Sabiporide Improves Cardiovascular Function, Decreases the Inflammatory Response and Reduces Mortality in Acute Metabolic Acidosis in Pigs

Dongmei Wu, Jeffrey A. Kraut, William M. Abraham

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Introduction: Acute metabolic acidosis impairs cardiovascular function and increases the mortality of critically ill patients. However, the precise mechanism(s) underlying these effects remain unclear. We hypothesized that targeting pH-regulatory protein, Na+/H+ exchanger (NHE1) could be a novel approach for the treatment of acute metabolic acidosis. The aim of the present study was to examine the impact of a novel NHE1 inhibitor, sabiporide, on cardiovascular function, blood oxygen transportation, and inflammatory response in an experimental model of metabolic acidosis produced by hemorrhage-induced hypovolemia followed by an infusion of lactic acid. Methods and Results: Anesthetized pigs were subjected to hypovolemia for 30 minutes. The animals then received a bolus infusion of sabiporide (3 mg/kg) or vehicle, followed by an infusion of lactic acid for 2 hours. The animals were continuously monitored for additional 3 hours. Hypovolemia followed by a lactic acid infusion resulted in a severe metabolic acidosis with blood pH falling to 6.8. In association with production of the acidemia, there was an excessive increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Treatment with sabiporide significantly attenuated the increase in PAP by 38% and PVR by 67%, as well as significantly improved cardiac output by 51%. Sabiporide treatment also improved mixed venous blood oxygen saturation (55% in sabiporide group vs. 28% in control group), and improved systemic blood oxygen delivery by 36%. In addition, sabiporide treatment reduced plasma levels of TNF-α (by 33%), IL-6 (by 63%), troponin-I (by 54%), ALT (by 34%), AST (by 35%), and urea (by 40%). Conclusion: These findings support the possible beneficial effects of sabiporide in the treatment of acute metabolic acidosis and could have implications for the treatment of metabolic acidosis in man.

Original languageEnglish
Article numbere53932
JournalPLoS One
Volume8
Issue number1
DOIs
StatePublished - Jan 17 2013
Externally publishedYes

Fingerprint

acidosis
Acidosis
Swine
inflammation
hypovolemic shock
swine
Mortality
Hypovolemia
lactic acid
Blood
pulmonary artery
Lactic Acid
oxygen
blood vessels
Oxygen
blood
Vascular Resistance
Pulmonary Artery
lungs
Animals

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Sabiporide Improves Cardiovascular Function, Decreases the Inflammatory Response and Reduces Mortality in Acute Metabolic Acidosis in Pigs. / Wu, Dongmei; Kraut, Jeffrey A.; Abraham, William M.

In: PLoS One, Vol. 8, No. 1, e53932, 17.01.2013.

Research output: Contribution to journalArticle

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title = "Sabiporide Improves Cardiovascular Function, Decreases the Inflammatory Response and Reduces Mortality in Acute Metabolic Acidosis in Pigs",
abstract = "Introduction: Acute metabolic acidosis impairs cardiovascular function and increases the mortality of critically ill patients. However, the precise mechanism(s) underlying these effects remain unclear. We hypothesized that targeting pH-regulatory protein, Na+/H+ exchanger (NHE1) could be a novel approach for the treatment of acute metabolic acidosis. The aim of the present study was to examine the impact of a novel NHE1 inhibitor, sabiporide, on cardiovascular function, blood oxygen transportation, and inflammatory response in an experimental model of metabolic acidosis produced by hemorrhage-induced hypovolemia followed by an infusion of lactic acid. Methods and Results: Anesthetized pigs were subjected to hypovolemia for 30 minutes. The animals then received a bolus infusion of sabiporide (3 mg/kg) or vehicle, followed by an infusion of lactic acid for 2 hours. The animals were continuously monitored for additional 3 hours. Hypovolemia followed by a lactic acid infusion resulted in a severe metabolic acidosis with blood pH falling to 6.8. In association with production of the acidemia, there was an excessive increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Treatment with sabiporide significantly attenuated the increase in PAP by 38{\%} and PVR by 67{\%}, as well as significantly improved cardiac output by 51{\%}. Sabiporide treatment also improved mixed venous blood oxygen saturation (55{\%} in sabiporide group vs. 28{\%} in control group), and improved systemic blood oxygen delivery by 36{\%}. In addition, sabiporide treatment reduced plasma levels of TNF-α (by 33{\%}), IL-6 (by 63{\%}), troponin-I (by 54{\%}), ALT (by 34{\%}), AST (by 35{\%}), and urea (by 40{\%}). Conclusion: These findings support the possible beneficial effects of sabiporide in the treatment of acute metabolic acidosis and could have implications for the treatment of metabolic acidosis in man.",
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AB - Introduction: Acute metabolic acidosis impairs cardiovascular function and increases the mortality of critically ill patients. However, the precise mechanism(s) underlying these effects remain unclear. We hypothesized that targeting pH-regulatory protein, Na+/H+ exchanger (NHE1) could be a novel approach for the treatment of acute metabolic acidosis. The aim of the present study was to examine the impact of a novel NHE1 inhibitor, sabiporide, on cardiovascular function, blood oxygen transportation, and inflammatory response in an experimental model of metabolic acidosis produced by hemorrhage-induced hypovolemia followed by an infusion of lactic acid. Methods and Results: Anesthetized pigs were subjected to hypovolemia for 30 minutes. The animals then received a bolus infusion of sabiporide (3 mg/kg) or vehicle, followed by an infusion of lactic acid for 2 hours. The animals were continuously monitored for additional 3 hours. Hypovolemia followed by a lactic acid infusion resulted in a severe metabolic acidosis with blood pH falling to 6.8. In association with production of the acidemia, there was an excessive increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Treatment with sabiporide significantly attenuated the increase in PAP by 38% and PVR by 67%, as well as significantly improved cardiac output by 51%. Sabiporide treatment also improved mixed venous blood oxygen saturation (55% in sabiporide group vs. 28% in control group), and improved systemic blood oxygen delivery by 36%. In addition, sabiporide treatment reduced plasma levels of TNF-α (by 33%), IL-6 (by 63%), troponin-I (by 54%), ALT (by 34%), AST (by 35%), and urea (by 40%). Conclusion: These findings support the possible beneficial effects of sabiporide in the treatment of acute metabolic acidosis and could have implications for the treatment of metabolic acidosis in man.

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