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

Abstract

Abstract-We have developed a new model of neurogenic hypertension in the rat, in which hypertension is caused by injecting 50 L 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)-1␤ 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-1␤ and neuronal NOS (nNOS) mRNA in the PH, PVN, and LC. Whether injected intravenously or in the lateral ventricle, losartan caused a significant (PϽ0.01) and dose-dependent inhibition of the effects of phenol on BP, NE secretion from the PH, and RSNA. Losartan also caused a significant (PϽ0.01) and dose-dependent rise in IL-1␤ and nNOS-mRNA gene expression in the PH, PVN, and LC of phenol-injected rats. Key Words: losartan Ⅲ sympathetic nervous system Ⅲ hypertension, renal Ⅲ nitric oxide synthase Ⅲ interleukins Ⅲ hypothalamus H ypertension remains a significant clinical problem in patients with renal diseases, and it is an important factor in the pathogenesis of renal failure. When uncontrolled, hypertension may hasten the progression to end-stage renal disease, and it may greatly contribute to cardiovascular morbidity and mortality.Several factors may play a role in the pathogenesis of renal hypertension, including sodium retention, volume expansion, increased activity of the renin-angiotensin system, 1 and increased sympathetic nervous system (SNS) activity. 2,3 In the 5/6 nephrectomized (CRF) rat, we observed a greater turnover rate of norepinephrine (NE) 4 and greater secretion of NE from the posterior hypothalamic nuclei (PH) compared with control rats. 5 Bilateral dorsal rhizotomy prevented the development of hypertension and the increase in SNS activity in these rats. 6 In dialysis patients, Converse et al 7 found that the rate of SNS discharge recorded from postganglionic sympathetic fibers in the peroneal nerves was greater in patients with their native kidneys than in those with bilateral nephrectomy. Collectively, these findings support the notion that increased afferent nervous impulses from injured kidneys to the central nervous system...

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