Losartan reduces central and peripheral sympathetic nerve activity in a rat model of neurogenic hypertension.
We have developed a new model of neurogenic hypertension in the rat, in which hypertension is caused by injecting 50 microL of 10% phenol in the lower pole of one kidney. Administration of phenol in the kidney causes an immediate and persistent rise in blood pressure (BP), norepinephrine (NE) secretion from the posterior hypothalamic nuclei (PH), and renal sympathetic nerve activity (RSNA). Because angiotensin II (Ang II) is known to stimulate central and peripheral sympathetic nervous system (SNS) activity, we have tested the hypothesis that losartan, a specific Ang II AT1 receptor antagonist, may lower BP, at least in part, by SNS inhibition. To this end, we studied the effects of losartan on BP and SNS activity following intrarenal phenol injection. Central SNS activity was measured by NE secretion from the PH using a microdialysis technique, and peripheral SNS activity was measured by direct recording of renal nerve activity. At the end of the experiments, brains were isolated and interleukin (IL)-1beta and nitric oxide synthase (NOS) mRNA gene expression was measured by RT-PCR in the PH, paraventricular nuclei (PVN), and locus ceruleus (LC). The intrarenal injection of phenol raised BP, as well as central and renal SNS activity, but reduced the abundance of IL-1beta and neuronal NOS (nNOS) mRNA in the PH, PVN, and LC. Whether injected intravenously or in the lateral ventricle, losartan caused a significant (P<0.01) and dose-dependent inhibition of the effects of phenol on BP, NE secretion from the PH, and RSNA. Losartan also caused a significant (P<0.01) and dose-dependent rise in IL-1beta and nNOS-mRNA gene expression in the PH, PVN, and LC of phenol-injected rats. In conclusion, these studies have shown that the intrarenal injection of phenol causes a rise in central and renal SNS activity and a decrease in IL-1beta and nNOS-mRNA in the PH, PVN, and LC. Losartan prevented the rise in BP and SNS activity, as well as the decrease in IL-1beta and nNOS mRNA abundance caused by phenol. These studies have demonstrated that the antihypertensive action of losartan in the phenol renal injury model is largely mediated by inhibition of central and peripheral SNS activity and suggest that activation of IL-1beta and nNOS, 2 important modulators of central SNS activity, mediates the inhibitory action of losartan on SNS activity.
Ye
Shaohua
S
Division of Nephrology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, Calif, USA.
Zhong
Huiquin
H
Duong
Vu Ngoc
VN
Campese
Vito M
VM
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002490:Central Nervous System / Q000187:drug effects*; D002552:Cerebral Ventricles; D006977:Hypertension, Renal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007034:Hypothalamus, Posterior / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects / Q000294:innervation; D007700:Kinetics; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D009638:Norepinephrine / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics / Q000008:administration & dosage / Q000494:pharmacology*
D000959:Antihypertensive Agents; D007375:Interleukin-1; D012333:RNA, Messenger; D013565:Sympatholytics; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D019808:Losartan; D009638:Norepinephrine