Combined levosimendan and Sacubitril/Valsartan markedly protected the heart and kidney against cardiorenal syndrome in rat

Pei Hsun Sung, Han Tan Chai, Chih Chao Yang, John Y. Chiang, Chih Hung Chen, Yi Ling Chen, Hon Kan Yip*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

2 Scopus citations

Abstract

Background: Cardiorenal syndrome (CRS) remains the leading cause of death in hospitalized patients for all disease entities. Sacubitril/Valsartan (Sac/Val) therapy has been proved to improve prognostic outcome in patients with heart failure or chronic kidney disease. This study tested the hypothesis that combined levosimendan and Sac/Val was superior to just one therapy on protecting the heart and kidney against simultaneous heart and kidney ischemia (I) (for 50-min)-reperfusion (R) (for 7-days) (i.e., double IR) injury (defined as CRS). Methods and results: Adult-male Spraque-Dawley rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (double IR), group 3 [double IR+levosimendan (10 mg/kg by intra-peritoneum administration at 30 min/followed by days 1–5 once daily after IR procedure)], group 4 [double IR+Sac/Val (10 mg/kg, orally at 30 min/followed by days 1–5 twice daily after IR procedure)], and group 5 (double IR+Sac/Val+levosimendan). By day 7 after double-IR, the left-ventricular-ejection fraction (LVEF)/left-ventricular-fraction-shortening (LVFS) were highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but they showed no difference between groups 3/4, whereas the circulatory heart-failure (brain-natriuretic peptide)/proinflammatory (suppression of tumorigenicity-2) biomarkers, blood-urea-nitrogen/creatinine and ratio of urine protein to creatinine (all p < 0.0001) exhibited an opposite pattern of LVEF among the groups. The protein expressions of inflammatory (tumor necrosis factor-α/interleukin-1ß/matrix metalloproteinase-9)/oxidative-stress (NOX-1/NOX-2/NOX-4)/apoptotic (mitochondrial-Bax/caspase-3/poly-(ADP-ribose)-polymerase)/fibrotic (Smad3/transforming growth factor-ß)/mitochondrial-damaged (cytosolic-cytochrome-C)/myocardial-hypertrophic (ß-MHC) biomarkers in LV myocardium exhibited an opposite pattern of LVEF among the groups (all p < 0.0001). The cellular expressions of inflammatory (CD68)/DNA-damaged (γ-H2AX) biomarkers and infarct/fibrotic areas in LV myocardium and kidney displayed an opposite pattern of LVEF among the groups (all p < 0.0001). Conclusion: Combined levosimendan and Sac/Val was superior to merely one therapy on protecting the heart and kidney as well as preserving their functions against double IR injury.

Original languageEnglish
Article number112745
JournalBiomedicine and Pharmacotherapy
Volume148
DOIs
StatePublished - 04 2022

Bibliographical note

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Keywords

  • Acute heart and kidney ischemia-reperfusion injury
  • Apoptosis
  • Fibrosis
  • Inflammation
  • Levosimendan
  • Oxidative stress
  • Sacubitril/valsartan

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