icatibant and Necrosis

Acute pancreatitis is characterized by two different courses of the disease, edematous and hemorrhagic-necrotizing pancreatitis. The pathogenesis and causes for the progression of pancreatitis are unknown. Ischemia/reperfusion with formation of oxygen free radicals, activation of leukocytes and consecutive failure of the microcirculation has gained attention as a causative factor. Furthermore, the degree of microcirculatory injury correlates with the severity of pancreatitis. The aim of the study was to investigate the influence of long term reperfusion after ischemia of the pancreas for 2 hours on morphological changes and enzyme release of the pancreas in rats. Since the characteristic features of postischemic pancreatic reperfusion injury are kinin-mediated we employed the bradykinin B2-receptor antagonist HOE 140 to inhibit the progression of postischemic changes of the pancreas.. Under ether anesthesia Sprague-Dawley rats (n = 28) were laparotomized, the 4 supplying arteries of the pancreas were isolated (gastroduodenal artery, left gastric artery, splenic artery and caudal pancreaticoduodenal artery) and occluded with microvascular clips for 2 hours. At the end of ischemia the abdomen was closed and the animals were allowed to awake. 15 minutes before end of ischemia an osmotic minipump filled with NaCl (ischemia group NaCl), phosphate buffer (ischemia group phosphate buffer) or HOE 140 dissolved in phosphate buffer (ischemia group HOE 140) was placed intraperitoneally. Control animals underwent sham operation without vessel occlusion; the osmotic minipump was filled with 0.9 % NaCl. Five days after ischemia the animals were sacrificed for histology. Amylase concentration and peripheral leukocyte count were determined at baseline and daily after operation.. After ischemia of 2 hours during reperfusion of 5 days all 14 animals developed histopathological changes as seen in hemorrhagic-necrotizing pancreatitis with a mortality rate of 50 %. These morphological changes were associated with a significant increase (p < 0.05) of pancreas amylase concentration from 1850 +/- 149 U/L before ischemia to a maximum of 3934 +/- 435 U/L at 1st postoperative day and decreased to 1518 +/- 399 U/L at 4th postoperative day. Leukocyte count increased significantly (p < 0.05) from 10 x 10(12)/L to 31 x 10(12)/L. In control animals as well as in animals receiving HOE 140, morphological and enzyme changes typical for acute pancreatitis were absent, leukocyte count increased only slightly.. Ischemia of the pancreas of 2 hours with ensuing reperfusion of 5 days induces morphological and biochemical changes as observed in hemorrhagic-necrotizing pancreatitis. Organ dysfunction after ischemia/ reperfusion can be effectively inhibited by administration of the bradykinin-antagonist HOE 140.

Topics: Amylases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Free Radicals; Ischemia; Leukocyte Count; Necrosis; Pancreas; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury

One of the vasoactive peptides that has been implicated in the progression from edematous to necrotizing pancreatitis is bradykinin. We have investigated the effect of bradykinin administration and bradykinin inhibition on an edematous model of acute pancreatitis in rats (10 micrograms/kg/h of caerulein i.v.). Within six hours i.v. bradykinin reduced circulating serum amylase levels significantly but neither affected tissue edema nor morphology. A bradykinin antagonist (HOE-140), on the other hand, reduced pancreatic edema by 70% and converted edematous pancreatitis into a hemorrhagic and necrotizing variety of the disease. In further experiments we determined the time course and the minimal dosage required for the induction of this severe and non-invasive disease variety. A single dose of caerulein (40 micrograms/kg i.p.) together with a single administration of the bradykinin antagonist HOE-140 (100 micrograms/kg s.c.) consistently resulted in hemorrhagic necrosis of the pancreas within six hours. We conclude that this simple protocol allows for the non-invasive induction of a vascular model of necrotizing pancreatitis and appears ideally suited to study the development of this severe form of the disease.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Ceruletide; Disease Models, Animal; Edema; Hemorrhage; Male; Necrosis; Pancreatitis; Rats; Rats, Wistar

Little is known about the pathophysiological factors that determine the clinical severity of acute pancreatitis. Because impairment of pancreatic circulation and oxygenation is associated with greater disease severity and morphological damage in experimental pancreatitis it has been suggested that various vasoactive mediators might participate in the progression from the oedematous to the necrotising variety of the disease. This study used an animal model of acute pancreatitis induced by intravenous caeruleint (10 micrograms/kg/h for up to six hours), which does not entail either haemorrhage or significant necrosis of the pancreas. This study considered whether the administration or the inhibition of either nitric oxide, bradykinin, or adrenergic mediators can convert this mild variety into haemorrhagic and necrotising pancreatitis. Neither nitric oxide nor catecholamines were involved in the progression from oedematous to haemorrhagic pancreatitis. Their substitution, activation, and inhibition all failed to change the severity of the disease process. Bradykinin alone seemed to be critically involved in the pathogenesis of pancreatic haemorrhage and necrosis. However, the inhibition of bradykinin and not its activation or substitution increased the severity of the disease.

Topics: Acute Disease; Animals; Arginine; Bradykinin; Catecholamines; Ceruletide; Edema; Labetalol; Male; Microcirculation; Microscopy, Electron, Scanning; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroglycerin; Pancreas; Pancreatitis; Phenylephrine; Rats; Rats, Wistar

The effect of bradykinin on nitric oxide generation and eicosanoid production in the early stage of an experimental model of acute necrotizing pancreatitis induced by sodium taurocholate has been evaluated. We have compared the effect of administering a long-acting bradykinin antagonist, HOE 140, and an inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl esther L-NAME) on pancreatic prostanoid synthesis. Plasma lipase levels were increased after acute pancreatitis induction, and reduced after HOE 140 or L-NAME administration. Nitric oxide production and thromboxane B2 levels were increased after pancreatitis induction and the increases were reduced by L-NAME or HOE 140 administration. In contrast, increased prostacyclin production, reflected as 6-keto-PGF1 alpha levels, was not modified by L-NAME or HOE 140. Bradykinin seems to be involved in nitric oxide and thromboxane synthesis during the initial phases of acute necrohemorrhagic pancreatitis.

Topics: Acute Disease; Animals; Arginine; Bradykinin; Lipase; Male; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pancreas; Pancreatitis; Rats; Rats, Wistar; Taurocholic Acid; Thromboxane B2

Converting enzyme inhibitor (CEI) therapy, but not angiotensin II subtype I receptor blockade, has been shown to attenuate left ventricular remodeling in the dog after transmyocardial direct current (DC) shock. The purpose of this study was to address the importance of preservation of bradykinin to the antiremodeling effect of CEI treatment in this model.. Twenty-four hours after DC shock, adult mongrel dogs were assigned to one of three groups: a control group; a group treated with ramipril 10 mg BID; and a group treated with ramipril 10 mg BID along with a continuous subcutaneous infusion of HOE 140, a bradykinin antagonist. To assess change in left and right ventricular structure, a magnetic resonance imaging (MRI) study was performed 4 weeks after DC shock and compared with a baseline MRI study performed before DC shock. The increase in left ventricular mass (mean +/- SEM) in the control group was similar to that observed in the CEI-HOE 140 group (+0.73 +/- 0.19 versus +0.75 +/- 0.18 g/kg, P = NS), but both were greater than the change in mass in the ramipril group (-0.48 +/- 0.13 g/kg, P = .004 and P = .0005, respectively). No significant change occurred in left ventricular volume or right ventricular structure in any group. Mean arterial pressure was reduced by ramipril compared with the control group (-8 +/- 2 versus +7 +/- 2 mm Hg, P = .03), and this effect was not blunted by the addition of HOE 140 (-7 +/- 3 mm Hg).. Prevention by ramipril of the early increase in left ventricular mass in the DC shock model appears to be related to the preservation of bradykinin.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Dogs; Electric Injuries; Heart Injuries; Hemodynamics; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Myocardium; Necrosis; Ramipril; Ventricular Function, Left