Previously, we have shown that an acute injury to the kidney produced by an intrarenal injection of phenol causes an immediate increase in blood pressure and in norepinephrine (NE) secretion from the posterior hypothalamus. The studies suggest that in this model afferent impulses from the kidney to central integrative structures in the brain may be responsible for the increase in blood pressure.To further evaluate whether a renal injury caused by the intrarenal injection of phenol leads to a permanent elevation of blood pressure and whether this is mediated by increased sympathetic nervous system activity, we examined the chronic effects (4 weeks) of an intrarenal injection of 50 L of 10% phenol on blood pressure and NE secretion from the posterior hypothalamus.Systolic blood pressure increased from 128 ؎ 2.1 to 176 ؎ 1.5 mm Hg (P < .01) 4 weeks after receiving the intrarenal injection of phenol, but it did not change in rats that received the vehicle (128 ؎ 2.4 and 135 ؎ 1.7 mm Hg) and in rats that were subjected to renal denervation (127 ؎ 3.4 and 124 ؎ 1.0 mm Hg). The secretion of NE from the posterior hypothalamic nuclei was greater (P < .01) in rats that received phenol (253 ؎ 9.6 pg/mL) than in controls (158 ؎ 8.6 pg/mL) and denervated rats (170 ؎ 2.1 pg/mL).These studies have shown that a limited injury to one kidney may cause a permanent elevation of blood pressure and this is associated with increased sympathetic nervous system activity. Am J Hypertens 1998;11:723-728 © 1998 American Journal of Hypertension, Ltd.KEY WORDS: Hypertension, sympathetic nerve activity, renal nerves, posterior hypothalamus, microdialysis.H ypertension remains a significant clinical issue in the patient with renal disease. Several factors may play a role in the pathogenesis of renal hypertension, including sodium retention, volume expansion, and increased activity of the renin-angiotensin system 1,2 and of the sympathetic nervous system. [3][4][5][6][7] We have shown greater turnover rates of norepinephrine (NE) in the posterior hypothalamic nuclei and in the locus ceruleus of rats with chronic renal failure (CRF) than control rats.8 Bilateral dorsal rhizotomy (T-10 to L-2) prevented the development of hypertension and the increase in NE turnover rates in the posterior hypothalamic nuclei and in the locus ceruleus of CRF rats. 9The secretion of NE, measured by the microdialysis technique, was greater from the posterior hypothalamus of CRF than control rats. 10 The decrease in arterial pressure observed in uremic patients after bilateral nephrectomy is associated with lower sympathetic

Increased sympathetic nervous system (SNS) activity plays a role in the genesis of hypertension in rats with chronic renal failure (CRF). The rise in central SNS activity is mitigated by increased local expression of neuronal nitric oxide synthase (NOS) mRNA and NO(2)/NO(3) production. Because interleukin (IL)-1beta may activate nitric oxide in the brain, we have tested the hypothesis that IL-1beta may modulate the activity of the SNS via regulation of the local expression of neuronal NOS (nNOS) in the brain of CRF and control rats. To this end, we first found that administration of IL-1beta in the lateral ventricle of control and CRF rats decreased blood pressure and norepinephrine (NE) secretion from the posterior hypothalamus (PH) and increased NOS mRNA expression. Second, we observed that an acute or chronic injection of an IL-1beta-specific antibody in the lateral ventricle raised blood pressure and NE secretion from the PH and decreased NOS mRNA abundance in the PH of control and CRF rats. Finally, we measured the IL-1beta mRNA abundance in the PH, locus coeruleus, and paraventricular nuclei of CRF and control rats by RT-PCR and found it to be greater in CRF rats than in control rats. In conclusion, these studies have shown that IL-1beta modulates the activity of the SNS in the central nervous system and that this modulation is mediated by increased local expression of nNOS mRNA.

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.