Pancreatic response to crystalloid resuscitation in experimental pancreatitis.

Restoration and maintenance of intravascular volume is crucial in acute pancreatitis to prevent hypotension and ensure normal organ perfusion. This study evaluated the hemodynamic and metabolic effects of adequate versus inadequate fluid replacement on the pancreas in a canine model of acute experimental pancreatitis. Bile-trypsin pancreatitis (BTP) was induced in 14 conditioned mongrel dogs. Lactated Ringer's solution was administered intravenously at high (HIR) and low (LIR) infusion rates (6.5 and 1.75 ml/kg/hr, respectively) to 7 dogs each for 4 h. Seven sham-operated controls (CON) received lactated Ringer's at 6.5 ml/kg/hr for 3 hr. Mean arterial pressure remained unchanged in all groups. Central venous pressure decreased in the LIR group (P less than 0.05) and remained unchanged in the other groups. Cardiac index fell uniformly (P less than 0.05) in all groups. Pancreatic blood flow (Qp) decreased in the LIR group (73%) to a significantly greater extent than in the HIR (23%) and CON (8%) groups, and in the HIR group significantly more than in the CON group. The fall in pancreatic oxygen consumption (O2Cp) in both the pancreatitis groups was significant compared to the rise in the CON group. Final changes in Qp and O2Cp from baseline were significant only in the LIR group. We conclude that inadequate crystalloid replacement after BTP results in a progressive fall in Qp and O2Cp. Vigorous fluid replacement incompletely prevents these effects.

Efficacy of pharmacologic glucagon in acute experimental pancreatitis.

Microcirculatory derangements in the pancreas associated with acute pancreatitis may contribute to a low-flow state and lead to pancreatic necrosis. This study investigated the effects of glucagon, a selective mesenteric arterial dilator, on pancreatic ischemia in canine bile-trypsin-induced pancreatitis (BTP). Measurements of cardiac Index (CI), total pancreatic blood flow (QP), pancreatic oxygen consumption (O2CP), and pancreatic arteriovenous shunt flow (QAVS) were obtained prior to and after inducing BTP. Bile-trypsin-induced pancreatitis was induced in 18 dogs. Nine received lactated Ringer's solution alone (LRPAN) at 6.5 mL/kg/hr, nine received lactated Ringer's solution plus continuous Intravenous (IV) glucagon hydrochloride (GLUPAN) at 1.0 micrograms/kg/min, and nine undergoing periportal dissection without BTP received IV glucagon (GLUCON). Following BTP, CI, QP, and O2CP decreased significantly and QAVS remained unchanged in crystalloid-treated animals (LRPAN). Glucagon administration (GLUPAN) transiently increased CI and QP but failed to improve O2CP and did not change QAVS. The decrease in O2CP observed after BTP in association with a constant QAVS suggests a metabolic block to oxygen uptake at the cellular level. Glucagon in pharmacologic doses does not reverse abnormalities in O2CP and is therefore of questionable physiologic benefit in the treatment of acute pancreatitis.

Identification of 2-tetradecylglycidyl coenzyme A as the active form of methyl 2-tetradecylglycidate (methyl palmoxirate) and its characterization as an irreversible, active site-directed inhibitor of carnitine palmitoyltransferase A in isolated rat liver mitochondria.

Methyl-2-tetradecylglycidic acid (MeTDGA) has been hypothesized to inhibit fatty acid oxidation by irreversible, active site-directed inactivation of carnitine palmitoyltransferase A after being converted to TDGA-CoA. Using synthetic TDGA-CoA, this hypothesis has been confirmed. Assessing enzyme inhibition in an isolated rat liver mitochondrial system, TDGA-CoA (synthetic or enzyme prepared) was more potent than TDGA or MeTDGA and retained activity in the absence of CoA or Mg2+-ATP. It inhibited palmitoyl-CoA but not palmitoyl carnitine oxidation. Enzyme inactivation was exponential, stereospecific, and fast (t0.5 = 38.5 s with 100 nM (R)-TDGA-CoA). TDGA-CoA was identified as a complexing type irreversible inhibitor (Ki approximately 0.27 microM) by the double reciprocal relationship between the pseudo-first order inactivation rate and its concentration, by the inverse dependence of the second order rate constant on its concentration, and by the independence of the first order rate from the enzyme concentration. Palmitoyl-CoA, CoA, and malonyl-CoA protected the enzyme, while L-carnitine and palmitoyl-L-carnitine were without effect. [3-14C] TDGA-CoA labeled a protein, Mr = 90,000, with a time course which paralleled that of enzyme inhibition; maximum specific binding was 16 pmol/mg of mitochondrial protein.

Low molecular weight dextran in experimental pancreatitis: effects on pancreatic microcirculation.

UNLABELLED: Although low molecular weight (LMW) dextran has been said to decrease the lethality of experimental acute pancreatitis (AP) by reversing stasis in the pancreatic microcirculation, the actual mechanism(s) of action is unknown. This investigation was designed to measure the effects of low molecular weight dextran on pancreatic capillary flow (QCAP) and arteriovenous shunt flow (QAVS), and on pancreatic oxygen consumption (O2CP) following bile-trypsin-induced AP in dogs. Total pancreatic blood flow (QT) was measured with an electromagnetic flow probe on the superior pancreaticoduodenal artery (SPDA). QAVS was measured by liver trapping of 99mTc-albumin microspheres after SPDA injection. QCAP was calculated as QT minus QAVS. Seventeen dogs were treated with lactated Ringer's (LR) solution at 6.5 ml/kg/hr; 10 dogs were treated with LMW dextran 10% in normal saline at 1.5 ml/kg/hr plus LR at 5.0 ml/kg/hr. Mean arterial and central venous pressures remained constant throughout the 4-hr experiment. In the dogs receiving LR only, QT decreased from 42.7 to 24.4 ml/min (P less than 0.001); QAVS remained constant at 1.35 +/- 0.04 ml/min. During the first 30 min O2CP decreased from 1.17 to 0.76 ml O2/min (P less than 0.05) and remained constant thereafter. LMW dextran treatment altered none of these hemodynamic or metabolic parameters significantly. CONCLUSIONS: bile trypsin AP in the dog causes significant decreases in QT and QCAP without altering QAVS. The decrease in O2CP in association with a constant QAVS suggests a metabolic block to oxygen uptake at the cellular level. Continuous infusion of LMW dextran at a dose of 1.5 ml/kg/hr in the dog does not reverse these abnormalities.