Features of the inducible nitric oxide synthase expression in paraventricular and supraoptic nuclei of hypothalamus in different models of arterial hypertension


  • Yu. M. Kolesnyk Zaporizhzhia State Medical University,
  • N. V. Kuzo Zaporizhzhia State Medical University,
  • O. V. Hancheva Zaporizhzhia State Medical University,
  • A. V. Abramov Zaporizhzhia State Medical University,




Hypothalamus, Experimental Arterial Hypertension, Rats, Magnocellular Neurons, Nitric Oxide Synthase


The regulation of the paraventricular (PVN) and supraoptic (SON) nuclei’s activity is carried out with a great amount of different neurotransmitters, in particular, with nitric oxide. In order to get clear understanding of the local NO effects in hypothalamus in normal condition and different models of hypertension it is necessary to study all isoforms of NOS in PVN and SON.

Our purpose was to find out the features of the inducible nitric oxide synthase (iNOS) expression in magnocellular SON and PVN in SHR and endocrine-saline model of hypertension in rats.

Materials and methods. For all rats the mean blood pressure (mBP) was measured. In Wistar rats mBP was stable during the experiment. In SHR mBP was higher than normal. In animals of the 3rd group with ESM the first measurement (before the modelling) demonstrated normal rates of mBP. Since the 7th day of modelling mBP started increase and became steadily increased from the 21st day. We obtained the frontal slices of hypothalamus and performed the assessment of iNOS expression using immunofluorescence assay.

The results showed the presence of the constitutive expression of iNOS in the magnocellular neurons of hypothalamus in Wistar rats as well as in both groups of experimental hypertension. The level of iNOS expression in magnocellular nuclei was dependent both on type of hypertension and topography of magnocellular neurons in hypothalamus. In SHR there was high expression of iNOS in PVN and low one in SON, whereas in endocrine-saline model there was high expression in SON and there were no substantial changes of the iNOS expression in PVN.

Conclusions. We believe the alteration of iNOS expression in magnocellular nuclei of hypothalamus could participate in development and/or adaptation to hypertension.


Sawchenko, P. & Swanson, L. (1982). Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat. The Journal Of Comparative Neurology, 205(3), 260–272. doi: 10.1002/cne.902050306.

Ventura, R., Aguiar, J., Antunes-Rodrigues, J., & Varanda, W. (2008). Nitric oxide modulates the firing rate of the rat supraoptic magnocellular neurons. Neuroscience, 155(2), 359–365. doi: 10.1016/j.neuroscience.

Yamova, L., Dmitriy, A., Glazova, M., Chernigovskaya, E., & Huang, P. (2007). Role of neuronal nitric oxide in the regulation of vasopressin expression and release in response to inhibition of catecholamine synthesis and dehydration. Neuroscience Letters, 426(3), 160–165. doi: 10.1016/j.neulet.2007.08.066.

Forstermann, U. & Sessa, W. (2012). Nitric oxide synthases: regulation and function. European Heart Journal, 33(7), 829–837. doi: 10.1093/eurheartj/ehr304.

Hardingham, N., Dachtler, J., & Fox, K. (2013). The role of nitric oxide in pre-synaptic plasticity and homeostasis. Frontiers In Cellular Neuroscience, 7. doi: 10.3389/fncel.2013.00190.

Brown, G. & Neher, J. (2010). Inflammatory Neurodegeneration and Mechanisms of Microglial Killing of Neurons. Molecular Neurobiology, 41(2-3), 242–247. doi: 10.1007/s12035-010-8105-9.

Stern, J. (2004). Nitric oxide and homeostatic control: an intercellular signalling molecule contributing to autonomic and neuroendocrine integration? Progress In Biophysics And Molecular Biology, 84(2–3), 197–215. http://dx.doi.org/10.1016/j.pbiomolbio.2003.11.015.

Watkins, N., Cork, S., & Pyner, S. (2009). An immunohistochemical investigation of the relationship between neuronal nitric oxide synthase, GABA and presympathetic paraventricular neurons in the hypothalamus. Neuroscience, 159(3), 1079–1088. doi: 10.1016/j.neuroscience.2009.01.012.

Weiss, M. L., Chowdhury, S. I., Patel, K. P., Kenney, M. J. & Huang, J. (2001). Neural circuitry of the kidney: NO-containing neurons. Brain Res. 919, 269–282. doi: 10.1016/S0006-8993(01)03030-X.

Li, D.-P., Chen, S.-R. & Pan, H.-L. (2002). Nitric oxide inhibits spinally projecting paraventricular neurons through potentiation of presynaptic GABA release. J. Neurophysiol. 88, 2664–2674. doi: 10.1152/jn.00540.2002.

Li, Y., Zhang, W., & Stern, Z. (2003). Nitric oxide inhibits the firing activity of hypothalamic paraventricular neurons that innervate the medulla oblongata: role of GABA. Neuroscience, 118, 585–601. doi: 10.1016/S0306-4522(03)00042-3. •

Kantzides, A. & Badoer, E. (2005). nNOS-containing neurons in the hypothalamus and medulla project to the RVLM. Brain Res., 1037, 25–34. doi: 10.1016/j.brainres.2004.11.032.

Pyner, S. & Coote, J. H. (1999) Identification of an efferent projection from the paraventricular nucleus of the hypothalamus terminating close to spinally projecting rostral ventrolateral medullary neurons. Neuroscience, 88, 949–957. doi: 10.1016/S0306-4522(98)00255-3.

Nyle´n, A., Skagerberg, G., Alm, P., Larsson, B., Holmqvist, B. & Andersson, K. E. (2001). Nitric oxide synthase in the hypothalamic paraventricular nucleus of the female rat: organisation of spinal projections and coexistence with oxytocin or vasopressin. Brain Res., 908, 10–24. http://dx.doi.org/10.1016/S0006-8993(01)02539-2.

Villanueva, C. & Giulivi, C. (2010). Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease. Free Radical Biology And Medicine, 49(3), 307–316. doi: 10.1016/j.freeradbiomed.2010.04.004.

Amitai, Y. (2010). Physiologic role for “inducible” nitric oxide synthase: A new form of astrocytic-neuronal interface. Glia, 58(15), 1775–1781. doi: 10.1002/glia.21057.

Koh, P. (2012). Ferulic acid modulates nitric oxide synthase expression in focal cerebral ischemia. Laboratory Animal Research, 28(4), 273. doi: 10.5625/lar.2012.28.4.273.

Wang, Y. & Golledge, J. (2012). Neuronal Nitric Oxide Synthase and Sympathetic Nerve Activity in Neurovascular and Metabolic Systems. CNR, 10(1), 81–89. doi: 10.2174/156720213804805963.

Kolesnyk, Y. M., Hancheva, O. V., & Kuzo, N. V. (2015). Osoblyvosti ekspresii konstytutyvnykh izoform syntazy oksydu azotu v paraventrykuliarnomu ta supraoptychnomu yadrakh hipotalamusa pry arterialnii hipertenzii riznoho henezu. [The features of expression of constitutive isoforms of the nitric oxide synthase in paraventricular and supraoptic nuclei of the hypothalamus in hypertension of different origins]. Patolohiia, 3(35), 21–25. [in Ukrainian]. doi: 10.14739/2310-1237.2015.3.56310.

Kolesnyk, Yu. M., Hancheva, O. V., Abramov, A. V., Ivanenko, T. V., Tishchenko, S. V., & Kuzo, N. V. (patentee) (2015) Patent Ukrainy №u 2015 03152 Sposib modeliuvannia symptomatychnoi arterialnoi hipertenzii u dribnykh hryzuniv [Patent of Ukraine №u 2015 03152 Method of Modeling of Symptomatic Hypertension in Rodents]. Biuleten, 20 [in Ukrainian]

Paxinos, G. & Watson, C. (2007). The rat brain in stereotaxic coordinates. Amsterdam: Elsevier.

Buskila, Y., Abu-Ghanem, Y., Levi, Y., Moran, A., Grauer, E., & Amitai, Y. (2007). Enhanced Astrocytic Nitric Oxide Production and Neuronal Modifications in the Neocortex of a NOS2 Mutant Mouse. Plos ONE, 2(9), e843. doi: 10.1371/journal.pone.0000843.

Buskila, Y. & Amitai, Y. (2010). Astrocytic iNOS-Dependent Enhancement of Synaptic Release in Mouse Neocortex. Journal Of Neurophysiology, 103(3), 1322–1328. doi: 10.1152/jn.00676.2009.

Grange-Messent, V., Raison, D., Dugas, B., & Calas, A. (2004). Noradrenaline up-regulates the neuronal and the inducible nitric oxide synthase isoforms in magnocellular neurons of rat brain slices. J. Neurosci. Res., 78(5), 683–690. doi: 10.1002/jnr.20331.

Chan, S., Wang, L., & Chan, J. (2003). Differential engagements of glutamate and GABA receptors in cardiovascular actions of endogenous nNOS or iNOS at rostral ventrolateral medulla of rats. British Journal Of Pharmacology, 138(4), 584–593. doi: 10.1038/sj.bjp.0705081.

Peng, J., Wang, Y., Wang, L., Yuan, W., Su, D., Ni, X. et al. (2009). Sympathoinhibitory mechanism of moxonidine: role of the inducible nitric oxide synthase in the rostral ventrolateral medulla. Cardiovascular Research, 84(2), 283–291. doi: 10.1093/cvr/cvp202.

Chan, S., Wang, L., Wang, S., & Chan, J. (2001). Differential cardiovascular responses to blockade of nNOS or iNOS in rostral ventrolateral medulla of the rat. British Journal Of Pharmacology, 133(4), 606–614. doi: 10.1038/sj.bjp.0704105.

Kishi, T. & Hirooka, Y. (2012). Oxidative stress in the brain causes hypertension via sympathoexcitation. Frontiers In Physiology, 3. doi: 10.3389/fphys.2012.00335.

Arnolda, L. (2002). Inducible nitric oxide synthase and cardiac dysfunction in salt-sensitive hypertension. Journal Of Hypertension, 20(12), 2355–2356. http://dx.doi.org/10.1097/00004872-200212000-00011.

Tan, D. Y., Meng, S., Cason, G. W., & Manning, R. D. (2000). Mechanisms of salt-sensitive hypertension: role of inducible nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol, 279, R2297–R2303.

Loscalzo, J. (2001). Salt-Sensitive Hypertension and Inducible Nitric Oxide Synthase: Form-Function Dichotomy of a Coding Region Mutation, Mutatis Mutandis. Circ Res, 89, 292–294.

Tian, N., Gannon, A., Khalil, R., & Manning, R. (2002). Mechanisms of salt-sensitive hypertension: role of renal medullary inducible nitric oxide synthase. American Journal Of Physiology - Regulatory, Integrative And Comparative Physiology, 284(2), R372–R379. doi: 10.1152/ajpregu.00509.2002.

McCloy, R. A., Rogers, S., Caldon, C. E., Lorca, T., Castro, A., & Burgess, A. (2014) Partial inhibition of Cdk1 in G 2 phase overrides the SAC and decouples mitotic events. Cell Cycle, 13, 1400–1412. doi: 10.4161/cc.28401.


How to Cite

Kolesnyk YM, Kuzo NV, Hancheva OV, Abramov AV. Features of the inducible nitric oxide synthase expression in paraventricular and supraoptic nuclei of hypothalamus in different models of arterial hypertension. Zaporozhye medical journal [Internet]. 2016Oct.13 [cited 2024Feb.23];18(4). Available from: http://zmj.zsmu.edu.ua/article/view/79681



Original research