Abstract
The goal of our study was to analyze the time course of the effect of NG-nitro-L-arginine methyl ester (L-NAME) on nitric oxide synthase (NOS) isoforms and nuclear factor–κB (NF-κB) protein expression, total NOS activity, and blood pressure (BP) in rats. Adult 12-week-old male Wistar rats were subjected to treatment with L-NAME (40 mg/kg/day) for four and seven weeks. BP was increased after 4- and 7-week L-NAME treatments. NOS activity decreased after 4-week-L-NAME treatment; however, the 7-week treatment increased NOS activity in the aorta, heart, and kidney, while it markedly decreased NOS activity in the brainstem, cerebellum, and brain cortex. The 4-week-L-NAME treatment increased eNOS expression in the aorta, heart, and kidney and this increase was amplified after 7 weeks of treatment. In the brain regions, eNOS expression remained unchanged after 4-week L-NAME treatment and prolonged treatment led to a significant decrease of eNOS expression in these tissues. NF-κB expression increased in both peripheral and brain tissues after 4 weeks of treatment and prolongation of treatment decreased the expression in the aorta, heart, and kidney. In conclusion, decreased expression of eNOS in the brain regions after 7-week L-NAME treatment may be responsible for a remarkable decrease of NOS activity in these regions. Since the BP increase persisted after 7 weeks of L-NAME treatment, we hypothesize that central regulation of BP may contribute significantly to L-NAME-induced hypertension.
Highlights
Chronic inhibition of nitric oxide synthase (NOS) by NG-nitro-L-arginine methyl ester (L-NAME) is a well-established model of experimental hypertension and organ damage within the cardiovascular system [1,2,3] and kidney [4,5,6]
We found that prolonging the L-NAME treatment from 4 to 7 weeks increased NOS activity in the aorta, heart, and kidney, while in the brain regions, such as the brainstem, cerebellum, and brain cortex, the activity was significantly decreased
Increased expression of eNOS protein may be responsible for increased NOS activity in the peripheral tissues, while decreased expression of the same NOS isoform in the brainstem, cerebellum, and brain cortex led to a very pronounced decrease of NOS activity
Summary
Chronic inhibition of nitric oxide synthase (NOS) by NG-nitro-L-arginine methyl ester (L-NAME) is a well-established model of experimental hypertension and organ damage within the cardiovascular system [1,2,3] and kidney [4,5,6]. The mechanisms responsible for blood pressure (BP) increase following the organ changes in this type of hypertension have not been fully elucidated. The mechanism of L-NAME-induced hypertension involves more than a simple inhibition of NO production with a consequent decrease of vasorelaxant activity. Attenuated vascular relaxation [7,8] and enhanced contraction in different parts of the vascular tree [9,10] are the first factors contributing to the increase of blood pressure. Increased production of prostaglandins [16] and reactive oxygen species (ROS) [17,18,19] were described as additional serious factors contributing to the development of L-NAME-induced hypertension
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