Published online Dec 28, 2016. doi: 10.3748/wjg.v22.i48.10545
Peer-review started: July 30, 2016
First decision: August 29, 2016
Revised: September 17, 2016
Accepted: October 10, 2016
Article in press: October 10, 2016
Published online: December 28, 2016
To evaluate the effects of asymmetric dimethylarginine (ADMA) in renal arteries from portal hypertensive and cirrhotic rats.
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.
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.
Cirrhosis increased the inhibitory effect of ADMA on basal- and induced-release of NO in renal arteries, and decreased DDAH activity in the kidney.
Core tip: Cirrhosis is associated with renal dysfunction and renal vasoconstriction. This constriction leads to decreased renal blood flow and glomerular filtration. Decreased nitric oxide (NO) bioavailability is involved in these effects. Although plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, are increased in cirrhosis, the effects of ADMA on renal arteries under this pathological condition are unknown. Therefore, the present work studied the effects of ADMA on basal- and stimulated-NO release in renal arteries from portal hypertensive and cirrhotic rats and the renal expression and activity of dimethylarginine dimethylaminohydrolase, an enzyme that catabolizes ADMA.