saralasin and ramiprilat

Acute pancreatitis is an inflammatory disease characterized by pancreatic tissue edema, acinar cell necrosis, hemorrhage and inflammation of the damaged gland. It is believed that acinar cell injury is initiated by the activation of digestive zymogens inside the acinar cells, leading finally to the autodigestion of the pancreas. Previous study in our laboratory demonstrated that cerulein-induced acute pancreatitis was associated with an up-regulation of local renin-angiotensin system (RAS) in rat pancreas. Therefore, the utilization of RAS inhibitors may provide a novel and alternative treatment for acute pancreatitis. By means of a rat model of cerulein-induced acute pancreatitis, results from the present study showed that an intravenous injection of saralasin, an antagonist for angiotensin II receptors, at a dose of 40 microg/kg 30 min before the induction of acute pancreatitis significantly attenuated pancreatic edema. Results from the biochemical measurements showed that pretreatment with saralasin at a dose of 20 microg/kg markedly reduced pancreatic injury, as evidenced by the decreased activities of alpha-amylase and lipase in plasma. However, the same recipe of ramiprilat, a specific inhibitor for angiotensin-converting enzyme, at a dose of 20 microg/kg did not provide any protective effect against acute pancreatitis. On the contrary, pretreatment with ramiprilat at a dose 40 microg/kg enhanced cerulein-induced pancreatic injury. Results from histopathological analysis of these RAS inhibitors further confirmed with those results as obtained from biochemical analysis. These data indicate that administration of saralasin but not ramiprilat could be protective against acute pancreatitis and that activation of pancreatic RAS in acute pancreatitis may play a role in pancreatic tissue injury.

Topics: Acute Disease; alpha-Amylases; Angiotensin Receptor Antagonists; Animals; Ceruletide; Disease Models, Animal; Edema; Injections, Intravenous; Lipase; Necrosis; Pancreatitis; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Saralasin

Local inhibition of angiotensin-converting enzyme (ACE, kininase II) produces both attenuation of angiotensin (Ang) II generation and bradykinin (BK) degradation. To delineate the participation of BK in the cardioprotective actions of ACE inhibitors, experiments were performed in rats and dogs with cardiac ischemia-reperfusion injuries. (I) In rat isolated perfused working hearts with regional myocardial ischemia, BK in concentrations as low as 1 X 10(-9) M increased coronary flow (CF) and reduced the incidence and duration of reperfusion ventricular fibrillation (VF). In addition, enzyme activities of lactate dehydrogenase (LDH) and creatine kinase as well as lactate output were decreased in the venous effluent of BK-perfused hearts, which also showed improved cardiodynamic and metabolic parameters. Even concentrations of BK lower than 1 X 10(-10) M, which were without influence on coronary flow, exerted comparable beneficial metabolic effects connected with reduced incidence and duration of VF. Combined perfusions with threshold concentrations of BK (1 X 10(-12) M) and the ACE inhibitor ramiprilat (2.58 X 10(-9) M), which were ineffective given alone, resulted in a marked cardioprotective effect. Perfusion with Ang II (1 X 10(-9) M) aggravated reperfusion arrhythmias and worsened myocardial metabolism. BK perfusion prevented this deterioration in a concentration-dependent manner, whereas the Ang II receptor antagonist saralasin was only marginally effective. The BK antagonist D-Arg-[Hyp2, Thi5,8, D-Phe7]-BK (1 X 10(-5) M) completely abolished the cardioprotective effects of BK or the ACE inhibitor. However, higher concentrations of BK (1 X 10(-7) M) or ramiprilat (2.58 X 10(-5) M) competitively reversed these properties of the BK antagonist. (II) In anesthetized dogs, BK was infused into the coronary artery in a dose of 1 ng/kg/min during occlusion (90 min) and reperfusion (30 min) of the left descending coronary artery (LAD)--a dose without effects on cardiovascular parameters. In line with the findings in isolated ischemic rat hearts, BK infusion reduced LDH activities and lactate concentrations in the coronary sinus blood, whereas myocardial tissue levels of glycogen and energy-rich phosphates were increased in the infarcted area. The cardioprotective effects produced by perfusion with BK or by reduction of BK degradation through local interference with ACE favor a role for BK in ischemia-reperfusion injuries in rats and dogs.

Topics: Anesthesia; Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Bradykinin; Coronary Circulation; Coronary Disease; Dogs; Female; Hemodynamics; In Vitro Techniques; L-Lactate Dehydrogenase; Lactates; Male; Myocardial Reperfusion Injury; Myocardium; Pyrroles; Ramipril; Rats; Rats, Inbred Strains; Saralasin

The effects of the converting enzyme inhibitors ramiprilat and enalaprilat on ischemia-induced release of noradrenaline (NA) were examined in the isolated perfused rat heart, submitted to 30 min of total flow restriction followed by 5 min of reperfusion. Ramiprilat (2.6 nM-2.6 microM) caused a concentration-dependent decrease in the efflux of NA at reperfusion. The maximal effect (about 70% reduction) was observed at a concentration of 26 nM. In contrast, enalaprilat (10 nM-10 microM) caused no reduction in NA efflux until at a high concentration (10 microM, NA efflux reduced by about 20%). Moreover, the prodrugs ramipril and enalapril (added to the perfusion medium) were without any significant effects on ischemia-induced NA release. Both the angiotensin II receptor antagonist saralasin (0.1 microM) and bradykinin (0.1 and 1 nM) caused marked reductions in ischemic NA efflux. However, when indomethacin (10 microM) was added to the perfusion medium, the effects of bradykinin (1 nM) and ramiprilat (26 nM) on NA efflux were abolished. Likewise, in the presence of angiotensin II (0.1 microM) the effect of ramiprilat was no longer evident. The magnitude of cellular injury, expressed as efflux of creatine kinase during reperfusion, was reduced by bradykinin (0.1 and 1 nM) and by ramiprilat (by about 55% at 2.6 microM). It is concluded that ramiprilat, at therapeutically relevant concentrations, attenuates the ischemia-induced mobilization of NA via a reduction in local angiotensin II production and/or bradykinin degradation. The lack of effect of enalaprilat in this model may reflect differences between converting enzyme inhibitors regarding tissue accumulation or the potency of local enzyme inhibition.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Coronary Disease; Creatine Kinase; Heart; In Vitro Techniques; Indomethacin; Male; Myocardium; Norepinephrine; Pyrroles; Ramipril; Rats; Rats, Inbred Strains; Saralasin