Gene transfer of endothelial nitric oxide synthase to the penis augments erectile responses in the aged rat

Champion, Hunter C.; Bivalacqua, Trinity J.; Hyman, Albert L.; Ignarro, L. J.; Hellstrom, Wayne J.G.; Kadowitz, Philip J.

doi:10.1073/pnas.96.20.11648

Cited by 151 publications

(141 citation statements)

References 26 publications

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“…17 However, in that study we used an adenovirus which had limited activity of expression of the eNOS gene, requiring repeated injections into the penis, which in turn could injure the vascular smooth muscle cells of the penis or, more importantly, cause a host-immune response. In the present study, instead of the cytomegalovirus promoter, we utilized the rous sarcoma promoter, which has been shown to exhibit a longer sustained duration of expression of a desired gene.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, our lab demonstrated enhanced erectile response to cavernosal nerve stimulation in aged rats after adenoviral gene transfer of eNOS. 17 However, in this study, the expression of eNOS in the penis was limited to only 5 days. In the present study, our aim was to investigate the effect of adenoviral gene transfer of eNOS using a different promoter which exhibits a longer duration of expression of eNOS.…”

Section: Introductionmentioning

confidence: 99%

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Adenoviral gene transfer of endothelial nitric oxide synthase (eNOS) to the penis improves age-related erectile dysfunction in the rat

et al. 2000

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Nitric oxide (NO) is the principal mediator of penile erection. NO is synthesized by a variety of nitric oxide synthases (NOS). It has been demonstrated that a decrease in NOS activity, as observed in aging, is associated with a diminished erectile response. The objective of this study was to determine if adenoviral-mediated gene transfer of eNOS could reverse age-related erectile dysfunction in the rat. Two groups of animals were transfected with adenoviruses: (1) aged rats (60 weeks) with AdRSVbgal; and (2) aged rats (60 weeks) with AdRSVeNOS. Five days after transfection, these study animals underwent cavernosal nerve stimulation (CNS) to assess erectile function and their responses were compared with young (20 weeks) control rats. Cross-sections of the rat penises transfected with AdRSVeNOS were examined after trichrome staining. Adenoviral transduction ef®ciency of b-galactosidase reporter gene was measured by a galacto-light chemiluminescent reporter gene assay in cavernosal tissues of rats administered AdRSVbgal. The transgene expression of eNOS was examined by RT-PCR in rats transfected with AdRSVbgal and AdRSVeNOS. eNOS and iNOS protein levels were measured by Western blot analysis, and cGMP levels were assessed in cavernosal tissue by enzyme immunoassay. Adenoviral expression of the b-galactosidase reporter gene was observed in cavernosal tissue for up to 30 days, with peak expression registered at 5 days after intracavernosal administration of AdRSVbgal. Cross-sections of the rat penises transfected with the AdRSVeNOS revealed no pathological (morphological or histological) changes. Five days after administration of AdRSVeNOS, eNOS protein, mRNA and cGMP levels in the corpora cavernosa were signi®cantly increased (P`0.05), while iNOS protein levels remained unchanged (P b 0.05). In conclusion, enhanced expression of eNOS employing an adenoviral vector signi®cantly increased the erectile response to cavernosal nerve stimulation in the aged rat, similar to the response observed in younger rats. These data suggest that in vivo adenoviral gene transfer of eNOS can physiologically improve erectile function in the aged rat.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adenoviral gene transfer of endothelial nitric oxide synthase (eNOS) to the penis improves age-related erectile dysfunction in the rat

et al. 2000

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“…Recent reports have shown that in vivo gene transfer with adenoviral vectors encoding eNOS and nNOS can reverse age-related ED in experimental animal models. [17][18][19][20] Additionally, overexpression of eNOS in the aged penis results in an increase in both cavernosal NOS activity and cGMP formation. 17,18,21 In the present study, we used the streptozotocin (STZ)-diabetic rat model that represents a model of type I DM.…”

Section: Introductionmentioning

confidence: 99%

Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats

et al. 2004

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Erectile dysfunction associated with diabetes mellitus is caused in part by disordered endothelial smooth muscle relaxation, neuropathy, and a decrease in cavernosal nitric oxide synthase (NOS) activity. The purpose of this study was to determine whether a combination of sildenafil and adenoviral gene transfer of endothelial NOS (eNOS) could enhance the erectile response in diabetic rats. Five groups of animals were utilized: (1) age-matched control rats, (2) streptozotocin (STZ)-induced diabetic rats (60 mg/kg i.p.), (3) STZ-rats þ sildenafil (2 mg/kg i.v.), (4) STZ-rats transfected with AdCMVbgal or AdCMVeNOS, and (5) STZ-rats transfected with AdCMVeNOS þ sildenafil (2 mg/kg i.v.). At 2 months after i.p. injection of STZ, groups 4 and 5 were transfected with the adenoviruses and 1-2 days after transfection, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Cyclic 3 0 ,5 0 -guanosine monophosphate (cGMP) levels were assessed in the cavernosal tissue. STZ-diabetic rats had a significant decrease in erectile function as determined by the peak intracavernosal pressure (ICP) and total ICP (area under the erectile curve; AUC) after CNS when compared to control rats. STZ-diabetic rats þ AdCMVeNOS had a peak ICP and AUC, which were similar to control animals. STZ-diabetic rats administered sildenafil demonstrated a significant increase in peak ICP at the 5 and 7.5 V settings, while the AUC was significantly increased at all voltage (V) settings. The increase in both ICP and AUC of STZ-diabetic rats transfected with AdCMVeNOS at all V settings was greater than STZ-diabetic rats transfected with AdCMVbgal. STZ-diabetic rats transfected with AdCMVeNOS and administered sildenafil had a significant increase in total ICP that was greater than eNOS gene therapy alone. Cavernosal cGMP levels were significantly decreased in STZ-diabetic rats, but were increased after transfection with AdCMVeNOS to values greater than control animals. In conclusion, overexpression of eNOS and cGMP in combination with sildenafil significantly increased both the peak ICP and total ICP to CNS in the STZ-diabetic rat, which was similar to the response observed in control rats. Moreover, the total erectile response was greater in STZ-diabetic rats receiving eNOS gene therapy plus sildenafil than STZ-rats receiving sildenafil or eNOS gene therapy alone.

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“…The fact that NO signals the biochemical mechanism of corpus cavernosal tissue relaxation established an essential foundation for the development of phosphodiesterase-5 inhibitor therapy for the therapeutic management of erectile dysfunction (ED). Additional translational efforts to harness the potential of this molecule for therapeutic purposes have suggested other possible therapies including pharmacologic NO precursors or actual NO donors, [1][2][3] NO-based gene therapy, 4,5 derivatives of NO synthase (NOS)-associated regulatory proteins, 6 and compounds targeting other components of the NO-based signal transduction pathway. 7,8 Ongoing basic scientific investigation of NO biology has revealed new concepts regarding the regulatory roles of this chemical, particularly those pertaining to mechanisms of activating NOS which synthesizes NO.…”

Section: Introductionmentioning

confidence: 99%

Novel nitric oxide signaling mechanisms regulate the erectile response

Burnett

2004

Int J Impot Res

131

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Nitric oxide (NO) is a physiologic signal essential to penile erection, and disorders that reduce NO synthesis or release in the erectile tissue are commonly associated with erectile dysfunction. NO synthase (NOS) catalyzes production of NO from L-arginine. While both constitutively expressed neuronal NOS (nNOS) and endothelial NOS (eNOS) isoforms mediate penile erection, nNOS is widely perceived to predominate in this role. Demonstration that blood-flow-dependent generation of NO involves phosphorylative activation of penile eNOS challenges conventional understanding of NO-dependent erectile mechanisms. Regulation of erectile function may not be mediated exclusively by neurally derived NO: Blood-flow-induced fluid shear stress in the penile vasculature stimulates phosphatidyl-inositol 3-kinase to phosphorylate protein kinase B, which in turn phosphorylates eNOS to generate NO. Thus, nNOS may initiate cavernosal tissue relaxation, while activated eNOS may facilitate attainment and maintenance of full erection.

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Gene transfer of endothelial nitric oxide synthase to the penis augments erectile responses in the aged rat

Cited by 151 publications

References 26 publications

Adenoviral gene transfer of endothelial nitric oxide synthase (eNOS) to the penis improves age-related erectile dysfunction in the rat

Adenoviral gene transfer of endothelial nitric oxide synthase (eNOS) to the penis improves age-related erectile dysfunction in the rat

Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats

Novel nitric oxide signaling mechanisms regulate the erectile response

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