Treatment of Bile Duct Ligated Rats with the NOS Transcription Enhancer AVE 9488 Significantly Ameliorates Portal Hypertension

Abstract

Aim: Nitric oxide (NO) is known to be one of the key players in the pathogenesis of portal hypertension. NO-levels are decreased in the cirrhotic liver and, in contrast, increased in the systemic and splanchnic vasculature. We investigated whether the oral application of the NOS transcription enhancer AVE 9488 to cirrhotic rats ameliorates portal hypertension. Methods: Male Sprague-Dawley rats were rendered cirrhotic by bile duct ligation (BDL). After 4 weeks, rats (n=8) were treated orally with 1.0mg/d AVE 9488 for 3 days. BDL animals (n=8) without pharmacological treatment served as controls. At the end of the treatment arterial pressure and portal pressure were measured. Organ blood flow was determined using the microsphere technique. Liver NOS–3 mRNA levels were measured by TaqMan real-time PCR and quantified using the ΔΔCt method. Statistical analysis was done using the Mann-Whitney-U test. Results: Rats in the AVE 9488 treated group had significantly higher liver NOS–3 mRNA levels (ΔΔCt 1.8, 3.6-fold increase, p=0.002). Arterial pressure (mm Hg) did not significantly differ between the treatment and the non-treatment group (102±21 vs. 102±20), respectively. Portal pressure (mmHg) was significantly lower in the AVE group (15.1±3.0 vs. 19.5±2.6, p=0.01). Hepatic portal-vascular resistance (3.3±0.9 vs. 1.7±0.7 mmHg*min*100g/ml, p<0.01) and splanchnic vascular resistance (17.0±6.7 vs. 7.7±3.5 mmHg*min*100g/ml, p<0.05) were significantly lower in the AVE 9488 treatment group than in the non-treatment group, respectively. Conclusions: The oral treatment of bile duct ligated rats with the NOS transcription enhancer AVE 9488 induces a significant increase in NOS–3 mRNA in the liver. This is paralleled by a decrease in intra-hepatic and splanchnic vascular resistance and an amelioration of portal hypertension and organ blood flow.