Candesartan, rather than losartan, improves motor dysfunction in thioacetamide-induced chronic liver failure in rats

Abstract

Minimal hepatic encephalopathy is more common than the acute syndrome. Losartan, the first angiotensin-II receptor blocker (ARB), and candesartan, another widely-used ARB, have protected against developing fibrogenesis, but there is no clear data about their curative antifibrotic effects. The current study was designed to examine their effects in an already-established model of hepatic fibrosis and also their effects on the associated motor dysfunction. Low-grade chronic liver failure (CLF) was induced in 3-month old Sprague-Dawley male rats using thioacetamide (TAA, 50 mg·kg−1·day−1) intraperitoneally for 2 weeks. The TAA-CLF rats were randomly divided into five groups (n=8) treated orally for 14 days (mg·kg−1·day−1) as follows: TAA (distilled water), losartan (5 and 10 mg/kg), and candesartan (0.1 and 0.3 mg/kg). Rats were tested for rotarod and open-field tests. Serum and hepatic biochemical markers, and hepatic histopathological changes were evaluated by H&E and Masson's staining. The TAA-CLF rats showed significant increases of hepatic malondialdehyde, hepatic expression of tumor necrosis factor-α (TNF-α), and serum ammonia, alanine aminotransferase, γ-glutamyl transferase, TNF-α, and malondialdehyde levels as well as significant decreases of hepatic and serum glutathione levels. All treatments significantly reversed these changes. The histopathological changes were moderate in losartan-5 and candesartan-0.1 groups and mild in losartan-10 and candesartan-0.3 groups. Only candesartan significantly improved TAA-induced motor dysfunction. In conclusion, therapeutic antifibrotic effects of losartan and candesartan in thioacetamide-induced hepatic fibrosis in rats are possibly through angiotensin-II receptor blocking, antioxidant, and anti-inflammatory activities. Improved motor dysfunction by candesartan could be attributed to better brain penetration and slower “off-rate” from angiotensin-II receptors. Clinical trials are recommended.

Losartan effects on liver cytochromes CYP3A, CYP2C and CYP2E1 functioning at metabolic syndrome in young and adult rats

“…But in groups of pubertal animals negative effects of MS and losartan administration on glutathione-S-transferase and glutathione reductase were more pronounced. Our data on glutathione system changes are in accordance with other authors' results obtained in experiments in vivo [35][36][37].…”

Candesartan in a rat model of testicular toxicity: New insight on its protective mechanism

“…11 Also, Cand showed a significant downregulation of hepatic TNF-α mRNA expression in a model of thioacetamide-induced hepatotoxicity and these findings confirming the anti-inflammatory effect of Cand. 12…”

“…1,2,[4][5][6][7][8] On the other hand, there are still limited experimental studies that discussed the amelioration of the angiotensin II receptor blocker (ARB) agents against the testicular damage induced in different models. 9,10 However, candesartan (Cand), a member of the ARB family, showed antioxidant, anti-inflammatory, and anti-apoptotic activities in various animal models including CDDP-induced nephrotoxicity, 11 thioacetamide-induced hepatic fibrosis, 12 and myocardium ischemia/reperfusion injury. 13…”

Inhibition of Methamphetamine Self-Administration and Reinstatement by Central Blockade of Angiotensin II Receptor in Rats

“…AT1R Blockade of Methamphetamine Self-Administration in Rats liver failure in rats (Gaur and Kumar, 2011;Murad et al, 2017). As mentioned previously, an increasing number of studies has highlighted the potential use of medications targeting cognitive impairments associated with executive function for METH use disorder (Sofuoglu et al, 2013).…”