Pyruvate Modulates Hepatic Mitochondrial Functions and Reduces Apoptosis Indicators during Hemorrhagic Shock in Rats
| Autor: | Paul D. Mongan, Pushpa Sharma, John Karaian, Kimberly A. Kerr-Knott, Kane T. Walsh |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Male
Pyruvate dehydrogenase kinase business.industry Apoptosis Mitochondria Liver Shock Hemorrhagic Pharmacology Mitochondrion Pyruvate dehydrogenase complex Rats Hypertonic saline Rats Sprague-Dawley chemistry.chemical_compound Anesthesiology and Pain Medicine Sodium pyruvate Biochemistry chemistry Mitochondrial matrix Pyruvic Acid Animals Medicine Liver function business Adenosine triphosphate |
| Zdroj: | Anesthesiology. 103:65-73 |
| ISSN: | 0003-3022 |
| DOI: | 10.1097/00000542-200507000-00013 |
| Popis: | Background: Dysfunctional mitochondria have been widely accepted as one of the key targets and a mediator of secondary cell injury and organ failure during hemorrhagic shock (HS). The liver is known to be the first organ to display the signs of injury during HS. This report describes experiments to determine whether modulation of hepatic mitochondrial dysfunctions by pharmacologic agents could prevent liver injury in rats subjected to HS. Methods: In this study, Sprague-Dawley rats were either treated as controls or subjected to computer-controlled arterial hemorrhage (40 mmHg) for 60 min followed by resuscitation with hypertonic saline, hypertonic -hydroxybutyrate, or hypertonic sodium pyruvate for the next 60 min before death. During the course of the experiment, animals were continuously monitored for hemodynamic and metabolic parameters. At the end of the experiment, the liver was excised and examined for oxidative injury, mitochondrial functions, expression of nitric oxide synthase, and indicators of apoptosis. Results: In comparison to hypertonic saline and hypertonic -hydroxybutyrate, pyruvate significantly protected the liver from oxidative injury, prevented the up-regulation of nitric oxide synthase, inhibited pyruvate dehydrogenase deactivation, and improved cellular energy charge and mitochondrial functions. In addition, pyruvate also reduced cleavage of poly‐ adenosine diphosphate ribose polymerase by preventing leakage of mitochondrial cytochrome c in the liver of HS animals. Conclusions: These data suggest that modulation of mitochondrial metabolic functions is likely to be one of the important mechanisms by which pyruvate exerts its protective effects on the liver during HS and resuscitation in rats. MULTIPLE organ failure in hemorrhagic shock (HS) has been commonly related to metabolic failure due to dysfunctional mitochondria. The liver is known to be the first organ to display the signs of injury during HS due to its high mitochondrial content, increased metabolic rate, lactic acid clearance, and increased production of oxygen and nitrogen species in comparison with other organs. 1–3 A relation between mitochondrial dysfunction and the irreversibility of pathologic damage in liver has been reported. 4–6 Therefore, it is logical to hypothesize that the pharmacologic agents that can reduce reactive oxygen and nitrogen species and prevent mitochondrial damage may offer a promising treatment for HS. To test our hypothesis, we examined and compared the effects of pyruvate with another pharmacologic agent, -hydroxybutyrate (-HOB), in resuscitative fluids of rats subjected to HS. The rationale for the use of pyruvate and -HOB is that they are antioxidants, decrease membrane permeability, and produce acetyl coenzyme A as the immediate substrate of the Krebs cycle to generate mitochondrial matrix reduced adenine dinucleotide for oxidative phosphorylation. 7 The uptake of -HOB by mitochondria is adenosine triphosphate (ATP) dependent, whereas pyruvate requires the activity of the mitochondrial enzyme pyruvate dehydrogenase, which is regulated by the content of its E-1 subunit. 8 However, it is not known whether pharmacologic activation of pyruvate dehydrogenase complex (PDH) and up-regulation of its E-1 subunit could be linked to the improved hepatococellular ATP, mitochondrial functions, and decreased apoptosis. In addition, the use of -HOB in the treatment of HS has not been extensively studied in HS. On the other hand, recent work from our laboratory and those of others have shown the use of pyruvate administration in restoring the cellular metabolic functions in the brain and heart and also in enhancing the survival rates during HS or ischemia by preventing the loss of ATP. 7,9 –12 Despite this, the mechanisms for these responses are not fully understood, and the role of pyruvate in restoring the mitochondrial energetic functions in one of the most important organs, the liver, is still unresolved. The use of pyruvate and -HOB as alternate adjuvants to metabolic resuscitative fluids may therefore provide a rational approach for the development of an effective metabolic therapy for HS by maintaining the hepatocellular functions. |
| Databáze: | OpenAIRE |
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