Role of L-arginine-nitric oxide pathway in myocardial reoxygenation injury.

In view of the recent findings that NO reacts with superoxide anion to generate hydroxyl radical, the present study was conducted to ascertain the role of endogenous NO in mediating myocardial reoxygenation injury in the hypoxic piglet on cardiopulmonary bypass. Anesthetized piglets were made hypoxic (PaO2 = 20-30 mmHg) for up to 120 min, followed by reoxygenation on cardiopulmonary bypass for 30 min. Reoxygenation caused rapidly developing myocardial injury characterized by decreased contractility (expressed as end-systolic elastance) and increased lipid peroxidation (measured as conjugated dienes). Systemic venous and coronary sinus blood content of NO decreased significantly during hypoxia and increased substantially above prehypoxic levels during reoxygenation on cardiopulmonary bypass. Administration of either the antioxidants mercaptopropionyl glycine and catalase or the NO synthase inhibitor, NG-nitro-L-arginine methyl ester, to the extracorporeal circuit afforded similar and nearly complete protection against myocardial reoxygenation injury. The protective effects of NG-nitro-L-arginine methyl ester were nullified by adding an excess of L-arginine to the pump circuit, suggesting that the L-arginine-NO pathway is involved in myocardial reoxygenation injury.

Effective hepatic blood flow during cardiopulmonary bypass.

Hepatic dysfunction following cardiopulmonary bypass (CPB) is a relatively frequent finding, and jaundice occurring after CPB is associated with an increased mortality rate. Post-CPB jaundice may be a consequence of inadequate liver perfusion during CPB. To evaluate the potential impact of CPB on effective hepatic blood flow, 10 patients undergoing CPB for cardiac procedures were studied. Effective hepatic blood flow was measured in each patient during the operative procedure but before institution of CPB and during CPB as well. Effective hepatic blood flow was measured by the galactose clearance technique. Blood lactate and pyruvate levels were also measured before and during CPB. During CPB, effective hepatic blood flow was consistently reduced by an average of 19%. Although for most patients this reduction seems well tolerated, in a minority of patients it may contribute to postoperative hepatic dysfunction.

Alterations in renal perfusion and renal energy charge in murine peritonitis.

Whether acute renal failure following overwhelming bacterial septicemia is a initially a consequence primarily of a cytotoxic insult or a perfusion insufficiency remains unclear. To assess the effects of intra-abdominal sepsis on the distribution of renal blood flow and renal cell bioenergy status, the glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and energy-charge ratios were measured in rats following cecal ligation/puncture (CLP) or sham laparotomies. The CLP animals demonstrated a decrease in ERPF of 42% and 58% from sham groups at ten and 20 hours, respectively. The GFR showed similar but more severe impairments of 53% and 71% at ten and 20 hours, respectively, following insult despite moderate increases in cardiac output. The disproportionate decrease in GFR over ERPF supports the hypothesis of a corticomedullary redistribution of renal blood flow in sepsis. Renal energy charge, unchanged at ten hours, decreased significantly at 20 hours. Diminished renal perfusion and the redistribution of renal blood flow precedes and may contribute to the renal cell bioenergy derangements in septic acute renal failure.

Effective hepatic blood flow and hepatic bioenergy status in murine peritonitis.

To assess the effects of sepsis on effective hepatic blood flow (EHBF) and hepatic tissue bioenergy status 250-350 g rats underwent either sham laparotomy or cecal ligation and perforation (CLP). At 5-, 10-, and 20-hr intervals cardiac output (CO), EHBF, and tissue adenine nucleotide levels were measured. CLP rats showed a hyperdynamic response to sepsis at 20 hr, with CO increased by 25% over sham rats. At all time intervals studied EHBF was decreased and at 20 hr it was maximally decreased by 35%. Hepatic energy charge (HEC) was calculated from tissue adenine nucleotide measurements. HEC was not statistically different in sham and CLP rats at 5 hr and was 11 and 9% reduced from sham levels in CLP rats at 10 and 20 hr, respectively. Thus, EHBF is decreased very early in sepsis; before any changes in hepatic bioenergy status are noted. In this hyperdynamic model of sepsis EHBF is decreased early and decreases progressively with time which may contribute to the significant decrease in HEC that is demonstrated.

Effective renal blood flow and renal energy charge in murine peritonitis.

The temporal sequence of physiological derangements preceding acute renal failure (ARF) observed in overwhelming bacterial septicemia remains controversial. In order to examine the relationship of renal circulatory alterations and cellular dysfunction in murine sepsis, effective renal plasma flow (ERPF), renal tissue metabolites, and energy charge ratios were determined in Sprague-Dawley rats at 10 and 20 hours following induction of peritonitis by cecal ligation and perforation (CLP) or cecal manipulation alone (sham). Tissue levels of adenine nucleotides, lactate, and pyruvate were assayed after freeze-clamping kidneys unilaterally followed by enzymatic determinations. Cardiac outputs were determined by thermodilution and ERPF by p-aminohippuric acid (PAH) clearance. Results indicate in this model, despite an increase in cardiac output (P less than 0.05), ERPF was significantly decreased at both 10 hours (P less than; 0.05) and 20 hours (P less than 0.01) following induction of peritonitis. Further, although tissue pyruvate/lactate ratios showed significant decreases by 10 hours (P less than 0.05), diminished energy charge ratios were not observed until 20 hours following septic insult. These findings support the hypothesis of diminished renal perfusion as contributory and antecedent to cellular dysfunction in septicemic ARF.

Effective organ blood flow and bioenergy status in murine peritonitis.

Whether organ dysfunction frequently encountered in overwhelming bacterial sepsis is a result of a direct cellular "toxic" effect or diminished cellular perfusion remains controversial. To assess the effects of peritonitis on cellular energy status and visceral blood flow, peritonitis was induced in rats by means of cecal ligation and perforation. Five, 10, or 20 hours after cecal ligation and perforation, cardiac outputs were determined by thermodilution, effective hepatic blood flow was determined by low-dose galactose clearance, and effective renal plasma flow was determined by paraminohippuric acid clearance. In similar groups of rats with peritonitis or sham controls, tissue samples of liver, kidney, and skeletal muscle were obtained by freeze-clamp technique for analysis of adenine nucleotides, energy charge, pyruvate, lactate, and pyruvate/lactate ratios (P/L). Despite an increase in cardiac output (p less than 0.05), results indicated in this model that effective hepatic blood flow and effective renal plasma flow were significantly reduced (p less than 0.05). The energy charge and P/L ratios of hepatic (p less than 0.01) and renal (p less than 0.05) tissues were also decreased. In contrast, skeletal muscle energy charge and P/L ratio were unchanged by 20 hours duration. These data support the hypothesis of diminished visceral perfusion as contributory to the cellular dysfunction observed in sepsis. Skeletal muscle appears either nonischemic or more tolerant of ischemia in sepsis.