Vito M. Campese

Increasing evidence indicates that afferent impulses from injured kidney may activate areas of the brain involved in the noradrenergic regulation of blood pressure and largely contribute to the development and maintenance of hypertension associated with renal diseases. A new model of hypertension developed in our laboratory by an intrarenal injection of phenol has largely substantiated this hypothesis. Our studies also provide evidence that complex interactions exist between interleukin (IL)-1Β and nitric oxide in the regulation of central sympathetic nervous system (SNS) activity and blood pressure. Following renal injury with phenol, the abundance of IL-1Β and neuronal isoform of nitric oxide synthase (nNOS) in the brain decreased, and this may mediate the rise in SNS activity. Finally, our studies provide evidence that locally produced angiotensin II in the brain may ultimately mediate the downregulation of IL-1Β and nNOS and result in increased SNS activity and hypertension in the phenol-renal-injury model.

We have developed a new model of neurogenic hypertension in the rat, in which hypertension is caused by injecting 50 μL 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 AT ₁ 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)-1β 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-1β and neuronal NOS (nNOS) mRNA in the PH, PVN, and LC. Whether injected intravenously or in the lateral ventricle, losartan caused a significant ( P P <0.01) and dose-dependent rise in IL-1β 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-1β 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-1β 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-1β and nNOS, 2 important modulators of central SNS activity, mediates the inhibitory action of losartan on SNS activity.

Hypertension is very common in patients with chronic renal failure and contributes to cardiovascular morbidity and mortality. Several mechanisms may contribute to hypertension in these patients, but recently a large body of evidence supports the notion that activation of the sympathetic nervous system (SNS) may play a very important role. In rats with 5/6 nephrectomy, the turnover rate of norepinephrine was increased in brain nuclei involved in the noradrenergic control of blood pressure, and dorsal rhizotomy prevented hypertension. Studies in human subjects with chronic renal failure and hypertension have also shown increased peripheral SNS activity measured my microneurography in the peroneal nerve and normalization with nephrectomy. In all, these studies indicate that renal injuries may activate renal afferent pathways that connect with integrative brain structures in SNS activity and blood pressure. We have also shown that central SNS activity is modulated by local expression of nitric oxide, which, in turn, is regulated by interleukin-1â.

— There is substantial evidence that angiotensin II (Ang II) enhances sympathetic nervous system (SNS) activity. We recently observed that nitric oxide and interleukin-1β (IL-1β) exert a tonic inhibitory action on central SNS activity. Moreover, in 2 rat models of neurogenic hypertension, one caused by intrarenal injection of phenol and the other by 5/6 nephrectomy, we observed that losartan, an Ang II type 1 receptor blocker, inhibits SNS activity and increases the abundance of IL-1β and the neuronal isoform of nitric oxide synthase (nNOS) in the posterior hypothalamic nuclei (PH), paraventricular nuclei (PVN), and locus ceruleus (LC). This raises the possibility that the stimulatory effects of Ang II on central SNS activity may be mediated by inhibition of nNOS and IL-1β. To test this hypothesis, we studied the effect of an intracerebroventricular (ICV) infusion of Ang II on blood pressure (BP), norepinephrine (NE) secretion from the PH, renal SNS activity (RSNA), and abundance of IL-1β and nNOS...

Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure ( P =0.008), ambulatory systolic blood pressure ( P =0.004), and ambulatory mean arterial pressure ( P =0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly ( P P <0.001) increased urinary excretion of cGMP over the 0- to 24- and 4- to 8-hour intervals compared with that from lisinopril. Neither drug had a diuretic, natriuretic, or kaliuretic effect. In conclusion, in salt-sensitive hypertensive patients, omapatrilat demonstrated the hormonal profile of a vasopeptidase inhibitor and lowered ambulatory diastolic and systolic blood pressures more than lisinopril.

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 NO₂/NO₃production. Because interleukin (IL)-1β may activate nitric oxide in the brain, we have tested the hypothesis that IL-1β 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-1β 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-1β-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-1β 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-1β modulates the activity of the SNS in the central nervous system and that this modulation is mediated by increased local expression of nNOS mRNA.

Hypertension is very common in patients with chronic renal failure (CRF) and it contributes to morbidity and mortality as well as to the progression of renal disease. Several mechanisms may play a role in the pathogenesis of hypertension in CRF, but the best known are sodium retention and activation of the renin-angiotensin-aldosterone system. More recently, evidence has accumulated to support a role for increased sympathetic nervous system (SNS) activity in the genesis of hypertension associated with CRF. Our laboratory findings indicate that specific renal injuries, caused by 5/6 nephrectomy and/or phenol injection in the kidney, activate renal afferent pathways that connect with integrative structures in the brain involved in the regulation of SNS activity and blood pressure. This results in a rise in blood pressure sustained by noradrenergic mechanisms. Our laboratory has also shown that the rise in central SNS activity is mitigated by increased local expression of nitric oxide synthase (NOS)-mRNA and nitric oxide (NO) production, and by upregulation of interleukin-1beta.