Sabiporide improves cardiovascular function, decreases the inflammatory response and reduces mortality in acute metabolic acidosis in pigs - PubMed (original) (raw)

Sabiporide improves cardiovascular function, decreases the inflammatory response and reduces mortality in acute metabolic acidosis in pigs

Dongmei Wu et al. PLoS One. 2013.

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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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Details of the experimental protocol are shown.

Anesthetized pigs were subjected to hypovolemia (30 ml/kg) for 30 minutes. The animals then received a bolus infusion of NHE1 inhibitor (3 mg/kg, sabiporide) or vehicle, followed by lactic acid infusion for 2 hours. The animals were continuously monitored for additional 3 hours.

Figure 2

Figure 2. Survival of animals.

Three of the eight control animals died either during infusion of lactic acid or after its discontinuation. By contrast, all six animals given sabiporide survived. *P = 0.0002 vs. the control group by chi square analysis for trend. BL: at baseline; H30: at 30 min of hemorrhage; T30 min, –T300 min: at 30 min, –and 300 min from lactic acid infusion.

Figure 3

Figure 3. Changes in pulmonary arterial pressure and pulmonary vascular resistance.

Pulmonary arterial pressure and vascular resistance rose in controls with lactic acid infusions and remained elevated throughout the study. The increase in both parameters was blunted with sabiporide. All values are the mean ± SD. N = 5–6. *p<0.05 vs. the control group; #p<0.05 vs. the baseline value.

Figure 4

Figure 4. Changes in mixed-venous blood oxygen saturation, oxygen delivery, oxygen extraction ratio and mixed-venous blood oxygenated hemoglobin/total Hb ratio (FO2Hb) ratio.

NHE1 inhibition with sabiporide prevented excessive fall in mixed-venous blood oxygen saturation following hypovolemia and lactic acidosis, and improved mixed-venous blood oxygen binding capacity of hemoglobin, resulting in improved oxygen delivery and decreased oxygen extraction ratio, suggesting improved tissue oxygenation. All values are the mean ± SD. N = 5–6. *p<0.05 vs. the control group; #p<0.05 vs. the baseline value.

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