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.