Effects of asymmetric dimethylarginine on renal arteries in portal hypertension and cirrhosis

World J Gastroenterol. 2016 Dec 28;22(48):10545-10556. doi: 10.3748/wjg.v22.i48.10545.

Abstract

Aim: To evaluate the effects of asymmetric dimethylarginine (ADMA) in renal arteries from portal hypertensive and cirrhotic rats.

Methods: Rat renal arteries from Sham (n = 15), pre-hepatic portal hypertension (PPVL; n = 15) and bile duct ligation and excision-induced cirrhosis (BDL; n = 15) were precontracted with norepinephrine, and additional contractions were induced with ADMA (10-6-10-3 mol/L), an endogenous inhibitor of nitric oxide (NO) synthase. Concentration-response curves to acetylcholine (1 × 10-9-3 × 10-6 mol/L) were determined in precontracted renal artery segments with norepinephrine in the absence and in the presence of ADMA. Kidneys were collected to determine the protein expression and activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes ADMA.

Results: In renal arteries precontracted with norepinephrine, ADMA caused endothelium-dependent contractions. The pD2 values to ADMA were similar in the Sham and PPVL groups (4.20 ± 0.08 and 4.11 ± 0.09, P > 0.05, respectively), but were lower than those of the BDL group (4.79 ± 0.16, P < 0.05). Acetylcholine-induced endothelium-dependent relaxation that did not differ, in terms of pD2 and maximal relaxation, among the 3 groups studied. Treatment with ADMA (3 × 10-4 mol/L) inhibited acetylcholine-induced relaxation in the 3 groups, but the inhibition was higher (P < 0.05) in the BDL group compared with that for the Sham and PPVL groups. The mRNA and protein expression of DDAH-1 were similar in kidneys from the three groups. Conversely, DDAH-2 expression was increased (P < 0.05) in PPVL and further enhanced (P < 0.05) in the BDL group. However, renal DDAH activity was significantly decreased in the BDL group.

Conclusion: Cirrhosis increased the inhibitory effect of ADMA on basal- and induced-release of NO in renal arteries, and decreased DDAH activity in the kidney.

Keywords: Asymmetric dimethylarginine; Cirrhosis; Dimethylarginine dimethylaminohydrolase; Nitric oxide; Nitric oxide inhibitors; Portal hypertension.

MeSH terms

  • Acetylcholine / pharmacology
  • Amidohydrolases / metabolism*
  • Animals
  • Arginine / analogs & derivatives*
  • Arginine / pharmacology
  • Endothelium / drug effects
  • Endothelium / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hypertension, Portal / blood
  • Hypertension, Portal / complications
  • Hypertension, Portal / metabolism
  • Kidney / blood supply
  • Kidney / enzymology
  • Liver Cirrhosis / blood
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / metabolism
  • Male
  • NG-Nitroarginine Methyl Ester / pharmacology*
  • Nitric Oxide / blood
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Norepinephrine / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Renal Artery / drug effects
  • Renal Artery / physiology*
  • Vasoconstriction / drug effects*
  • Vasoconstrictor Agents / pharmacology

Substances

  • Enzyme Inhibitors
  • Vasoconstrictor Agents
  • Nitric Oxide
  • N,N-dimethylarginine
  • Arginine
  • Nitric Oxide Synthase
  • Amidohydrolases
  • dimethylargininase
  • Acetylcholine
  • NG-Nitroarginine Methyl Ester
  • Norepinephrine