Role of the central nervous system in the development of hypertension produced by chronic nitric oxide blockade in rats.
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.
Nakata
T
T
Clinical Pharmacology, Kyoto Pharmaceutical University, Japan.
Takeda
K
K
Harada
S
S
Oguni
A
A
Hatta
T
T
Kawa
T
T
Itoh
H
H
Sasaki
S
S
Nakagawa
M
M
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002490:Central Nervous System / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced*; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008839:Microelectrodes; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D005680:gamma-Aminobutyric Acid; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester