Losartan reduces sympathetic nerve outflow from the brain of rats with chronic renal failure.
Sympathetic nervous system (SNS) activity, measured by norepinephrine (NE) turnover rate, was greater in the posterior hypothalamic (PH) nuclei, the paraventricular nuclei (PVN), and the locus coeruleus (LC) of 5/6 nephrectomised (CRF) rats than of control rats. NE secretion from the PH was also greater in CRF than in control rats. These findings demonstrate that SNS activity plays an important role in the genesis of hypertension associated with CRF. The increase in central SNS activity was mitigated by increased local expression of nitric oxide synthase (NOS)-mRNA and nitric oxide (NOx) production. Because angiotensin II may stimulate the central SNS, we tested the hypothesis that losartan, a specific angiotensin II AT(1)-receptor antagonist, may lower blood pressure (BP), at least in part, by central noradrenergic inhibition. To this end, we studied two groups of CRF rats. One group received losartan (10 mg/kg body weight) in drinking water between the 3rd and 4th week after nephrectomy, the second group received drinking water without losartan. SNS activity was measured by NE secretion from the PH using the microdialysis technique. NOS-mRNA gene expression was also measured by RT-PCR in the PH, PVN, and LC of CRF and control rats. Losartan reduced systolic BP from 184+/-3.7 to 152+/-3.1 mmHg and NE secretion from the PH from 340+/-9.7 to 247+/-4.8 pg/ml. CRF rats treated with losartan manifested a significant (p<0.01) increase in the expression of nNOS-mRNA in the PH (from 84+/-1.2 to 99+/-2.6), the PVN (from 44+/-1.5 to 63+/-2.1), and the LC (from 59+/-6.7 to 76+/-2.1). CRF rats also manifested a significant increase (p<0.01) in the expression of IL-1beta the PH (from 41.6+/-2.8 to 54.3+/-1.4), PVN (from 44+/-1.9 to 54+/-1.5), and LC (from 35.5+/-1.6 to 53.5+/-1.9). In conclusion, these studies suggest that the antihypertensive action of losartan in CRF rats may be mediated, at least in part, by inhibition of central SNS outflow. The studies also suggest that the inhibitory action of losartan on the SNS may be mediated by activation of IL-1beta, which, in turn, stimulates nNOS, an important modulator of central SNS activity.
Campese
V M
VM
Division of Nephrology, University of Southern California, Los Angeles, California, CA 90033, USA. campese@hsc.usc.edu
Ye
S
S
Truong
R H
RH
Gamburd
M
M
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D007034:Hypothalamus, Posterior / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D009638:Norepinephrine / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology*
D057911:Angiotensin Receptor Antagonists; D007375:Interleukin-1; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D019808:Losartan; D009638:Norepinephrine