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Cardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive
- Source :
- JTCVS Open. 8:338-354
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
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.
- Subjects :
- EDP, end-diastolic pressure
DZX, diazoxide
Ischemia
ischemia
basic science
Pharmacology
Nitric oxide
Contractility
chemistry.chemical_compound
ROS, reactive oxygen species
preconditioning
KATP, adenosine triphosphate–sensitive potassium
Diazoxide
medicine
Myocyte
LV, left ventricular
Cardioprotection
NO, nitric oxide
business.industry
ion channels
medicine.disease
Adenosine
chemistry
MitoSNO, mitochondrial-selective S–nitrosating agent
SDH, succinate dehydrogenase
KHB, Krebs–Henseleit buffer
Potassium channel opener
CPG, cardioplegia
SUR, sulfonylurea
business
LVDP, left ventricular developed pressure
medicine.drug
Subjects
Details
- ISSN :
- 26662736
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- JTCVS Open
- Accession number :
- edsair.doi.dedup.....724f4c8391ce086c6d263714423a312d