Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Jul 18;92(15):6823–6827. doi: 10.1073/pnas.92.15.6823

Cerebrovascular alterations in mice lacking neuronal nitric oxide synthase gene expression.

K Irikura 1, P L Huang 1, J Ma 1, W S Lee 1, T Dalkara 1, M C Fishman 1, T M Dawson 1, S H Snyder 1, M A Moskowitz 1
PMCID: PMC41421  PMID: 7542777

Abstract

Nitric oxide (NO) is known to mediate increases in regional cerebral blood flow elicited by CO2 inhalation. In mice with deletion of the gene for neuronal NO synthase (NOS), CO2 inhalation augments cerebral blood flow to the same extent as in wild-type mice. However, unlike wild-type mice, the increased flow in mutants is not blocked by the NOS inhibition, N omega-nitro-L-arginine, and CO2 exposure fails to increase brain levels of cGMP. Topical acetylcholine elicits vasodilation in the mutants which is blocked by N omega-nitro-L-arginine, indicating normal functioning of endothelial NOS. Moreover, immunohistochemical staining for endothelial NOS is normal in the mutants. Thus, following loss of neuronal NOS, the cerebral circulatory response is maintained by a compensatory system not involving NO.

Full text

PDF

Images in this article

6824Fig. 1
on p.6824

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. 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]
  2. Bredt D. S., Snyder S. H. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci U S A. 1989 Nov;86(22):9030–9033. doi: 10.1073/pnas.86.22.9030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dinerman J. L., Dawson T. M., Schell M. J., Snowman A., Snyder S. H. Endothelial nitric oxide synthase localized to hippocampal pyramidal cells: implications for synaptic plasticity. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4214–4218. doi: 10.1073/pnas.91.10.4214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dirnagl U., Lindauer U., Villringer A. Role of nitric oxide in the coupling of cerebral blood flow to neuronal activation in rats. Neurosci Lett. 1993 Jan 4;149(1):43–46. doi: 10.1016/0304-3940(93)90343-j. [DOI] [PubMed] [Google Scholar]
  5. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr, Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. doi: 10.1038/356215a0. [DOI] [PubMed] [Google Scholar]
  6. Garthwaite J., Garthwaite G., Palmer R. M., Moncada S. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol. 1989 Oct 17;172(4-5):413–416. doi: 10.1016/0922-4106(89)90023-0. [DOI] [PubMed] [Google Scholar]
  7. Huang P. L., Dawson T. M., Bredt D. S., Snyder S. H., Fishman M. C. Targeted disruption of the neuronal nitric oxide synthase gene. Cell. 1993 Dec 31;75(7):1273–1286. doi: 10.1016/0092-8674(93)90615-w. [DOI] [PubMed] [Google Scholar]
  8. Huang Z., Huang P. L., Panahian N., Dalkara T., Fishman M. C., Moskowitz M. A. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science. 1994 Sep 23;265(5180):1883–1885. doi: 10.1126/science.7522345. [DOI] [PubMed] [Google Scholar]
  9. Iadecola C. Does nitric oxide mediate the increases in cerebral blood flow elicited by hypercapnia? Proc Natl Acad Sci U S A. 1992 May 1;89(9):3913–3916. doi: 10.1073/pnas.89.9.3913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Iadecola C., Pelligrino D. A., Moskowitz M. A., Lassen N. A. Nitric oxide synthase inhibition and cerebrovascular regulation. J Cereb Blood Flow Metab. 1994 Mar;14(2):175–192. doi: 10.1038/jcbfm.1994.25. [DOI] [PubMed] [Google Scholar]
  11. Iadecola C., Zhang F., Xu X. SIN-1 reverses attenuation of hypercapnic cerebrovasodilation by nitric oxide synthase inhibitors. Am J Physiol. 1994 Jul;267(1 Pt 2):R228–R235. doi: 10.1152/ajpregu.1994.267.1.R228. [DOI] [PubMed] [Google Scholar]
  12. Irikura K., Maynard K. I., Lee W. S., Moskowitz M. A. L-NNA decreases cortical hyperemia and brain cGMP levels following CO2 inhalation in Sprague-Dawley rats. Am J Physiol. 1994 Aug;267(2 Pt 2):H837–H843. doi: 10.1152/ajpheart.1994.267.2.H837. [DOI] [PubMed] [Google Scholar]
  13. Kontos H. A., Raper A. J., Patterson J. L. Analysis of vasoactivity of local pH, PCO2 and bicarbonate on pial vessels. Stroke. 1977 May-Jun;8(3):358–360. doi: 10.1161/01.str.8.3.358. [DOI] [PubMed] [Google Scholar]
  14. Lambert L. E., Whitten J. P., Baron B. M., Cheng H. C., Doherty N. S., McDonald I. A. Nitric oxide synthesis in the CNS endothelium and macrophages differs in its sensitivity to inhibition by arginine analogues. Life Sci. 1991;48(1):69–75. doi: 10.1016/0024-3205(91)90426-c. [DOI] [PubMed] [Google Scholar]
  15. Morikawa E., Rosenblatt S., Moskowitz M. A. L-arginine dilates rat pial arterioles by nitric oxide-dependent mechanisms and increases blood flow during focal cerebral ischaemia. Br J Pharmacol. 1992 Dec;107(4):905–907. doi: 10.1111/j.1476-5381.1992.tb13382.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Niwa K., Lindauer U., Villringer A., Dirnagl U. Blockade of nitric oxide synthesis in rats strongly attenuates the CBF response to extracellular acidosis. J Cereb Blood Flow Metab. 1993 May;13(3):535–539. doi: 10.1038/jcbfm.1993.70. [DOI] [PubMed] [Google Scholar]
  17. O'Dell T. J., Huang P. L., Dawson T. M., Dinerman J. L., Snyder S. H., Kandel E. R., Fishman M. C. Endothelial NOS and the blockade of LTP by NOS inhibitors in mice lacking neuronal NOS. Science. 1994 Jul 22;265(5171):542–546. doi: 10.1126/science.7518615. [DOI] [PubMed] [Google Scholar]
  18. Pelligrino D. A., Koenig H. M., Albrecht R. F. Nitric oxide synthesis and regional cerebral blood flow responses to hypercapnia and hypoxia in the rat. J Cereb Blood Flow Metab. 1993 Jan;13(1):80–87. doi: 10.1038/jcbfm.1993.10. [DOI] [PubMed] [Google Scholar]
  19. Rudnicki M. A., Braun T., Hinuma S., Jaenisch R. Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development. Cell. 1992 Oct 30;71(3):383–390. doi: 10.1016/0092-8674(92)90508-a. [DOI] [PubMed] [Google Scholar]
  20. Sandor P., Komjati K., Reivich M., Nyary I. Major role of nitric oxide in the mediation of regional CO2 responsiveness of the cerebral and spinal cord vessels of the cat. J Cereb Blood Flow Metab. 1994 Jan;14(1):49–58. doi: 10.1038/jcbfm.1994.8. [DOI] [PubMed] [Google Scholar]
  21. Stein P. L., Lee H. M., Rich S., Soriano P. pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells. Cell. 1992 Sep 4;70(5):741–750. doi: 10.1016/0092-8674(92)90308-y. [DOI] [PubMed] [Google Scholar]
  22. Toda N., Ayajiki K., Enokibori M., Okamura T. Monkey cerebral arterial relaxation caused by hypercapnic acidosis and hypertonic bicarbonate. Am J Physiol. 1993 Sep;265(3 Pt 2):H929–H933. doi: 10.1152/ajpheart.1993.265.3.H929. [DOI] [PubMed] [Google Scholar]
  23. Wang D. B., Blocher N. C., Spence M. E., Rovainen C. M., Woolsey T. A. Development and remodeling of cerebral blood vessels and their flow in postnatal mice observed with in vivo videomicroscopy. J Cereb Blood Flow Metab. 1992 Nov;12(6):935–946. doi: 10.1038/jcbfm.1992.130. [DOI] [PubMed] [Google Scholar]
  24. Wang Q., Paulson O. B., Lassen N. A. Indomethacin abolishes cerebral blood flow increase in response to acetazolamide-induced extracellular acidosis: a mechanism for its effect on hypercapnia? J Cereb Blood Flow Metab. 1993 Jul;13(4):724–727. doi: 10.1038/jcbfm.1993.92. [DOI] [PubMed] [Google Scholar]
  25. Wang Q., Pelligrino D. A., Koenig H. M., Albrecht R. F. The role of endothelium and nitric oxide in rat pial arteriolar dilatory responses to CO2 in vivo. J Cereb Blood Flow Metab. 1994 Nov;14(6):944–951. doi: 10.1038/jcbfm.1994.126. [DOI] [PubMed] [Google Scholar]
  26. You J. P., Wang Q., Zhang W., Jansen-Olesen I., Paulson O. B., Lassen N. A., Edvinsson L. Hypercapnic vasodilatation in isolated rat basilar arteries is exerted via low pH and does not involve nitric oxide synthase stimulation or cyclic GMP production. Acta Physiol Scand. 1994 Dec;152(4):391–397. doi: 10.1111/j.1748-1716.1994.tb09821.x. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES