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The participation of brain NO synthase in blood pressure control of adult spontaneously hypertensive rats

Molecular and Cellular Biochemistry volume 297, Article number: 21 (2007) Cite this article

Abstract

Increased blood pressure (BP) in genetic hypertension is usually caused by high activity of sympathetic nervous system (SNS) which is enhanced by central angiotensin II but lowered by central nitric oxide (NO). We have therefore evaluated NO synthase (NOS) activity as well as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) protein expression in brainstem and midbrain of adult spontaneously hypertensive rats (SHR) characterized by enhanced sympathetic vasoconstriction. We also studied possible participation of brain NO in antihypertensive effects of chronic captopril treatment of adult SHR. NOS activity was increased in midbrain of SHR compared to Wistar-Kyoto (WKY) rats. This could be ascribed to enhanced iNOS expression, whereas nNOS expression was unchanged and eNOS expression was reduced in this brain region. In contrast, no significant changes of NOS activity were found in brainstem of SHR in which nNOS and iNOS expression was unchanged, but eNOS expression was increased. Chronic captopril administration lowered BP of adult SHR mainly by attenuation of sympathetic tone, whereas the reduction of angiotensin II-dependent vasoconstriction and the decrease of residual BP (amelioration of structural remodeling of resistance vessels) were less important. This treatment did not affect significantly either NOS activity or expression of any NOS isoform in the two brain regions. Our data do not support the hypothesis that altered brain NO formation contributes to sympathetic hyperactivity and high BP of adult SHR with established hypertension.

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References

  1. Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 87:682–685

    PubMed  Article  CAS  Google Scholar 

  2. Schuman EM, Madison DV (1994) Nitric oxide and synaptic function. Annu Rev Neurosci 17:153–183

    PubMed  Article  CAS  Google Scholar 

  3. Vincent SR, Kimura H (1992) Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience 46:755–784

    PubMed  Article  CAS  Google Scholar 

  4. Krukoff TL (1998) Central regulation of autonomic function: NO brakes? Clin Exp Pharmacol Physiol 25:474–478

    PubMed  CAS  Google Scholar 

  5. Leenen FHH, Ruzicka M, Huang BS (2002) The brain, salt-sensitive hypertension. Curr Hypertens Rep 4:129–135

    PubMed  Google Scholar 

  6. Ramchandra R, Barrett CJ, Malpas SC (2005) Nitric oxide and sympathetic nerve activity in the control of blood pressure. Clin Exp Pharmacol Physiol 32:440–446

    PubMed  Article  CAS  Google Scholar 

  7. Ganten D, Speck G (1978) The brain rennin–angiotensin system: a model for the synthesis of peptides in the brain. Biochem Pharmacol 27:2379–2389

    PubMed  Article  CAS  Google Scholar 

  8. Brody MJ, Fink GD, Buggy J, Haywood JR, Gordon FJ, Johnson AK (1978) The role of the anteroventral third ventricle (AV3V) region in experimental hypertension. Circ Res 43(Suppl I):I2-I13

    Google Scholar 

  9. Osborn JW (2005) Hypothesis: set-points and long-term control of arterial pressure. A theoretical argument for a long-term arterial pressure control system in the brain rather than the kidney. Clin Exp Pharmacol Physiol 32:384–393

    PubMed  Article  CAS  Google Scholar 

  10. Allen AM (2002) Inhibition of the hypothalamic paraventricular nucleus in spontaneously hypertensive rats dramatically reduces sympathetic vasomotor tone. Hypertension 39:275–280

    PubMed  Article  CAS  Google Scholar 

  11. Ito S, Komatsu K, Tsukamoto K, Kanmatsuse K, Sved AF (2002) Ventrolateral medulla AT1 receptors support blood pressure in hypertensive rats. Hypertension 40:552–559

    PubMed  Article  CAS  Google Scholar 

  12. Ferguson AV (1988) Paraventricular nucleus neurons projecting to the dorsomedial medulla are influenced by systemic angiotensin. Brain Res Bull 20:197–201

    PubMed  Article  Google Scholar 

  13. Ferguson AV, Bains JS (1997) Actions of angiotensin in the subfornical organ and area postrema: implications for long term control of autonomic output. Clin Exp Pharmacol Physiol 24:96–101

    PubMed  CAS  Google Scholar 

  14. Wright JW, Harding JW (1992) Regulatory role of brain angiotensins in the control of physiological and behavioral responses. Brain Res Rev 17:227–262

    PubMed  Article  CAS  Google Scholar 

  15. Veerasingham SJ, Raizada MK (2003) Brain rennin–angiotensin system dysfunction in hypertension: recent advances and perspectives. Br J Pharmacol 139:191–202

    PubMed  Article  CAS  Google Scholar 

  16. De Jonge A, Knape JT, van Meel JC, Kalkman HO, Wilffert B, Thoolen MJ, Van Brummelen P, Timmermanns PB, van Zwieten PA (1983) Effect of captopril on sympathetic neurotransmission in pithed normotensive rats. Eur J Pharmacol 88:231–240

    PubMed  Article  Google Scholar 

  17. Balt JC, Mathy MJ, Pfaffendorf M, van Zwieten PA (2001) Inhibition of angiotensin II-induced facilitation of sympathetic neurotransmission in the pithed rat: a comparison between losartan, irbesartan, telmisartan, and captopril. J Hypertens 19:465–473

    PubMed  Article  CAS  Google Scholar 

  18. Balt JC, Mathy MJ, Pfaffendorf M, van Zwieten PA (2002) Sympatho-inhibitory properties of various AT1 receptor antagonists. J Hypertens 20(Suppl 5):S3–S11

    CAS  Google Scholar 

  19. Minami N, Imai Y, Hashimoto J, Abe K (1995) Contribution of vascular nitric oxide to basal blood pressure in conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Clin Sci 89:177–182

    PubMed  CAS  Google Scholar 

  20. Yamazaki J, Fujita N, Nagao T (1991) NG-monomethyl-l-arginine-induced pressor response at developmental and established stages in spontaneously hypertensive rats. J Pharmacol Exp Ther 259:52–57

    PubMed  CAS  Google Scholar 

  21. Zicha J, Dobešová Z, Kuneš J (2001) Relative deficiency of nitric oxide-dependent vasodilation in salt-hypertensive Dahl rats: the possible role of superoxide anions. J Hypertens 19:247–254

    PubMed  Article  CAS  Google Scholar 

  22. Dobešová Z, Kuneš J, Zicha J (2002) The altered balance between sympathetic nervous system and nitric oxide in salt hypertensive Dahl rats: ontogenetic and F2 hybrid studies. J Hypertens 20:945–955

    PubMed  Article  Google Scholar 

  23. Kuneš J, Dobešová Z, Zicha J (2002) Altered balance of main vasopressor and vasodepressor systems in rats with genetic hypertension and hypertriglyceridaemia. Clin Sci 102:269–277

    PubMed  Article  Google Scholar 

  24. Dampney RA, Horiuchi J, Killinger S, Sheriff MJ, Tan PS, McDowall LM (2005) Long-term regulation of arterial blood pressure by hypothalamic nuclei: some critical questions. Clin Exp Pharmacol Physiol 32:419–425

    PubMed  Article  CAS  Google Scholar 

  25. Cabrera CL, Bealer SL, Bohr DF (1996) Central depressor action of nitric oxide is deficient in genetic hypertension. Am J Hypertens 9:237–241

    PubMed  Article  CAS  Google Scholar 

  26. Kagiyama S, Tsuchihashi I, Abe I, Fujishima M (1998) Enhanced depressor response to nitric oxide in the rostral ventrolateral medulla of spontaneously hypertensive rats. Hypertension 31:1030–1034

    PubMed  CAS  Google Scholar 

  27. Plochocka-Zulinska D, Krukoff TL (1997) Increased gene expression of neuronal nitric oxide synthase in brain of adult spontaneously hypertensive rats. Brain Res Mol Brain Res 48:291–297

    PubMed  Article  CAS  Google Scholar 

  28. Qadri F, Arens T, Schwarz E-C, Häuser W, Dendorfer A, Dominiak P (2003) Brain nitric oxide synthase activity in spontaneously hypertensive rats during the development of hypertension. J Hypertens 21:1687–1694

    PubMed  Article  CAS  Google Scholar 

  29. Edwards MA, Loxley RA, Powers-Martin K, Lipski J, McKitrick DJ, Arnolda LF, Philips JK (2004) Unique levels of expression of N-methyl-d-aspartate receptor subunits and neuronal nitric oxide synthase in the rostral ventrolateral medulla of the spontaneously hypertensive rat. Brain Res Mol Brain Res 129:33–43

    PubMed  Article  CAS  Google Scholar 

  30. Chan JYH, Wang LL, Wu KLH, Chan SHH (2001) Reduced functional expression and molecular synthesis of inducible nitric oxide synthase in rostral ventrolateral medulla of spontaneously hypertensive rats. Circulation 104:1676–1681

    PubMed  CAS  Google Scholar 

  31. Yamakawa H, Ježová M, Ando H, Saavedra JM (2003) Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J Cereb Blood Flow Metab 23:371–380

    PubMed  Article  CAS  Google Scholar 

  32. Häuser W, Sassmann A, Qadri F, Johren O, Dominiak P (2005) Expression of nitric oxide synthase isoforms in hypothalamo-pituitary-adrenal axis during the development of spontaneous hypertension in rats. Brain Res Mol Brain Res 138:198–204

    PubMed  Article  CAS  Google Scholar 

  33. Paxinos G (ed): The Rat Nervous System, Vol. 1. Forebrain and Midbrain. Academic Press, Sydney, 1985, pp 89–101, 119–126

  34. Bredt DS, Snyder SH (1992) Nitric oxide, a novel neuronal messenger. Neuron 8:3–11

    PubMed  Article  CAS  Google Scholar 

  35. Pecháňová O, Bernátová I, Pelouch V, Šimko F (1997) Protein remodelling of the heart in NO-deficient hypertension: the effect of captopril. J Mol Cell Cardiol 29:3365–3374

    PubMed  Article  Google Scholar 

  36. De Jonge A, Knape JT, van Meel JC, Kalkman HO, Wilffert B, Thoolen MJ, Timmermanns PB, van Zwieten PA (1982) Effect of converting enzyme inhibition and angiotensin receptor blockade on the vasoconstriction mediated by α1- and α2-adrenoceptor stimulation in pithed normotensive rats. Naunyn-Schmiedebergs Arch Pharmacol 321:309–313

    PubMed  Article  Google Scholar 

  37. Ferrari MFR, Fior-Chadi DR (2005) Differential expression of nNOS mRNA and protein in the nucleus tractus solitarii of young and aged Wistar-Kyoto and spontaneously hypertensive rats. J Hypertens 23:1683–1690

    PubMed  CAS  Article  Google Scholar 

  38. Chou TC, Yen MH, Li CY, Ding YA (1998) Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension 31:643–648

    PubMed  CAS  Google Scholar 

  39. Millatt LJ, Abdel-Rahman EM, Siragy HM (1999) Angiotensin II and nitric oxide: a question of balance. Regul Pept 81:1–10

    PubMed  Article  CAS  Google Scholar 

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Acknowledgements

The authors wish to thank M. Schützová for NOS activity determination. This work was in part supported by the Grant Agency of Ministry of Health of the Czech Republic (Grant NR 7786-3/2004).

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Affiliations

  1. Institute of Physiology AS CR, Charles University, Videnska 1083, 142 20, Prague 4, Czech Republic

    Silvie Hojná, Michaela Kadlecová, Zdenka Dobešová, Josef Zicha & Jaroslav Kuneš

  2. Institute of Physiology, Second Faculty of Medicine, Charles University, Prague, Czech Republic

    Věra Valoušková

  3. Cardiovascular Research Center, Prague, Czech Republic

    Silvie Hojná, Michaela Kadlecová, Zdenka Dobešová, Věra Valoušková, Josef Zicha & Jaroslav Kuneš

Authors
  1. Silvie Hojná
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  2. Michaela Kadlecová
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  3. Zdenka Dobešová
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  4. Věra Valoušková
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  5. Josef Zicha
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  6. Jaroslav Kuneš
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Correspondence to Jaroslav Kuneš.

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Hojná, S., Kadlecová, M., Dobešová, Z. et al. The participation of brain NO synthase in blood pressure control of adult spontaneously hypertensive rats. Mol Cell Biochem 297, 21 (2007). https://doi.org/10.1007/s11010-006-9318-0

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  • DOI: https://doi.org/10.1007/s11010-006-9318-0

Keywords

  • angiotensin II-dependent vasoconstriction
  • brainstem
  • endothelial NOS
  • genetic hypertension
  • inducible NOS
  • midbrain
  • neuronal NOS
  • NO-dependent vasodilation
  • sympathetic vasoconstriction