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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Feb 1;99(3):540–548. doi: 10.1172/JCI119191

Nitric oxide (NO) modulates the neurogenic control of blood pressure in rats with chronic renal failure (CRF).

S Ye 1, S Nosrati 1, V M Campese 1
PMCID: PMC507830  PMID: 9022090

Abstract

Increased sympathetic nervous system (SNS) activity plays a role in the genesis of hypertension in rats with chronic renal failure (CRF). Because nitric oxide (NO) modulates the activity of the SNS, a deficit of NO synthesis could be responsible for the increased SNS activity in these animals. In the present study, we evaluated the effects of L-arginine and L-NAME on blood pressure and SNS activity-in Sprague Dawley 5/6 nephrectomized or sham-operated rats. SNS activity was determined by measuring norepinephrine turnover rate in several brain nuclei involved in the regulation of blood pressure. In the same brain nuclei, we measured NO content and nitric oxide synthase (NOS) gene expression by semiquantitative measurements of NOS mRNA reverse transcription polymerase chain reaction. In CRF rats, norepinephrine turnover rate was increased in the posterior hypothalamic nuclei, locus coeruleus, paraventricular nuclei, and the rostral ventral medulla, whereas NOS mRNA gene expression and NO2/NO3 content were increased in all brain nuclei tested. L-NAME increased blood pressure and NE turnover rate in several brain nuclei of both control and 5/6 nephrectomized rats. In CRF rats, a significant relationship was present between the percent increment in NOS mRNA gene expression related to the renal failure, and the percent increase in norepinephrine turnover rate caused by L-NAME. This suggests that endogenous NO may partially inhibit the activity of the SNS in brain nuclei involved in the neurogenic regulation of blood pressure, and this inhibition is enhanced in CRF rats. In summary, the increase in SNS activity in the posterior hypothalamic nuclei and in the locus coeruleus of CRF rats is partially mitigated by increased local expression of NOS m-RNA.

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Selected References

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  1. Aisaka K., Gross S. S., Griffith O. W., Levi R. NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo? Biochem Biophys Res Commun. 1989 Apr 28;160(2):881–886. doi: 10.1016/0006-291x(89)92517-5. [DOI] [PubMed] [Google Scholar]
  2. Amezcua J. L., Dusting G. J., Palmer R. M., Moncada S. Acetylcholine induces vasodilatation in the rabbit isolated heart through the release of nitric oxide, the endogenous nitrovasodilator. Br J Pharmacol. 1988 Nov;95(3):830–834. doi: 10.1111/j.1476-5381.1988.tb11711.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Armstrong D. M., Ross C. A., Pickel V. M., Joh T. H., Reis D. J. Distribution of dopamine-, noradrenaline-, and adrenaline-containing cell bodies in the rat medulla oblongata: demonstrated by the immunocytochemical localization of catecholamine biosynthetic enzymes. J Comp Neurol. 1982 Dec 1;212(2):173–187. doi: 10.1002/cne.902120207. [DOI] [PubMed] [Google Scholar]
  4. Atuk N. O., Bailey C. J., Turner S., Peach M. J., Westervelt F. B., Jr Red blood cell catechol-o-methyl transferase, plasma catecholamines and renin in renal failure. Trans Am Soc Artif Intern Organs. 1976;22:195–200. [PubMed] [Google Scholar]
  5. Barinaga M. Is nitric oxide the "retrograde messenger"? Science. 1991 Nov 29;254(5036):1296–1297. doi: 10.1126/science.1962189. [DOI] [PubMed] [Google Scholar]
  6. Bigazzi R., Kogosov E., Campese V. M. Altered norepinephrine turnover in the brain of rats with chronic renal failure. J Am Soc Nephrol. 1994 May;4(11):1901–1907. doi: 10.1681/ASN.V4111901. [DOI] [PubMed] [Google Scholar]
  7. Bredt D. S., Hwang P. M., Snyder S. H. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature. 1990 Oct 25;347(6295):768–770. doi: 10.1038/347768a0. [DOI] [PubMed] [Google Scholar]
  8. Brodie B. B., Costa E., Dlabac A., Neff N. H., Smookler H. H. Application of steady state kinetics to the estimation of synthesis rate and turnover time of tissue catecholamines. J Pharmacol Exp Ther. 1966 Dec;154(3):493–498. [PubMed] [Google Scholar]
  9. Buñag R., Eferakeya A. Immediate hypotensive after-effects of posterior hypothalamic lesions in awake rats with spontaneous, renal, or Doca hypertension. Cardiovasc Res. 1976 Nov;10(6):663–671. doi: 10.1093/cvr/10.6.663. [DOI] [PubMed] [Google Scholar]
  10. Campese V. M., Kogosov E. Renal afferent denervation prevents hypertension in rats with chronic renal failure. Hypertension. 1995 Apr;25(4 Pt 2):878–882. doi: 10.1161/01.hyp.25.4.878. [DOI] [PubMed] [Google Scholar]
  11. Chalmers J. P. Brain amines and models of experimental hypertension. Circ Res. 1975 Apr;36(4):469–480. doi: 10.1161/01.res.36.4.469. [DOI] [PubMed] [Google Scholar]
  12. Chalmers J., Pilowsky P. Brainstem and bulbospinal neurotransmitter systems in the control of blood pressure. J Hypertens. 1991 Aug;9(8):675–694. doi: 10.1097/00004872-199108000-00001. [DOI] [PubMed] [Google Scholar]
  13. Ciriello J., Calaresu F. R. Role of paraventricular and supraoptic nuclei in central cardiovascular regulation in the cat. Am J Physiol. 1980 Jul;239(1):R137–R142. doi: 10.1152/ajpregu.1980.239.1.R137. [DOI] [PubMed] [Google Scholar]
  14. Converse R. L., Jr, Jacobsen T. N., Toto R. D., Jost C. M., Cosentino F., Fouad-Tarazi F., Victor R. G. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med. 1992 Dec 31;327(27):1912–1918. doi: 10.1056/NEJM199212313272704. [DOI] [PubMed] [Google Scholar]
  15. Cuche J. L., Prinseau J., Selz F., Ruget G., Baglin A. Plasma free, sulfo- and glucuro-conjugated catecholamines in uremic patients. Kidney Int. 1986 Oct;30(4):566–572. doi: 10.1038/ki.1986.222. [DOI] [PubMed] [Google Scholar]
  16. Enoch D. M., Kerr F. W. Hypothalamic vasopressor and vesicopressor pathways. I. Functional studies. Arch Neurol. 1967 Mar;16(3):290–306. doi: 10.1001/archneur.1967.00470210066008. [DOI] [PubMed] [Google Scholar]
  17. Fisler J. S., Yoshida T., Bray G. A. Catecholamine turnover in S 5B/P1 and Osborne-Mendel rats: response to a high-fat diet. Am J Physiol. 1984 Aug;247(2 Pt 2):R290–R295. doi: 10.1152/ajpregu.1984.247.2.R290. [DOI] [PubMed] [Google Scholar]
  18. Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
  19. Glowinski J., Iversen L. L. Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem. 1966 Aug;13(8):655–669. doi: 10.1111/j.1471-4159.1966.tb09873.x. [DOI] [PubMed] [Google Scholar]
  20. Granata A. R., Ruggiero D. A., Park D. H., Joh T. H., Reis D. J. Brain stem area with C1 epinephrine neurons mediates baroreflex vasodepressor responses. Am J Physiol. 1985 Apr;248(4 Pt 2):H547–H567. doi: 10.1152/ajpheart.1985.248.4.H547. [DOI] [PubMed] [Google Scholar]
  21. Harada S., Tokunaga S., Momohara M., Masaki H., Tagawa T., Imaizumi T., Takeshita A. Inhibition of nitric oxide formation in the nucleus tractus solitarius increases renal sympathetic nerve activity in rabbits. Circ Res. 1993 Mar;72(3):511–516. doi: 10.1161/01.res.72.3.511. [DOI] [PubMed] [Google Scholar]
  22. Henrich W. L., Katz F. H., Molinoff P. B., Schrier R. W. Competitive effects of hypokalemia and volume depletion on plasma renin activity, aldosterone and catecholamine concentrations in hemodialysis patients. Kidney Int. 1977 Oct;12(4):279–284. doi: 10.1038/ki.1977.112. [DOI] [PubMed] [Google Scholar]
  23. Higuchi R., Dollinger G., Walsh P. S., Griffith R. Simultaneous amplification and detection of specific DNA sequences. Biotechnology (N Y) 1992 Apr;10(4):413–417. doi: 10.1038/nbt0492-413. [DOI] [PubMed] [Google Scholar]
  24. Howe P. R., Costa M., Furness J. B., Chalmers J. P. Simultaneous demonstration of phenylethanolamine N-methyltransferase immunofluorescent and catecholamine fluorescent nerve cell bodies in the rat medulla oblongata. Neuroscience. 1980;5(12):2229–2238. doi: 10.1016/0306-4522(80)90139-6. [DOI] [PubMed] [Google Scholar]
  25. Hu L., Manning R. D., Jr, Brands M. W. Long-term cardiovascular role of nitric oxide in conscious rats. Hypertension. 1994 Feb;23(2):185–194. doi: 10.1161/01.hyp.23.2.185. [DOI] [PubMed] [Google Scholar]
  26. Ignarro L. J. Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol. 1990;30:535–560. doi: 10.1146/annurev.pa.30.040190.002535. [DOI] [PubMed] [Google Scholar]
  27. Izzo J. L., Jr, Izzo M. S., Sterns R. H., Freeman R. B. Sympathetic nervous system hyperactivity in maintenance hemodialysis patients. Trans Am Soc Artif Intern Organs. 1982;28:604–607. [PubMed] [Google Scholar]
  28. Johnson R. A., Freeman R. H. Sustained hypertension in the rat induced by chronic blockade of nitric oxide production. Am J Hypertens. 1992 Dec;5(12 Pt 1):919–922. doi: 10.1093/ajh/5.12.919. [DOI] [PubMed] [Google Scholar]
  29. Juskevich J. C., Robinson D. S., Whitehorn D. Effect of hypothalamic stimulation in spontaneously hypertensive and Wistar-Kyoto rats. Eur J Pharmacol. 1978 Oct 15;51(4):429–439. doi: 10.1016/0014-2999(78)90435-1. [DOI] [PubMed] [Google Scholar]
  30. Kalia M., Fuxe K., Goldstein M. Rat medulla oblongata. II. Dopaminergic, noradrenergic (A1 and A2) and adrenergic neurons, nerve fibers, and presumptive terminal processes. J Comp Neurol. 1985 Mar 15;233(3):308–332. doi: 10.1002/cne.902330303. [DOI] [PubMed] [Google Scholar]
  31. Kilbourn R. G., Gross S. S., Jubran A., Adams J., Griffith O. W., Levi R., Lodato R. F. NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci U S A. 1990 May;87(9):3629–3632. doi: 10.1073/pnas.87.9.3629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lazarus J. M., Hampers C., Merrill J. P. Hypertension in chronic renal failure. Treatment with hemodialysis and nephrectomy. Arch Intern Med. 1974 Jun;133(6):1059–1066. [PubMed] [Google Scholar]
  33. Nakata T., Berard W., Kogosov E., Alexander N. Microdialysis in the posterior hypothalamus: sodium chloride affects norepinephrine release, mean arterial pressure, heart rate and behavior in awake rats. Brain Res Bull. 1990 Oct;25(4):593–598. doi: 10.1016/0361-9230(90)90117-i. [DOI] [PubMed] [Google Scholar]
  34. Noris M., Benigni A., Boccardo P., Aiello S., Gaspari F., Todeschini M., Figliuzzi M., Remuzzi G. Enhanced nitric oxide synthesis in uremia: implications for platelet dysfunction and dialysis hypotension. Kidney Int. 1993 Aug;44(2):445–450. doi: 10.1038/ki.1993.264. [DOI] [PubMed] [Google Scholar]
  35. Palkovits M., Záborszky L. Neuroanatomy of central cardiovascular control. Nucleus tractus solitarii: afferent and efferent neuronal connections in relation to the baroreceptor reflex arc. Prog Brain Res. 1977;47:9–34. doi: 10.1016/S0079-6123(08)62709-0. [DOI] [PubMed] [Google Scholar]
  36. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  37. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  38. Palmer R. M., Rees D. D., Ashton D. S., Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun. 1988 Jun 30;153(3):1251–1256. doi: 10.1016/s0006-291x(88)81362-7. [DOI] [PubMed] [Google Scholar]
  39. Patel K. P., Kline R. L. Influence of renal nerves on noradrenergic responses to changes in arterial pressure. Am J Physiol. 1984 Oct;247(4 Pt 2):R615–R620. doi: 10.1152/ajpregu.1984.247.4.R615. [DOI] [PubMed] [Google Scholar]
  40. Peuler J. D., Johnson G. A. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci. 1977 Sep 1;21(5):625–636. doi: 10.1016/0024-3205(77)90070-4. [DOI] [PubMed] [Google Scholar]
  41. Rees D. D., Palmer R. M., Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A. 1989 May;86(9):3375–3378. doi: 10.1073/pnas.86.9.3375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Remuzzi G., Perico N., Zoja C., Corna D., Macconi D., Viganò G. Role of endothelium-derived nitric oxide in the bleeding tendency of uremia. J Clin Invest. 1990 Nov;86(5):1768–1771. doi: 10.1172/JCI114904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Ruggiero D. A., Gatti P. J., Gillis R. A., Norman W. P., Anwar M., Reis D. J. Adrenaline-synthesizing neurons in the medulla of the cat. J Comp Neurol. 1986 Oct 22;252(4):532–542. doi: 10.1002/cne.902520409. [DOI] [PubMed] [Google Scholar]
  44. SPECTOR S., SJOERDSMA A., UDENFRIEND S. BLOCKADE OF ENDOGENOUS NOREPINEPHRINE SYNTHESIS BY ALPHA-METHYL-TYROSINE, AN INHIBITOR OF TYROSINE HYDROXYLASE. J Pharmacol Exp Ther. 1965 Jan;147:86–95. [PubMed] [Google Scholar]
  45. Sakaguchi T., Takahashi M., Bray G. A. Lateral hypothalamus and sympathetic firing rate. Am J Physiol. 1988 Sep;255(3 Pt 2):R507–R512. doi: 10.1152/ajpregu.1988.255.3.R507. [DOI] [PubMed] [Google Scholar]
  46. Sakuma I., Togashi H., Yoshioka M., Saito H., Yanagida M., Tamura M., Kobayashi T., Yasuda H., Gross S. S., Levi R. NG-methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone? Circ Res. 1992 Mar;70(3):607–611. doi: 10.1161/01.res.70.3.607. [DOI] [PubMed] [Google Scholar]
  47. Schalekamp M. A., Schalekamp-Kuyken M. P., de Moor-Fruytier M., Meininger T., Vaandrager-Kranenburg D. J., Birkenhäger W. H. Interrelationships between blood pressure, renin, renin substrate and blood volume in terminal renal failure. Clin Sci Mol Med. 1973 Oct;45(4):417–428. doi: 10.1042/cs0450417. [DOI] [PubMed] [Google Scholar]
  48. Shapoval L. N., Sagach V. F., Pobegailo L. S. Nitric oxide influences ventrolateral medullary mechanisms of vasomotor control in the cat. Neurosci Lett. 1991 Oct 28;132(1):47–50. doi: 10.1016/0304-3940(91)90430-2. [DOI] [PubMed] [Google Scholar]
  49. Takeda K., Buñag R. D. Sympathetic hyperactivity during hypothalamic stimulation in spontaneously hypertensive rats. J Clin Invest. 1978 Sep;62(3):642–648. doi: 10.1172/JCI109171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Taubin H. L., Djahanguiri B., Landsberg L. Noradrenaline concentration and turnover in different regions of the gastrointestinal tract of the rat: an approach to the evaluation of sympathetic activity in the gut. Gut. 1972 Oct;13(10):790–795. doi: 10.1136/gut.13.10.790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Toda N., Kitamura Y., Okamura T. Neural mechanism of hypertension by nitric oxide synthase inhibitor in dogs. Hypertension. 1993 Jan;21(1):3–8. doi: 10.1161/01.hyp.21.1.3. [DOI] [PubMed] [Google Scholar]
  52. Togashi H., Sakuma I., Yoshioka M., Kobayashi T., Yasuda H., Kitabatake A., Saito H., Gross S. S., Levi R. A central nervous system action of nitric oxide in blood pressure regulation. J Pharmacol Exp Ther. 1992 Jul;262(1):343–347. [PubMed] [Google Scholar]
  53. Vallance P., Leone A., Calver A., Collier J., Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992 Mar 7;339(8793):572–575. doi: 10.1016/0140-6736(92)90865-z. [DOI] [PubMed] [Google Scholar]
  54. Vincent S. R., Kimura H. Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience. 1992;46(4):755–784. doi: 10.1016/0306-4522(92)90184-4. [DOI] [PubMed] [Google Scholar]
  55. Ward D. G., Gunn C. G. Locus coeruleus complex: elicitation of a pressor response and a brain stem region necessary for its occurrence. Brain Res. 1976 May 7;107(2):401–406. doi: 10.1016/0006-8993(76)90236-5. [DOI] [PubMed] [Google Scholar]
  56. Whittle B. J., Lopez-Belmonte J., Rees D. D. Modulation of the vasodepressor actions of acetylcholine, bradykinin, substance P and endothelin in the rat by a specific inhibitor of nitric oxide formation. Br J Pharmacol. 1989 Oct;98(2):646–652. doi: 10.1111/j.1476-5381.1989.tb12639.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Yanagisawa M., Kurihara H., Kimura S., Tomobe Y., Kobayashi M., Mitsui Y., Yazaki Y., Goto K., Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988 Mar 31;332(6163):411–415. doi: 10.1038/332411a0. [DOI] [PubMed] [Google Scholar]
  58. Yoshida T., Bray G. A. Catecholamine turnover in rats with ventromedial hypothalamic lesions. Am J Physiol. 1984 Apr;246(4 Pt 2):R558–R565. doi: 10.1152/ajpregu.1984.246.4.R558. [DOI] [PubMed] [Google Scholar]
  59. Zanzinger J., Czachurski J., Seller H. Inhibition of basal and reflex-mediated sympathetic activity in the RVLM by nitric oxide. Am J Physiol. 1995 Apr;268(4 Pt 2):R958–R962. doi: 10.1152/ajpregu.1995.268.4.R958. [DOI] [PubMed] [Google Scholar]

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