Gene Transfer of Endothelial Nitric Oxide Synthase to the Penis Augments Erectile Responses in the Aged Rat

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1999 Sep 29

PMID 10500231

Citations 27

Authors

H C Champion

T J Bivalacqua

A L HYMAN

L J Ignarro

W J Hellstrom

P J Kadowitz

Affiliations

Soon will be listed here.

Abstract

Nitric oxide (NO), a mediator involved in penile erection, is synthesized by the nitric oxide synthase (NOS) family of enzymes. It has been shown that NOS activity decreases with age. To determine whether adenoviral-mediated overexpression of endothelial NOS (eNOS) could enhance erectile responses, we administered a recombinant adenovirus containing the eNOS gene (AdCMVeNOS) into the corpora cavernosum of the aged rat. Adenoviral expression of the beta-galactosidase reporter gene was observed in cavernosal tissue 1 day after intracavernosal administration of AdCMVbetagal; 1 day after administration of AdCMVeNOS, transgene expression was confirmed by immunoblot staining of eNOS protein, and cGMP levels were increased. The increase in cavernosal pressure in response to cavernosal nerve stimulation was enhanced in animals transfected with eNOS, and erectile responses to acetylcholine and zaprinast were enhanced at a time when the erectile response to the NO donor sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate was not altered. These results suggest that in vivo gene transfer of eNOS, alone or in combination with a type V phosphodiesterase inhibitor, may constitute a new therapeutic intervention for the treatment of erectile dysfunction.

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References

Melis M, Succu S, Argiolas A . Dopamine agonists increase nitric oxide production in the paraventricular nucleus of the hypothalamus: correlation with penile erection and yawning. Eur J Neurosci. 1996; 8(10):2056-63. DOI: 10.1111/j.1460-9568.1996.tb00725.x. View

Champion H, Bivalacqua T, DSouza F, Ortiz L, Jeter J, Toyoda K . Gene transfer of endothelial nitric oxide synthase to the lung of the mouse in vivo. Effect on agonist-induced and flow-mediated vascular responses. Circ Res. 1999; 84(12):1422-32. DOI: 10.1161/01.res.84.12.1422. View

Ignarro L, Bush P, Buga G, Wood K, Fukuto J, Rajfer J . Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun. 1990; 170(2):843-50. DOI: 10.1016/0006-291x(90)92168-y. View

Melis M, Argiolas A . Role of central nitric oxide in the control of penile erection and yawning. Prog Neuropsychopharmacol Biol Psychiatry. 1997; 21(6):899-922. DOI: 10.1016/s0278-5846(97)00088-2. View

Rodman D, San H, Simari R, Stephan D, Tanner F, Yang Z . In vivo gene delivery to the pulmonary circulation in rats: transgene distribution and vascular inflammatory response. Am J Respir Cell Mol Biol. 1997; 16(6):640-9. DOI: 10.1165/ajrcmb.16.6.9191465. View

Burnett A . Role of nitric oxide in the physiology of erection. Biol Reprod. 1995; 52(3):485-9. DOI: 10.1095/biolreprod52.3.485. View

Ooboshi H, Toyoda K, Faraci F, LANG M, Heistad D . Improvement of relaxation in an atherosclerotic artery by gene transfer of endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol. 1998; 18(11):1752-8. DOI: 10.1161/01.atv.18.11.1752. View

Garban H, Marquez D, Magee T, Moody J, Rajavashisth T, Rodriguez J . Cloning of rat and human inducible penile nitric oxide synthase. Application for gene therapy of erectile dysfunction. Biol Reprod. 1997; 56(4):954-63. DOI: 10.1095/biolreprod56.4.954. View

Christ G, Melman A . The application of gene therapy to the treatment of erectile dysfunction. Int J Impot Res. 1998; 10(2):111-2. DOI: 10.1038/sj.ijir.3900326. View

10.

Ooboshi H, Chu Y, Rios C, Faraci F, Davidson B, Heistad D . Altered vascular function after adenovirus-mediated overexpression of endothelial nitric oxide synthase. Am J Physiol. 1997; 273(1 Pt 2):H265-70. DOI: 10.1152/ajpheart.1997.273.1.H265. View

11.

Ignarro L . Physiology and pathophysiology of nitric oxide. Kidney Int Suppl. 1996; 55:S2-5. View

12.

Champion H, Bivalacqua T, Wang R, Kadowitz P, Keefer L, Saavedra J . Induction of penile erection by intracavernosal and transurethral administration of novel nitric oxide donors in the cat. J Urol. 1999; 161(6):2013-9. View

13.

Feldman H, Goldstein I, Hatzichristou D, Krane R, McKinlay J . Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994; 151(1):54-61. DOI: 10.1016/s0022-5347(17)34871-1. View

14.

Garban H, Vernet D, FREEDMAN A, Rajfer J, Gonzalez-Cadavid N . Effect of aging on nitric oxide-mediated penile erection in rats. Am J Physiol. 1995; 268(1 Pt 2):H467-75. DOI: 10.1152/ajpheart.1995.268.1.H467. View

15.

Andersson K, Wagner G . Physiology of penile erection. Physiol Rev. 1995; 75(1):191-236. DOI: 10.1152/physrev.1995.75.1.191. View

16.

Anderson K . Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev. 1993; 45(3):253-308. View

17.

Christ G, Rehman J, Day N, Salkoff L, Valcic M, Melman A . Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in penile function. Am J Physiol. 1998; 275(2):H600-8. DOI: 10.1152/ajpheart.1998.275.2.H600. View

18.

Janssens S, Bloch K, Nong Z, Gerard R, Zoldhelyi P, Collen D . Adenoviral-mediated transfer of the human endothelial nitric oxide synthase gene reduces acute hypoxic pulmonary vasoconstriction in rats. J Clin Invest. 1996; 98(2):317-24. PMC: 507433. DOI: 10.1172/JCI118795. View

19.

Kaplan J, Pennington S, St George J, Woodworth L, Fasbender A, Marshall J . Potentiation of gene transfer to the mouse lung by complexes of adenovirus vector and polycations improves therapeutic potential. Hum Gene Ther. 1998; 9(10):1469-79. DOI: 10.1089/hum.1998.9.10-1469. View

20.

Rajfer J, Aronson W, Bush P, Dorey F, Ignarro L . Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med. 1992; 326(2):90-4. DOI: 10.1056/NEJM199201093260203. View