Hepatic microsomal adenosine triphosphatase and mitochondrial function. Response to cold and warm ischemia.

We investigated the response of mitochondrial function and microsomal adenosine triphosphatase (ATPase) activity in rat liver tissue subjected to in vitro ischemia at either 0 degree C to 4 degrees C or 37 degrees C for 30 to 60 minutes. Mitochondrial coupling, expressed as respiratory control index, was preserved at up to 60 minutes' cold ischemia. However, respiratory control index was decreased significantly from control by 30 minutes of warm ischemia. Both microsomal magnesium-activated ATPase and sodium-potassium ATPase activity were significantly increased by 60 minutes of warm ischemia yet were unaltered by 60 minutes of ischemia at 0 degree C to 4 degrees C. Warm ischemia produces deleterious effects on energy-generating (mitochondria) and energy-utilizing (ATPase) activity. Hypothermia provides a significant prolongation of cellular viability in ischemic tissue in terms of bioenergetic status. In addition to organ procurement and transplantation, hypothermic cytoprotection may prove valuable in areas such as shock, ischemia, and other clinical conditions of compromised visceral perfusion.

Isovolemic hemodilution: correlations of mitochondrial and myocardial performance.

Subsarcolemmal (SS) and interfibrillar (IF) cardiac mitochondrial respiratory activities were examined under conditions of isovolemic hemodilution in rats. Experimental animals (mean Hct, 21%) had significantly higher cardiac indices than controls (mean Hct, 41.5%) 18 hours following isovolemic hemodilution with 0.9% NaCl. A 40% increase in cardiac output was associated with a significant increase in the respiratory control index (RCI) of the IF mitochondria. This increase in IF RCI occurred as a result of a significant decline in the ADP-independent (State 4) respiratory rate. These data demonstrate the ability of cardiac mitochondria to respond to increased myocardial demand by increasing mitochondrial efficiency and support the concept of subspecialized populations of mitochondria within the myocardial cell.

Alterations of hepatic mitochondrial function in a model of peritonitis in immature rats.

Severe intra-abdominal infection results in significant metabolic dysfunction, multiple systems failure, and mortality. Although the course of peritonitis is particularly rapid and severe in neonates and small children, its physiologic consequences have been poorly studied in these age groups. In order to assess hepatic mitochondrial integrity in a model of fulminant peritonitis in immature animals, the following study was undertaken. Thirty-three immature Sprague-Dawley rats (21 to 28 days of age) and 32 mature rats (weight greater than 250 g) were anesthetized and laparotomies performed. The animals received either cecal ligation and gross perforation (CLP) or cecal manipulation alone (sham). Animals were killed at 2 and 4 hours and livers removed. Mitochondria were isolated by differential centrifugation. Mitochondrial respirations were studied polarographically with glutamate and succinate as substrates in the presence (state 3) and absence (state 4) of adenosine diphosphate (ADP). The Respiratory Control Index (RCI) is the ratio of state 3 to state 4 respiration and is a sensitive indicator of mitochondrial coupling. Results revealed that in mature animals, peritonitis produced a significant increase in RCI with glutamate as substrate (5.2 +/- 0.2) by 4 hours duration as compared with sham operated rats (4.3 +/- 0.1, P less than 0.01). Succinate as substrate revealed no significant alteration in mitochondrial coupling in mature rat hepatic mitochondria in animals subjected to peritonitis. By contrast, peritonitis in immature animals produced a significantly decreased RCI (3.6 +/- 0.2) with glutamate as substrate as compared with sham operated animals (4.8 +/- 0.2, P less than 0.01) by two hours duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitochondrial and myocardial performance. Response to ischemia and reperfusion.

The relationships between cardiac bioenergy metabolism and myocardial function were examined in a model of global myocardial ischemia and reperfusion. The respiratory activity of distinct populations of subsarcolemmal and interfibrillar mitochondria was correlated with max dP/dt (an index of myocardial contractility with respect to time). Max dP/dt was significantly reduced to 27% of the preischemic value following two hours of cardioplegia-protected, warm, global, ischemia in dogs during the cardiopulmonary bypass period. Reperfusion resulted in improved myocardial function such that by 60 minutes of reperfusion, max dP/dt returned to baseline. Significant declines in both state 3 respiratory rates and respiratory control indexes for subsarcolemmal and interfibrillar mitochondria were noted following the ischemic interval. Mitochondrial function similarly returned to baseline values following 60 minutes of reperfusion. These data demonstrate a close association between mitochondrial and myocardial activity.

Subpopulations of skeletal muscle mitochondria: response to ischemia.

The respiratory activity of distinct populations of subsarcolemmal (SS) and interfibrillar (IF) skeletal muscle mitochondria was studied in rat hindlimb muscle subjected to 30 min of global ischemia at 37 C. State 3 (ADP-dependent) and state 4 (ADP-independent) rates of respiration were determined polarographically using glutamate as the substrate, in order to calculate the respiratory control index (RCI). The RCI is the ratio of state 3 to state 4 respirations and is a sensitive indicator of mitochondrial coupling. An approximately 20 per cent decline in RCI was noted in the SS mitochondria following 30 min of warm ischemia. This decrease was a direct result of a significant decline in the state 3 respiratory rates. IF RCIs following the ischemic interval were not different from control. These data support the concept of separate populations of mitochondria within the skeletal muscle cell and demonstrate a specific injury pattern in the response to ischemia.