Role of the Central Nervous System in the Development of Hypertension Produced by Chronic Nitric Oxide Blockade in Rats.

Abstract

We examined the role of the central nervous system, and particularly the renin-angiotensin (RA) system, in the development of hypertension produced by chronic inhibition of NO synthesis. In experiment 1, Wistar rats drank either nitro-L-arginine-methyl ester (L-NAME) or tap water. Before L-NAME treatment rats were divided into 6 groups. Four of them were administered either losartan or artificial cerebroventricular fluid (a-CSF) intracerebroventricularly (i.c.v.) for 1 week using an osmotic mini pump. The other two groups were administered the same amount of losartan intravenously (i.v.). In experiment 2, cardiovascular responses to acute i.c.v. losartan and muscimol, a GABA(A) agonist, were examined in conscious L-NAME-treated rats. Finally, in experiment 3, effects of ablation of the AV3V (anteroventral third ventricle) area, known to be one of the centers of cardiovascular control, were tested in the development of L-NAME hypertension. The development of hypertension by L-NAME treatment was attenuated with chronic i.c.v. losartan in a dose-dependent manner, while i.v. losartan had no effect. One week after cessation of i.c.v. losartan, blood pressure was elevated to the same level as in a-CSF-infused, L-NAME-treated rats. Acute i.c.v. losartan produced no cardiovascular changes in either L-NAME-treated or control rats. On the other hand, although i.c.v. muscimol elicited depressor effects in both groups, these responses were significantly larger in L-NAME-treated rats. Cardiovascular responses to i.v. hexamethonium were similar in both groups. The existence of prior lesions in the AV3V area significantly attenuated the development of L-NAME-induced hypertension. These results indicate that the central RA system plays an important role in the development of hypertension produced by chronic inhibition of NO synthase. Moreover, disorder of the central GABA system, rather than that of the RA system, might be important in the maintenance of hypertension in this model.

Enhanced Depressor Response to Endothelial Nitric Oxide Synthase Gene Transfer into the Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats

“…Similarly to our observations, in other models of hypertension, nNOS expression in the brain has been shown to be decreased or unchanged, and the decreases depend on the phase of development of hypertension (34)(35)(36). Second, recent studies have been shown that central nervous system mechanisms are involved in hypertension caused by chronic NOS inhibition (37,38). Eshima et al suggested that activation of the renin-angiotensin system in the NTS contributes to this neurogenic hypertension (38).…”

Antihypertensive Mechanisms of Chronic Captopril or N-Acetylcysteine Treatment in L-NAME Hypertensive Rats

“…administration of angiotensin II (29), and chronic i.c.v. infusion of losartan attenuates the development of L-NAME hypertension (30).…”

Role of Brain and Peripheral Angiotensin II in Hypertension and Altered Arterial Baroreflex Programmed during Fetal Life in Rat

“…Elevated brain AngII binding sites have also been reported in spontaneously hypertensive fetal and newborn rats (47,48), and blockade of central RAS in adult spontaneously hypertensive rat can reverse their chronic hypertension (49). The underlying mechanisms and regulatory processes that lead to increased AT 1 receptor brain expression in 9% offspring are unknown but may involve a defect in nitric oxide pathway (27,50,51), positive feedback regulation by elevated brain AngII (52,53), and glucocorticoids (12,54,55).…”