardioprotection in multiple animal models. Nitric oxide donors are similarly cardioprotective, and their combination with KATP activation may provide synergistic benefit. We hypothesized that mitochondria-targeted S-nitrosating agent (MitoSNO) would provide synergistic cardioprotection with DZX. Methods: Myocyte volume and contractility were compared following Tyrode's physiologic solution (20 minutes) and stress (hyperkalemic cardioplegia [CPG] ± DZX; n = 5-20 each; 20 minutes) with or without MitoSNO (n = 5-11 each) at the end of stress, followed by Tyrode's solution (20 minutes). Isolated mouse hearts received CPG ± DZX (n = 8-10 each) before global ischemia (90 minutes) with or without MitoSNO (n = 8 each) at the end of ischemia, followed by reperfusion (30 minutes). Left ventricular (LV) pressures were compared using a linear mixed model to assess the impact of treatment on the outcome, adjusting for baseline and balloon volume. Results: Stress (CPG) was associated with reduced myocyte contractility that was prevented by DZX and MitoSNO individually; however, their combination was associated with loss of cardioprotection. Similarly, DZX and MitoSNO improved LV function after prolonged ischemia compared with CPG alone, and cardioprotection was lost with their combination. Conclusions: MitoSNO and DZX provide cardioprotection that is lost with their combination, suggesting mutually exclusive mechanisms of action. The lack of a synergistic beneficial effect informs the current knowledge of the cardioprotective mechanisms of DZX and will aid planning of future clinical trials.

Description

Keywords

CPG, cardioplegia, DZX, diazoxide, EDP, end-diastolic pressure, KATP, adenosine triphosphate–sensitive potassium, KHB, Krebs–Henseleit buffer, LV, left ventricular, LVDP, left ventricular developed pressure, MitoSNO, mitochondrial-selective S–nitrosating agent, NO, nitric oxide, ROS, reactive oxygen species, SDH, succinate dehydrogenase, SUR, sulfonylurea, basic science, ion channels, ischemia, preconditioning

Journal Title

The Journal of Thoracic and Cardiovascular Surgery

Conference Name

Journal ISSN

0022-5223
2666-2736

Volume Title

8

Publisher

Elsevier
Sponsorship
MRC (MC_UU_00015/3)
Wellcome Trust (220257/Z/20/Z)
Medical Research Council (MC_UU_00015/3)