ceruletide and Hypotension

The protective effects of human urinary trypsin inhibitor against pancreatic injuries in multifactor-related experimental model of acute pancreatitis were evaluated.. Experimental study.. Acute pancreatitis was induced by short-termed (1-hour) pancreatico-biliary duct obstruction with cerulein stimulation (30 minutes; 0.2 microgram/kg per hour) and systemic hypotension (30 minutes; 30% reduction of mean arterial pressure) in rats. In this model, the protective effects of UTI against pancreatic injuries were evaluated at a dose of 10,000 U/kg per hour.. In this model, significant increases in portal serum amylase, cathepsin B and malate dehydrogenase levels were observed as compared with the control rats. The redistribution of cathepsin B from the lysosomal to the zymogen fraction and activation of trypsinogen were also observed. Moreover, the increased lysosomal and mitochondrial fragility as well as impaired pancreatic adenylate energy metabolism were noted. The therapeutic administration of human urinary trypsin inhibitor had significant protective effects against these pancreatic injuries. Furthermore, the combined prophylactic and therapeutic administration of human urinary trypsin inhibitor had more significant protective effects than only therapeutic treatment.. These results suggest the importance of timing and of selecting a pertinent protease inhibitor, such as urinary trypsin inhibitor, in the treatment of pancreatitis.

Topics: Acute Disease; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Amylases; Animals; Cathepsin B; Ceruletide; Cholestasis; Disease Models, Animal; Drug Evaluation, Preclinical; Glycoproteins; Hypotension; Infusions, Intravenous; Malate Dehydrogenase; Male; Pancreatitis; Rats; Rats, Wistar; Trypsin; Trypsin Inhibitors

The effects of short-termed (2 hours) obstruction of pancreatico-biliary duct (PBDO) and exocrine stimulation (IDH) by caerulein infusion (0.2 microgram/kg.hr) with systemic hypotension (SH) (30% reduction of mean arterial pressure for 30 min) on the exocrine pancreas were evaluated in the rat. PBDO and IDH with SH caused more significant rises in portal serum amylase, cathepsin B and malate dehydrogenase levels, and pancreatic water content as well as more significant redistribution of cathepsin B activity from the lysosomal fraction to the zymogen fraction in the subcellular fractionations than only PBDO, or PBDO with IDH, or PBDO with SH group. In addition, more accelerated lysosomal and mitochondrial fragility were observed in the PBDO and IDH with SH group. Moreover, PBDO and IDH with SH caused an activation of larger amount of trypsinogen in the pancreas compared with other groups (PBDO with IDH and PBDO with SH group). These results indicate that present model of short-termed PBDO and exocrine stimulation with systemic hypotension seems to be pertinent model for gallstone pancreatitis in humans, and that redistribution of lysosomal enzymes and subcellular organellar fragility seem to play an important role in the pathogenesis of pancreatic injuries by PBDO, particularly with exocrine stimulation and pancreatic ischaemia, probably via activation of trypsinogen to trypsin by lysosomal enzyme such as cathepsin B.

Topics: Animals; Bile Ducts; Ceruletide; Cholelithiasis; Disease Models, Animal; Hypotension; Male; Pancreas; Pancreatic Ducts; Pancreatitis; Rats; Rats, Wistar

Alpha-adrenergic drugs commonly are used to treat hypotension resulting from severe acute pancreatitis. It was shown previously that although systemic arterial pressure is increased by phenylephrine, pancreatic microcirculatory perfusion is decreased. Because inadequate tissue perfusion may be critical in the progression of edematous pancreatitis to parenchymal necrosis, it was hypothesized that vasoconstrictors might be harmful in pancreatitis. Therefore the effect of phenylephrine on cerulein-induced mild pancreatitis were studied. Sprague-Dawley rats (n = 54) were randomly allocated to 6 experimental groups and subjected to the following infusion regimens: (1) cerulein (cae) + phenylephrine (phe), (2) cae + saline (NS), (3) NS + phe, (4) cae + phenoxybenzamine (pbz) + phe, (5) NS + pbz + phe, and (6) NS. Initial and terminal hematocrit, serum amylase activity, and blood ionized calcium concentration were determined. The animals were killed 9 hours after starting the infusion. Macroscopic and histologic changes were scored by a 'blinded' pathologist. Phenylephrine increased the severity of cerulein-induced pancreatitis as manifested by statistically significant adverse changes in serum amylase, hematocrit, ionized calcium, peripancreatitic soap formation, and acinar cell vacuolization. These changes were antagonized by alpha-adrenergic receptor blockade with phenoxybenzamine. It is concluded that phenylephrine is deleterious in acute experimental pancreatitis, the first demonstration of such an effect by a pharmacologic vasoconstrictor, and suggested that microcirculatory changes may be important in the transition of mild to severe pancreatitis. Caution in the use of vasoconstrictor drugs in patients with acute pancreatitis is recommended.

Topics: Acute Disease; Amylases; Animals; Calcium; Ceruletide; Fat Necrosis; Hematocrit; Hemodynamics; Hypotension; Male; Pancreas; Pancreatitis; Phenylephrine; Random Allocation; Rats; Rats, Inbred Strains; Regional Blood Flow