Role of the renin-angiotensin system in hepatic ischemia reperfusion injury in rats

Abstract

It has been shown that the renin-angiotensin system (RAS) plays key roles in the development of fibrosis in numerous organs, including the liver. Other studies have suggested that the RAS also may play roles in diseases of chronic inflammation. However, whether the RAS also can mediate acute inflammation in liver is unclear. The purpose of this study therefore was to determine the effect of the RAS inhibitors captopril and losartan on acute liver damage and inflammation caused by hepatic ischemia and subsequent reperfusion. Accordingly, male rats were subjected to 1 hour of hepatic ischemia (70%) followed by reperfusion; animals were killed 3, 8, or 24 hours after reperfusion. The effect of captopril or losartan (100 or 5 mg/kg intragastrically, respectively) was compared with that of vehicle (saline). The expression of angiotensinogen in liver increased fivefold 3 hours after reperfusion. Indices of liver damage and inflammation (e.g., alanine aminotransferase levels, pathological features, tumor necrosis factor-␣ levels, and intercellular adhesion molecule-1 expression) all were significantly elevated in vehicle-treated animals after hepatic ischemia and subsequent reperfusion. Ischemia and reperfusion also caused an increase in the accumulation of protein adducts of 4-hydroxynonenal, an index of oxidative stress. Captopril or losartan treatment showed profound protective effects under these conditions, significantly blunting the increase in all these parameters caused by ischemia and reperfusion. In conclusion, RAS inhibitors prevent acute liver injury in a model of inflammation caused by ischemia and reperfusion. These data further suggest that the RAS may play a key role in mediating such responses in the liver and suggest a novel role for this system. (HEPATOLOGY 2004;40:583-589.)

Evaluation of Effects of Losartan on Random Pattern Skin Flap Model of Rats

“…[2,[6][7][8][9][10][11] The renin angiotensin system (RAS) is a regulator of blood pressure with well-known effects on the kidneys and vessels. Recently, local angiotensin receptors have been demonstrated in many organs including the skin, [12][13][14][15] which are upregulated during ischemia. [12,14] Activation of these receptors causes an increase in inflammatory response.…”

“…Recently, local angiotensin receptors have been demonstrated in many organs including the skin, [12][13][14][15] which are upregulated during ischemia. [12,14] Activation of these receptors causes an increase in inflammatory response. [12,[16][17][18][19] Losartan, which is an angiotensin type 1 (AT1) receptor blocker, has antiinflammatory properties via acting on local systems.…”

“…[12,14] Activation of these receptors causes an increase in inflammatory response. [12,[16][17][18][19] Losartan, which is an angiotensin type 1 (AT1) receptor blocker, has antiinflammatory properties via acting on local systems. Zhu and Sato et al showed this drug's ability to reduce the area of infarction in the myocardium.…”

“…Zhu and Sato et al showed this drug's ability to reduce the area of infarction in the myocardium. [20,21] Moreover, losartan prevents ischemia-reperfusion injury in many organs including the heart, [16,22] liver, [12] lungs, [23] endothelium, [24] brain, [25] and large intestine. [19] We hypothesize that ischemic damage in the skin may also be decreased if proinflammatory properties of angiotensin were inhibited.…”

“…[2,3,6,10,16] Inhibition of neutrophil functions has been shown to improve flap survival. [2,4,6,10] We hypothesized that AT1 blockers may improve flap survival by inhibiting adhesion of neutrophils to the endothelium, [16,17,19] decreasing tumor necrosis factor (TNF) alpha and interleukin (IL)-8 levels, [12,15] modifying nitric oxide production, [16] inhibiting platelet aggregation, [30,31] and preventing apoptosis. [21,24,25] Despite our expectations, comparison of flap survivals did not yield any differences between the study groups.…”