Dopamine in models of alcoholic acute pancreatitis.

Abstract

Acute oedematous pancreatitis and acute haemorrhagic pancreatitis were studied using the low pressure duct perfusion models of alcoholic pancreatitis in cats. After creating either form over 24 hours, each pancreas was histologically graded and assigned an inflammatory score (0-16; absent-severe (IQR 2, p<0 05 v group 1), and in group 4 it was 7 (IQR 4, p<0 05 v group 1). This was matched by significantly lower levels of urinary tripsinogen activation peptide at 24 hours. In experiment 2 (group 5) we tried to reduce microvascular permeability further by combining dopamine with antihistamines, but there was no improvement in the inflammatory score. As oedematous pancreatitis is the commoner and milder form of acute pancreatitis in clinical practice, in experiment 3 we looked at the effect ofdopamine in this model. In group 6 control cats (no treatment), the inflammatory score was 7 (IQR 3, p<0 05 v group 1). In group 7 cats given dopamine (5 ,ug/kg.min for six hours) from 12 hours after the onset of acute oedematous pancreatitis, the inflammatory score was reduced to 4 (IQR 2, p<0 05 v group 6). This was matched by a significant reduction in the 24 hour urinary tripsin activation peptide concentration. (Gut 1994; 35: 547-55 Here, in a further progression of these experiments, we analysed three more issues. In experiment 1 we examined the effect ofvarying the dose of dopamine in the original model of alcoholic AHP. In experiment 2 we investigated whether the addition of the H,/H, blockers, diphenhydramine and cimetidine, might have a synergistic effect if combined with dopamine as these latter agents would be expected to reduce microvascular permeability by an action through different receptors. In experiment 3 we investigated the effect of dopamine in the model of alcoholic AOP because in humans alcohol often leads to the milder oedematous form of acute pancreatitis. Methods THE MODELSThe models have been described in detail previously"A and are considered briefly here.Alcoholic AOP Fasted cats were anaesthetised and after drawing samples for estimating basal serum lipase and urinary tripsinogen activation peptide (TAP), a laparotomy was performed. The body of the stomach was cannulated with the tip of the cannula sited in the antrum. The main pancreatic duct was cannulated in the tail of the pancreas with plastic tubing that had previously been filled with a physiological salt solution (standard per-

Dopamine D2 receptor signalling controls inflammation in acute pancreatitis via a PP2A‐dependent Akt/NF‐κB signalling pathway

“…Previous studies showed that dopamine is an effective treatment for experimental AP, as a result of the reduction in pancreatic microvascular permeability and inflammatory cytokines (Karanjia et al ., ; ; Zhang et al ., ). However, Kaya indicated that a low dose of dopamine attenuates the lung injury but not the local pancreatic injury in 5% Na‐taurocolic acid‐induced AP in rats (Kaya et al ., ).…”

“…Taken together, these results indicate that dopamine signalling may be an endogenous inhibitor of inflammation in AP, which encouraged us to further explore the role of dopamine signalling in AP. Previous studies showed that dopamine is an effective treatment for experimental AP, as a result of the reduction in pancreatic microvascular permeability and inflammatory cytokines (Karanjia et al, 1991;1994;Zhang et al, 2007). However, Kaya indicated that a low dose of dopamine attenuates the lung injury but not the local pancreatic injury in 5% Na-taurocolic acid-induced AP in rats (Kaya et al, 2005).…”

“…Notably, the pancreas is an important source of non‐neuronal dopamine in the body, and this dopamine has an important role in protecting the pancreas and intestinal mucosa, but its role and the exact molecular mechanism involved in the pancreas is still unclear (Mezey et al, ). Previous studies showed that dopamine is an effective treatment for experimental AP, as a result of its ability to reduce pancreatic microvascular permeability (Karanjia et al, ; Karanjia et al, ). However, the role of the pancreatic dopaminergic system in the pathogenesis of AP remains unclear.…”

Towards a Novel Treatment Strategy for Acute Pancreatitis

“…It is thus of interest that dopexamine, which has this profile, is reported to reduce complication rate and mortality – when given in a dose to increase the oxygen delivery index to greater than 600 ml/min/m 2 – in a randomised clinical trial in 107 high-risk surgical patients, of whom 20 had acute pancreatitis [158]. A dose of 5 µg/kg/min of dopamine seems to be optimal for acute pancreatitis, judging by experimental studies [80, 82]: the effect of this dose on gut oxygen delivery and consumption has not been reported but the smaller dose of 2 µg/kg/min is noted to hasten gut ischaemia in a porcine model of haemorrhagic shock [159]. Finally, a non-randomised but controlled trial of dobutamine at an average dose of 7.3 µg/kg/min in 10 critically ill patients with acute pancreatitis is reported to increase systemic blood flow but not to improve splanchnic perfusion [160].…”

“…Table 2 lists measures that have been beneficial when instituted once acute pancreatitis is under way and shows that the common denominator is the control of mast cell pathology [9, 28, 29, 57, 71, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98]. Since impedance to exocytosis in the acinar cell is the detonating event and this is best explained by oxidant-induced interruption to the flow of methyl groups [1], it is logical to regard the resumption of that flow as the reason why re-feeding with methionine [73]or treatment with an analogue of ascorbate [74]– which facilitates the recycling of methyl groups from homocysteine via the folate-vitamin B 12 shuttle – ameliorate in the choline-deficient ethionine-supplemented (CDE) dietary model of severe disease.…”