Involvement of inducible nitric oxide synthase and dimethylarginine dimethylaminohydrolase in Nω‐Nitro‐L‐arginine methyl ester (L‐NAME)‐induced hypertension (LB676)

Abstract

Chronic administration of L‐NAME in rats is an excellent model to study the induction and progression of a NO deficiency‐induced endothelial dysfunctional state. This study was performed to determine how different vascular beds compensate for the loss in nitric oxide. Male Wistar rats received L‐NAME (50mg/kg/day in drinking water) or no drug for 6 weeks. Aorta, pulmonary and renal arteries were isolated for determination of basal cGMP production, PDE5 activity, dimethylarginine dimethylaminohydrolase (DDAH) and hemeoxygenase (HO) activity. mRNA expression studies were done by real time PCR. Plasma IL‐1β level was measured by ELISA. Results: L‐NAME‐induced hypertension was associated with an increase in mean arterial pressure and plasma IL‐1β. The treatment had varied effects on mRNA expression levels of eNOS, soluble guanylyl cyclase, PDE5 and HO1 but showed an increased iNOS and decreased DDAH2 expression in all three tissues studied. Basal cGMP levels were decreased in all tissues, but PDE5 activity was increased only in renal and pulmonary artery. DDAH activity was significantly reduced, whereas HO activity was significantly increased in all the tissues. This study showed that different vascular beds do not react similarly to chronic NO inhibition and that vascular inflammation triggered by an increase in iNOS and indirectly by a decrease in DDAH activity might be the causative factors for the progression of vascular dysfunction in this model.