Arginine vasopressin V1a receptor is highly expressed in liver. The aim of this article is to perform a molecular analysis of the effects of a novel nonpeptide V1a receptor (V1aR) antagonist, FR218944 (2-methoxy-N-(2-methyl-1H-benzimidazol-4-yl)-4-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-ylcarbonyl)benzamide methanesulfonate), on plasma glucose (Glu) and triglyceride (TG) levels in diabetic db/db mice in comparison with those of a peroxisome proliferator-activated receptor g (PPARg) agonist, pioglitazone, and a PPARa agonist, fenofibrate. FR218944 significantly lowered the plasma TG level but not plasma Glu level after oral administration at 32 mg/kg twice a day for 2 weeks. On the other hand, 10 mg/kg pioglitazone significantly lowered both TG and Glu levels, and 10 mg/kg fenofibrate significantly lowered only the TG level. Significant weight gain was observed only with pioglitazone treatment. db/db mice had lower levels of hepatic V1aR mRNA than normal +/+ mice. The three compounds lowered the mRNA level further. FR218944 significantly raised mRNA levels of b-oxidation enzymes, Acyl-CoA oxidase and bifunctional enzymes (BFE). Pioglitazone significantly increased mRNA levels of all the tested enzymes for b-oxidation and fatty acid synthesis. Fenofibrate significantly increased mRNA levels of AcylCoA synthase and BFE for b-oxidation and decreased the mRNA level of sterol regulatory element-binding protein 1, which transactivates many enzymes for fatty acid synthesis. In conclusion, chronic administration of FR218944, a V1aR antagonist, would lower the plasma TG level by increasing energy consumption via upregulation of b-oxidation enzymes. Furthermore, the compound expresses its antilipemic effect via a different gene-regulatory pathway from pioglitazone and fenofibrate. FR218944 has the potential to become a new drug for hyperlipemia. Drug. Dev. Res. 60:241-251, 2003.