Losartan reduces sympathetic nerve outflow from the brain of rats with chronic renal failure

Abstract

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.

Downregulation of Neuronal Nitric Oxide Synthase and Interleukin-1β Mediates Angiotensin II-Dependent Stimulation of Sympathetic Nerve Activity

“…We observed that Ang II reduced the abundance of IL-1␤ and nNOS and decreased NOx secretion from the PH. When these studies are analyzed in the context of previous observations from our laboratory, 22,25,28 they suggest that the stimulatory action of Ang II on SNS activity may be mediated by downregulation of IL-1␤ and nNOS expression.…”

“…[22][23][24][25] Administration of interleukin-1␤ (IL-1␤) in the lateral ventricle of control and chronic renal failure (CRF) rats causes a dose-dependent increase in nNOS-mRNA abundance and a decrease in BP and norepinephrine (NE) secretion from the posterior hypothalamic nuclei (PH). 26 Moreover, in 2 rat models of neurogenic hypertension, one caused by an intrarenal injection of phenol 27 and the other by 5/6 nephrectomy, 28 losartan reduced SNS activity 29,30 and raised the abundance of IL-1␤ and nNOS in the PH, paraventricular nuclei (PVN), and locus ceruleus (LC). These findings suggest that inhibition of nNOS and IL-1␤ may mediate the stimulatory effects of Ang II on SNS activity.…”

Revisiting the Dialysate Sodium Prescription as a Tool for Better Blood Pressure and Interdialytic Weight Gain Management in Hemodialysis Patients

“…For example, hypernatremia increases central sympathetic outflow in some animals (young Dahl salt-sensitive rats), although not in others (59 -61). Increased brain sodium and osmolality are also responsible for inducing increases in angiotensin 2 levels, a factor that results in increased sympathetic outflow in several models, including renal mass reduction (56,60,62,63). It is possible that this potential relationship with mismatched dialysate sodium is responsible, at least part, for the well-documented increases in sympathetic tone in advanced kidney disease (58), which paired with the well-known vasoconstrictive and vasculotoxic effects of angiotensin 2 could contribute to the development of HTN and vascular injury.…”

Losartan Reduces Central and Peripheral Sympathetic Nerve Activity in a Rat Model of Neurogenic Hypertension

“…NE secretion from the PH was measured according to a method previously described by us. 9 NE was measured by a highly sensitive microradioenzymatic assay. 10 …”

“…Moreover, the inhibitory action of losartan on central SNS activity appeared to be mediated by local activation of interleukin (IL)-1␤ and nNOS in the PH. 9 In the present studies, we have used the phenol renal injury model of neurogenic hypertension to further evaluate whether losartan lowers BP by inhibiting central and peripheral SNS activity and whether this inhibition is mediated by increased abundance of IL-1␤ and neuronal nitric oxide synthase (nNOS) mRNA in the brain.…”