Prophylactic and therapeutic treatments with AT 1 and AT 2 receptor antagonists and their effects on changes in the severity of pancreatitis.
Previous studies showed that a local pancreatic renin-angiotensin system (RAS) was upregulated in experimental acute pancreatitis. RAS inhibition could attenuate pancreatic inflammation and fibrosis, which casts a new light on the role of the pancreatic RAS in pancreatitis. The present study explores the prophylactic and therapeutic potentials, and possible molecular mechanism for the antagonism of angiotensin II receptors on the changes in the severity of pancreatic injury induced by acute pancreatitis. Experimental pancreatitis was induced by an intraperitoneal injection of supra-maximal dose of cerulein. The differential effects of angiotensin II receptors inhibitors losartan and PD123319 on the pancreatic injury were assessed by virtue of using the pancreatic water content, biochemical and histological analyses. Blockade of the AT(1) receptor by losartan at a dose of 200microg/kg could markedly ameliorate the pancreatic injury induced by cerulein, as evidenced by biochemical and histopathological studies. However, blockade of the AT(2) receptor by PD123319 appeared not to provide any beneficial role in cerulein-induced pancreatic injury. Both prophylactic and therapeutic treatments with losartan were effective against cerulein-induced pancreatic injury. The protective action of losartan was linked to an inhibition of NAD(P)H oxidase activity, thus consequential oxidative modification of pancreatic proteins in the pancreas. Inhibition of the AT(1) receptor, but not AT(2) receptor, may play a beneficial role in ameliorating the severity of acute pancreatitis. The differential effects of AT(1) and AT(2) inhibitors on cerulein-induced pancreatic injury might be due to the distinctive mechanism of the AT(1) and AT(2) receptors on the activation of NAD(P)H oxidase. Thus the protective role of AT(1) receptor antagonist, losartan, could be mediated by the inhibition of NAD(P)H oxidase-dependent generation of reactive oxygen species (ROS).
Tsang
Siu Wai
SW
Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Shatin, PR China.
Ip
Siu Po
SP
Leung
Po Sing
PS
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D002108:Ceruletide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation; D019808:Losartan / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009929:Organ Size; D010100:Oxygen / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000188:drug therapy* / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D000516:alpha-Amylases / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; C073402:PD 123319; D002108:Ceruletide; D019255:NADPH Oxidases; D000516:alpha-Amylases; D019808:Losartan; D010100:Oxygen