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Nitric Oxide-Dependent Penile Erection in Mice Lacking Neuronal Nitric Oxide Synthase

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Abstract

Background

Nitric oxide (NO) has been implicated as a mediator of penile erection, because the neuronal isoform of NO synthase (NOS) is localized to the penile innervation and NOS inhibitors selectively block erections. NO can also be formed by two other NOS isoforms derived from distinct genes, inducible NOS (iNOS) and endothelial NOS (eNOS). To clarify the source of NO in penile function, we have examined mice with targeted deletion of the nNOS gene (nNOS− mice).

Materials and Methods

Mating behavior, electro-physiologically induced penile erection, isolated erectile tissue isometric tension, and eNOS localization by immunohistochemistry and Western blot were performed on nNOS− mice and wild-type controls.

Results

Both intact animal penile erections and isolated erectile tissue function are maintained in nNOS mice, in agreement with demonstrated normal sexual behaviors, but is stereospecifically blocked by the NOS inhibitor, L-nitroarginine methyl ester (L-NAME). eNOS is abundantly present in endothelium of penile vasculature and sinusoidal endothelium within the corpora cavernosa, with levels that are significantly higher in nNOS− mice than in wild-type controls.

Conclusions

eNOS mediates NO-dependent penile erection in nNOS− animals and normal penile erection. These data clarify the role of nitric oxide in penile erection and may have implications for therapeutic agents with selective effects on NOS isoforms.

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References

  1. Nathan C. (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J. 6: 3051–3064.

    Article  CAS  PubMed  Google Scholar 

  2. Marietta MA. (1993) Nitric oxide synthase structure and mechanism. J. Biol. Chem. 268: 12231–12234.

    Google Scholar 

  3. Moncada S, Higgs A. (1993) The l-argininenitric oxide pathway. N. Engl. J. Med. 329: 2002–2012.

    Article  CAS  Google Scholar 

  4. Ignarro LJ. (1989) Endothelium-derived nitric oxide: actions and properties. FASEB J. 3: 31–36.

    Article  CAS  PubMed  Google Scholar 

  5. Dawson TM, Snyder SH. (1994) Gases as biological messengers: Nitric oxide and carbon monoxide in the brain. J. Neurosci. 14: 5147–5159.

    Article  CAS  PubMed  Google Scholar 

  6. Garthwaite J, Boulton CL. (1995) Nitric oxide signaling in the central nervous system. Annu. Rev. Physiol. 57: 683–706.

    Article  CAS  PubMed  Google Scholar 

  7. Bredt DS, Snyder SH. (1994) Nitric oxide: A physiologic messenger molecule. Annu. Rev. Biochem. 63: 175–195.

    Article  CAS  PubMed  Google Scholar 

  8. Bredt DS, Glatt CE, Hwang PM, Fotuhi M, Dawson TM, Snyder SH. (1991) Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron 7: 615–624.

    Article  CAS  PubMed  Google Scholar 

  9. Bult H, Boeckxstaens GE, Pelckmans PA, Jordaens FH, Van Maercke YM, Herman AG. (1990) Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature 345: 346–347.

    Article  CAS  PubMed  Google Scholar 

  10. Cocks TM, Angus JA. (1990) Comparison of relaxation responses of vascular and nonvascular smooth muscle to endothelium-derived relaxing factor (EDRF), acidified sodium nitrite (NO) and sodium nitroprusside. Naunyn Schmiedebergs Arch Pharmacol 341: 364–372.

    Article  CAS  PubMed  Google Scholar 

  11. Tottrup A, Svane D, Forman A. (1991) Nitric oxide mediating NANC inhibition in opossum lower esophageal sphincter. Am. J. Physiol. 260: G385–G389.

    PubMed  CAS  Google Scholar 

  12. Desai KM, Sessa WC, Vane JR. (1991) Involvement of nitric oxide in the reflex relaxation of the stomach to accommodate food or fluid. Nature 351: 477–479.

    Article  CAS  PubMed  Google Scholar 

  13. Saenz de Tejada I, Goldstein I, Krane RJ. (1988) Local control of penile erection, nerves, smooth muscle and endothelium. In: Krane RJ (ed). Urol Clinic North America: Impotence. W. B. Saunders, Philadelphia, pp. 9–15.

    Google Scholar 

  14. Benson GS. (1983) Penile erection: In search of a neurotransmitter. World J. Urol. 1: 209–212.

    Article  Google Scholar 

  15. Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J. (1990) Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem. Biophys. Res. Commun. 170: 843–850.

    Article  CAS  PubMed  Google Scholar 

  16. Kim N, Azadzoi KM, Goldstein I, Saenz de-Tejada I. (1991) A nitric-oxide like factor mediates nonadrenergic-noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. J. Clin. Invest. 88: 112–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pickard RS, Powell PH, Zar MA. (1991) The effect of inhibitors of nitric oxide biosynthesis and cyclic GMP formation on nerve evoked relaxation of human cavernosal smooth muscle. Br. J. Pharmacol. 104: 755–759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Knispel HH, Goessl C, Beckman R. (1991) Basal and acetylcholine-stimulated nitric oxide formation mediates relaxation of rabbit cavernous smooth muscle. J. Urol. 146: 1429–1433.

    Article  CAS  PubMed  Google Scholar 

  19. Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ. (1992) Nitric oxide as a mediator of the corpus cavernosum in response to nonadrenergic noncholinergic transmission. N. Engl. J. Med. 326: 90–94.

    Article  CAS  PubMed  Google Scholar 

  20. Holmquist F, Hedlund H, Anderson KE. (1992) Characterisation of inhibitory neurotransmission in the isolated corpus cavernosum from rabbit and man. J. Physiol. 449: 295–311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Burnett AL, Lowenstein CJ, Bredt DS, Chang TSK, Snyder SH. (1992) Nitric oxide: A physiologic mediator of penile erection. Science 257: 401–403.

    Article  CAS  PubMed  Google Scholar 

  22. Burnett AL, Tillman SL, Chang TSK, et al. (1993) Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the human penis. J. Urol. 150: 73–76.

    Article  CAS  PubMed  Google Scholar 

  23. Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC. (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75: 1273–1286.

    Article  CAS  PubMed  Google Scholar 

  24. O’Dell TJ, Huang PL, Dawson TM, et al. (1994) Blockade of long-term potentiation by inhibitors of nitric oxide synthase in mice lacking the neuronal isoform suggests a role for the endothelial isoform. Science 265: 542.

    Article  PubMed  Google Scholar 

  25. Linden DJ, Dawson TM, Dawson VL. (1995) An evaluation of the nitric oxide/cGMP/cGMP-dependent protein kinase cascade in the induction of cerebellar long-term depression in culture. J. Neurosci. 15: 5098–5105.

    Article  CAS  PubMed  Google Scholar 

  26. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. (1994) Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265: 1883–1885.

    Article  CAS  PubMed  Google Scholar 

  27. Roskams AJ, Bredt DS, Dawson TM, Ronnett GV. (1994) Nitric oxide mediates the formation of synaptic connections in developing and regenerating olfactory receptor neurons. Neuron 13: 289–299.

    Article  CAS  PubMed  Google Scholar 

  28. Koutts J, Howard MA, Firkin BG. (1974) Factor 8 physiology and pathology in man. Semin. Hematol. 11: 115–145.

    Google Scholar 

  29. Dawson TM, Bredt DS, Fotuhi M, Hwang PM, Snyder SH. (1991) Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc. Natl. Acad. Sci. U.S.A. 88: 7797–7801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hope BT, Michael GJ, Knigge KM, Vincent SR. (1991) Neuronal NADPH diaphorase is a nitric oxide synthase. Proc. Natl. Acad. Sci. U.S.A. 88: 2811–2814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dinerman JL, Dawson TM, Schell MJ, Snowman A, Snyder SH. (1994) Endothelial nitric oxide synthase localized to hippocampal pyramidal cells: Implications for synaptic plasticity. Proc. Natl. Acad. Sci. U.S.A. 91: 4214–4218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shirai M, Sasaki K, Rikimaru A. (1972) Histochemical investigation on the distribution of adrenergic and cholinergic nerves in human penis. Tohoku J. 107: 403–404.

    Article  Google Scholar 

  33. Gu J, Polak JM, Islam KN, et al. (1983) Peptidergic innervation of human male genital tract. J. Urol. 130: 386–391.

    Article  CAS  PubMed  Google Scholar 

  34. Irikura K, Maynard KI, Lee WS, Moskowitz MA. (1994) l-NNA decreases cortical hyperemia and brain cGMP levels following CO2 inhalation in Sprague-Dawley rats. Am. J. Physiol. 267: H837–H843.

    PubMed  CAS  Google Scholar 

  35. Irikura K, Huang PL, Ma JL, et al. (1995) Cerebrovascular alterations in mice lacking neuronal nitric oxide synthase gene expression. Proc. Natl. Acad. Sci. U.S.A. 92: 6823–6827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by a New Investigator Grant from the American Foundation for Urologic Disease with funds contributed by G. D. Searle (ALB); USPHS Grants HD22201 and CA58618 (RJN); USPHS Grant DA-00266 and Research Scientist Award DA-0074 (SHS), USPHS CIDA NS-01578 and NS33277, the Paul Beeson Physician Scholars in Aging Research Program, and the International Life Sciences Institute (TMD); and USPHS Grant NS33142 (VLD).

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Authors and Affiliations

  1. Department of Urology, The Johns Hopkins Hospital, Baltimore, Maryland, USA

    Arthur L. Burnett, David C. Calvin & Jian-Xiang Liu

  2. Department of Psychology, Behavioral Neuroendocrinology Group, The Johns Hopkins University, Baltimore, Maryland, USA

    Randy J. Nelson, Gregory E. Demas, Sabra L. Klein & Lance J. Kriegsfeld

  3. Department of Neurology, The Johns Hopkins University, Baltimore, Maryland, USA

    Valina L. Dawso & Ted M. Dawson

  4. Department of Neuroscience, The Johns Hopkins University, Baltimore, Maryland, USA

    Valina L. Dawso, Ted M. Dawson & Solomon H. Snyder

  5. Department of Physiology, The Johns Hopkins University, Baltimore, Maryland, USA

    Valina L. Dawso

  6. Departments of Pharmacology and Molecular Sciences, The Johns Hopkins University, Baltimore, Maryland, USA

    Solomon H. Snyder

  7. Departments of Psychiatry and Behavioral Sciences, The Johns Hopkins University, 725 North Wolfe Street, Baltimore, Maryland, 21205, USA

    Solomon H. Snyder

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  1. Arthur L. Burnett
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Burnett, A.L., Nelson, R.J., Calvin, D.C. et al. Nitric Oxide-Dependent Penile Erection in Mice Lacking Neuronal Nitric Oxide Synthase. Mol Med 2, 288–296 (1996). https://doi.org/10.1007/BF03401627

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