Pharmacologic inhibition of the renin-angiotensin system did not attenuate hepatic toxicity induced by carbon tetrachloride in rats

Abstract

<jats:p> The renin-angiotensin system (RAS) subserves vital physiological functions and also implicated in certain pathological states. Modulation of this system has been proposed in recent studies to be a promising strategy in treating liver fibrosis. We investigated the effect of the pharmacologic inhibition of RAS with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in CCl<jats:sub>4</jats:sub>-induced liver injury with a view to ascertaining the chemopreventive benefit. Fifty-six Wistar albino rats were divided into eight experimental groups of seven rats/group. Groups 1–4 received normal saline (10 ml/kg), enalapril (0.6 mg/kg), losartan (1.4 mg/kg) and CCl<jats:sub>4</jats:sub> (80 mg/kg), respectively. Groups 5–8 were pretreated with enalapril (0.3 mg/kg), enalapril (0.6 mg/kg), losartan (0.7 mg/kg) and losartan (1.4 mg/kg) 1 hour before CCl<jats:sub>4</jats:sub> administration. Experiment lasted 11 days and dosing was via oral route. Rats were killed 24 hours after the last treatment. Serum activities of alkaline phosphatase, aspartate and alanine aminotransferases increased significantly ( p &lt; 0.05) by 46.0%, 90.6% and 122.3%, respectively, with severe hepatic centrilobular necrosis, fatty infiltration and increase in liver weight ( p &lt; 0.05) in the CCl<jats:sub>4</jats:sub>-treated rats. Enalapril (0.6 mg/kg) and losartan (1.4 mg/kg) significantly ( p &lt; 0.05) increased aspartate aminotransferase activity by 37.0% and 94.7% and produced mild centrilobular and periportal hepatic necrosis, respectively, with enalapril significantly ( p &lt; 0.05) increasing liver weight. Serum total cholesterol, triglyceride, albumin and total protein did not change significantly in these rats. Also, glutathione, malondialdehyde and uric acid levels were not significantly altered. Enalapril and losartan failed to attenuate liver injury associated with CCl<jats:sub>4</jats:sub> treatment. Although both drugs did not significantly alter serum biochemistry in the CCl<jats:sub>4</jats:sub>-treated rats, they however produced slight elevations in biomarkers of liver function and appear to worsen liver histopathology. Overall, the chemopreventive benefits of RAS inhibitors in liver disease remain doubtful and should be used with caution during hepatic dysfunction. </jats:p>

Antihyperglycemic, hypolipidemic, hepatoprotective and antioxidative effects of dietary clove (Szyzgium aromaticum) bud powder in a high-fat diet/streptozotocin-induced diabetes rat model

“…70 Normalizing the activity of the renin-angiotensin system may slow or prevent glomerular hypertension, which is a major factor in the development of diabetic nephropathy. 71 As observed in Fig. 2, lung ACE activity was significantly (P < 0.05) increased in the type 2 diabetic control rat group when compared with the NC rat group.…”

“…ACE is a powerful vasoconstrictor that plays a crucial role in blood pressure regulation . Normalizing the activity of the renin–angiotensin system may slow or prevent glomerular hypertension, which is a major factor in the development of diabetic nephropathy . As observed in Fig.…”

“…This is in agreement with an earlier report by Hosseini et al , in which garlic was reported to reduce serum ACE activity in non‐diabetic and STZ‐diabetic rats. Studies have also reported ACE inhibitors and possibly angiotensin receptor blockers to be capable of producing greater hypotension in the presence of hepatotoxicity . It is possible therefore that the hypotension secondary to ACE inhibition and/or angiotensin receptor blocker administration may decrease liver perfusion and stimulation, causing secondary hypoxia and exacerbating hepatotoxicity .…”

“…Studies have also reported ACE inhibitors and possibly angiotensin receptor blockers to be capable of producing greater hypotension in the presence of hepatotoxicity . It is possible therefore that the hypotension secondary to ACE inhibition and/or angiotensin receptor blocker administration may decrease liver perfusion and stimulation, causing secondary hypoxia and exacerbating hepatotoxicity . Thus ACE inhibitors and angiotensin receptor blockers may have a direct cytotoxic effect on the liver …”

“…71 It is possible therefore that the hypotension secondary to ACE inhibition and/or angiotensin receptor blocker administration may decrease liver perfusion and stimulation, causing secondary hypoxia and exacerbating hepatotoxicity. 71 Thus ACE inhibitors and angiotensin receptor blockers may have a direct cytotoxic effect on the liver. 71 Type 2 diabetic rats also exhibited defects in lipid metabolism as revealed from elevated TG, TC and LDLC levels in this study.…”