Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats

Abstract

Portal hypertension (PH), a pathophysiological derangement of liver cirrhosis, is characterized by hyperdynamic circulation, angiogenesis, and portosystemic collaterals. These may lead to lethal complications, such as variceal bleeding. Caffeine has been noted for its effects on liver inflammation, fibrogenesis, and vasoreactiveness. However, the relevant influences of caffeine in cirrhosis and PH have not been addressed. Spraque-Dawley rats with common bile duct ligation-induced cirrhosis or sham operation received prophylactic or therapeutic caffeine treatment (50 mg/kg/day, the first or 15th day since operation, respectively) for 28 days. Compared to vehicle (distilled water), caffeine decreased cardiac index, increased systemic vascular resistance, reduced portal pressure (PP), superior mesenteric artery flow, mesenteric vascular density, portosystemic shunting (PSS), intrahepatic angiogenesis, and fibrosis without affecting liver and renal biochemistry. The beneficial effects were reversed by selective adenosine A1 agonist N6-cyclopentyladenosine (CPA) or A2A agonist GCS21680. Both prophylactic and therapeutic caffeine treatment decreased portal resistance and PP in thioacetamide (200mg/kg, thrice-weekly for 8 weeks)-induced cirrhotic rats. Caffeine down-regulated endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), phospho-VEGFR2, and phospho-Akt mesenteric protein expression. Caffeine adversely affected viability of hepatic stellate and sinusoidal endothelial cells, which was reversed by CPA and GCS21680. On the other hand, caffeine did not modify vascular response to vasoconstrictors in splanchnic, hepatic, and collateral vascular beds. Conclusions: Caffeine decreased PP, ameliorated hyperdynamic circulation, PSS, mesenteric angiogenesis, hepatic angiogenesis, and fibrosis in cirrhotic rats. Caffeine may be a feasible candidate to ameliorate PH-related complications in cirrhosis. (HEPATOLOGY 2015;61:1672-1684

The Impact of Spironolactone on the Severity of Portal-Systemic Collaterals and Hepatic Encephalopathy in Cirrhotic Rats

“…It also reflects the pathophysiologic changes of the reninangiotensin-aldosterone axis during the progression of liver cirrhosis (Jonassen et al, 1998;Kim et al, 2006). In terms of pharmacologic studies, prophylactic and therapeutic strategies can be designed with this model, depending on the timing of treatments (Hsu et al, 2015). Because liver fibrosis usually develops on day 14 and liver cirrhosis on day 28 after BDL (Kountouras et al, 1984), therapeutic agents administered Fig.…”

“…Male Sprague-Dawley rats weighing 240-270 g at the time of surgery were used for experiments. Secondary biliary cirrhosis was induced by common BDL as previously described elsewhere Hsu et al, 2015). Under ketamine anesthesia (100 mg/kg, intramuscularly), the common bile duct was exposed through a midline abdominal incision, catheterized by a PE-10 catheter, and doubly ligated with 3-0 silk.…”

“…Splanchnic angiogenesis was evaluated by assessing the CD31-labeled microvascular networks in rat mesenteric connective tissue windows, which was performed as previously described elsewhere Hsu et al, 2015). Immunofluorescent images at 100Â magnification were assessed using an upright fluorescent microscope (AX80; Olympus, Tokyo, Japan) and thresholded by ImageJ software.…”

“…Accumulating evidence demonstrates that angiogenesis, the formation of new vessels from a pre-existing vasculature, plays a pivotal role in the development and maintenance of portal hypertension (Fernandez et al, 2004). In addition, amelioration of splanchnic angiogenesis effectively ameliorates portal-systemic shunting Hsu et al, 2015).…”

“…Protein expression was analyzed by Western blotting as previously described elsewhere Hsu et al, 2015). Blots were incubated with the primary antibody: inducible nitric oxide synthases (iNOS), endothelial nitric oxide synthases (eNOS), cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2) (all Cell Signaling Technology, Beverly, MA), and VEGF and phospho-vascular endothelial growth factor receptor 2 (VEGFR-2) (Santa Cruz Biotechnology, Santa Cruz, CA).…”