Nitric oxide (NO) is well established as a neurotransmitter in the central and peripheral nervous systems1. More recently, another gas, carbon monoxide (CO) has also been implicated in neurotransmission. In the nervous system CO is formed by a subtype of heme oxygenase (HO) designated HO2 (ref. 2). HO2 is localized to discrete neuronal populations in the brain resembling localizations of soluble guanylyl cyclase, which is activated by CO (ref. 3). CO may also function in the peripheral autonomic nervous system, in conjunction with NO. The majority of ganglia in the myenteric plexus possess both HO2 and neuronal NO synthase (NOS)4. Defects in myenteric plexus neurotransmission occur both in mice with targeted deletion of genes for HO2 and neuronal NOS (ref. 5). HO2 also occurs in other autonomic ganglia including the petrosal, superior cervical and nodose ganglia4. Neuronal NOS is localized to neurons regulating male reproductive behavior, such as penile erection, and NOS inhibitors prevent erection6. Because of the other parallels between NO and CO, we speculated that CO may play a role in male reproductive behavior. In the present study we describe HO2 localization in neuronal structures regulating copulatory reflexes. Reflex activity of the bulbospongiosus muscle, which mediates ejaculation and ejaculatory behavior, is markedly diminished in mice with targeted deletion of the gene for HO2 (HO2−).
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Jaffrey, S.R. & Snyder, S.H. Nitric oxide: A neural messenger molecule. Cell. Dev. Biol. 11, 417–440 (1995).
Maines, M.D. The heme oxygenase system: A regulator of second messenger gases. Annu. Rev. Pharmacol. Toxicol. 37, 517–554 (1997).
Verma, A., Hirsch, D.J., Glatt, C.E., Ronnett, G.V. & Snyder, S.H. Carbon monoxide: A putative neural messenger. Science 259, 381–384 (1993).
Zakhary, R. et al. Heme oxygenase 2: endothelial and neuronal localization and role in endothelium-dependent relaxation. Proc. Natl. Acad. Sci. USA 93, 795–798 (1996).
Zakhary, R. et al. Targeted gene deletion of heme oxygenase 2 reveals neural role for carbon monoxide. Proc. Natl. Acad. Sci. USA (in the press).
Burnett, A.L., Lowenstein, C.J., Bredt, D.S., Chang, T.S.K. & Snyder, S.H. Nitric oxide: A physiologic mediator of penile erection. Science 257, 401–403 (1992).
McKenna, K.E., Chung, S.K. & McVary, K.T. A model for the study of sexual function in anesthetized male and female rats. Am. J. Physiol. 30, R1276–R1285 (1991).
Poss, K.D., Thomas, M.J., Ebralidze, A.K., O'Dell, T.J. & Tonegawa, S. Hippocampal long-term potentiation is normal in heme oxygenase-2 mutant mice. Neuron 15, 867–873 (1995).
McGill, T.E. & Tucker, G.R. Genotype and sex drive in intact and castrated male mice. Science 145, 514–515 (1964).
Nelson, R.J. et al. Behavioral abnormalities in male mice lacking neuronal nitric oxide synthase. Nature 378, 383–386 (1995).
Everitt, B.J. Sexual motivation: A neural and behavioral analysis of the mechanisms underlying appetitive and copulatory responses of male rats. Neurosci. Biobehav. Rev. 14, 217–232 (1990).
Rajfer, J., Aronson, W.J., Bush, P.A., Dorey, F.J. & Ignarro, L.J. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to non-adrenergic, non-cholinergic neurotransmission. N. Engl. J. Med. 326, 90–94 (1992).
Burnett, A.L. et al. Nitric oxide dependent penile erection in mice lacking neuronal nitric oxide synthase. Mol. Med. 2, 288–296 (1996).
Benson, G.M., Erection, emission and ejaculation, in The Physiology of Reproduction (eds. Knobil, E. & Neill, J.D.,) 1489–1506 (Raven, New York, 1994).
Marson, L. & McKenna, K.E. Serotonergic neurotoxic lesions facilitate male sexual reflexes. Pharmacol. Biochem. Behav. 47, 883–888 (1994).
Janicak, P.G., Davis, J.M., Preskorn, S.H. & Ayd, F.J., Jr., Principles and Practice of Psychopharmacotherapy (Williams and Wilkins, Baltimore, MD, 1994).
Spector, I.P. & Carey, M.P. Incidence and prevalence of the sexual dysfunctions: A critical review of the empirical literature. Arch. Sex. Behav. 19, 389–408 (1990).
Prabhakar, N.R., Dinerman, J.L., Agani, F.H. & Snyder, S.H. Carbon monoxide: A role in carotid body chemoreception. Proc. Natl. Acad. Sci. USA 92, 1994–1997 (1995).
Gulbenkian, S., Wharton, J. & Polak, J.M. The visualization of cardiovascular innervation in the guinea pig using an antiserum to protein gene product 9.5 (PGP 9.5). J. Autonom. Nerv. Sys. 18, 235–247 (1987).
Kriegsfeld, L.J. & Nelson, R.J. Gonadal and photoperiodic influences on body mass regulation in adult male and female prairie voles. Am. J. Physiol. 270, R1013–1018 (1996).
About this article
Cite this article
Burnett, A., Johns, D., Kriegsfeld, L. et al. Ejaculatory abnormalities in mice with targeted disruption of the gene for heme oxygenase-2. Nat Med 4, 84–87 (1998). https://doi.org/10.1038/nm0198-084
New Arylethanolimidazole Derivatives as HO-1 Inhibitors with Cytotoxicity against MCF-7 Breast Cancer Cells
International Journal of Molecular Sciences (2020)
Fertility and Sterility (2015)
British Journal of Pharmacology (2015)
Cellular and Molecular Life Sciences (2015)