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Trinity J Bivalacqua

Publications and source records attributed to Trinity J Bivalacqua.

At least 37 records · Page 2Linked to original sources
PubMed2004

RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction.

Significant impairment in endothelial-derived nitric oxide is present in the diabetic corpus cavernosum. RhoA/Rho-kinase may suppress endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that RhoA/Rho-kinase contributes to diabetes-related erectile dysfunction and down-regulation of eNOS in the streptozotocin (STZ)-diabetic rat penis. Colocalization of Rho-kinase and eNOS protein was present in the endothelium of the corpus cavernosum. RhoA/Rho-kinase protein abundance and MYPT-1 phosphorylation at Thr-696 were elevated in the STZ-diabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive NOS activity, and cGMP levels were reduced in the STZ-diabetic penis. To assess the functional role of RhoA/Rho-kinase in the penis, we evaluated the effects of an adeno-associated virus encoding the dominant-negative RhoA mutant (AAVTCMV19NRhoA) on RhoA/Rho-kinase and eNOS and erectile function in vivo in the STZ-diabetic rat. STZ-diabetic rats transfected with AAVCMVT19NRhoA had a reduction in RhoA/Rho-kinase and MYPT-1 phosphorylation at a time when cavernosal eNOS protein, constitutive NOS activity, and cGMP levels were restored to levels found in the control rats. There was a significant decrease in erectile response to cavernosal nerve stimulation in the STZ-diabetic rat. AAVT19NRhoA gene transfer improved erectile responses in the STZ-diabetic rat to values similar to control. These data demonstrate a previously undescribed mechanism for the down-regulation of penile eNOS in diabetes mediated by activation of the RhoA/Rho-kinase pathway. Importantly, these data imply that inhibition of RhoA/Rho-kinase improves eNOS protein content and activity thus restoring erectile function in diabetes.

Adenoviridae↗
PubMed2004

Relationship between the severity of penile curvature and the presence of comorbidities in men with Peyronie's disease.

PURPOSE: We investigated the relationship between penile curvature severity and co-morbidities in men with Peyronie's disease (PD) and assessed whether the severity of curvature had an impact on penile vascular status and/or erectile function. MATERIALS AND METHODS: Based on a 10-year period 469 patients with PD were retrospectively evaluated in regard to age at diagnosis, type and degree of penile curvature, erectile dysfunction (ED) and other comorbidities, such as diabetes mellitus, hypertension, serum lipid abnormalities, smoking and ischemic heart disease. To assess penile vascular status all men with PD underwent penile duplex Doppler ultrasound evaluation. The severity of penile curvature was classified using the Kelami system, that is grade 1--curvature 30 degrees or less, grade 2--30 to 60 degrees and grade 3--greater than 60 degrees. RESULTS: Mean patient age was 54.8 +/- 4.3 years (range 18 to 79) and the mean duration of symptoms was 24.8 +/- 13.7 months (range 3 to 120). The most common penile abnormality was dorsal curvature in 47.1% of patients. The most frequently documented co-morbid conditions in association with PD were hypertension in 27.2% of cases, smoking in 25.5%, hypercholesterolemia in 18.3%, diabetes mellitus in 17.2%, hyperlipidemia in 15.7% and a history of penile trauma in 13.2%. There was no relationship between the number or severity of each of these co-morbid conditions and the severity of the penile abnormality. In addition, there was no relationship between the severity of penile curvature and penile vascular status in patients with PD. Moreover, the prevalence of these comorbidities, except smoking and penile trauma history, was significantly higher in patients with PD and concurrent ED than in patients with PD only. CONCLUSIONS: While co-morbid conditions, such as hypertension, smoking, hypercholesterolemia, diabetes mellitus and hyperlipidemia, are commonly seen in patients with PD and may seem to be risk factors for PD, there was no statistical relationship between penile curvature severity and any of these comorbidities. Similarly there was no statistically significant relationship between the severity of curvature and penile vascular status or ED. The fact that the prevalence of associated comorbidities is higher in patients with PD and ED than in patients with PD only indicates that these comorbidities are more likely related to ED than to the pathogenesis of PD.

Adolescent↗
PubMed2004

Stratification of penile vascular pathologies in patients with Peyronie's disease and in men with erectile dysfunction according to age: a comparative study.

PURPOSE: Erectile dysfunction (ED) occurs in 20% to 54% of men with Peyronie's disease (PD). We investigated the role of vascular status in the pathophysiology of ED in patients with PD. MATERIALS AND METHODS: A total of 509 consecutive men with PD (group 1--impotent 259, 1a, and potent 250, 1b, mean age +/- SD 54.6 +/- 4.4 years) and 507 consecutive men with ED only (group 2--mean age 49.4 +/- 12.4 years) underwent penile duplex ultrasonography (PDU). Detailed sexual and medical history, and focused physical examination were performed in all patients. Patients in the 2, groups were stratified according to age (18 to 80 years) and classified according to PDU results (normal vascular status, arterial insufficiency, veno-occlusive dysfunction [VOD] and mixed vascular pathology). RESULTS: VOD was observed in 23.1% and 42.8% of patients in groups 1 and 2, respectively (p <0.05). Although VOD was significantly more common in group 2 (ED alone) than in group 1a (PD plus ED) in the third decade (p <0.05), overall PDU results showed no statistical difference for VOD between these 2 groups (p >0.05). Of note, mixed vascular pathologies were significantly higher in group 1a than in group 2 in the third through fifth decades (p <0.05), while arterial insufficiency was more common in the seventh decade (p <0.05). CONCLUSIONS: While many groups have investigated the vascular causes of ED, the exact etiology of ED in men with PD remains controversial. A possible relationship between ED and VOD in patients with PD has been previously reported. The current PDU study demonstrates that for all ages except 30 to 39 years the prevalence of VOD in patients with PD plus ED is similar to that of patients with ED alone.

Adolescent↗
PubMed2004

Intralesional interferon-alpha-2B injections for the treatment of Peyronie's disease.

BACKGROUND: Intralesional therapies provide an alternative to surgical treatment of Peyronie's disease (PD). This study examines the efficacy of intraplaque injections of interferon-alpha-2B (IFN-alpha-2B) in the treatment of PD. METHODS: Twenty-five patients were enrolled in the study with 21 completing the study. The average age of the study participants was 55.8 years, with 10 of the 21 having diabetes, hypertension, or both. Seven patients received placebo injections using 10 ml saline biweekly for 6 weeks before interferon therapy, and all 21 patients received biweekly injections of 2 x 10(6) U IFN-alpha-2B for 6 weeks before reevaluation. Patients were evaluated with duplex Doppler ultrasonography to assess penile curvature and blood flow. RESULTS: The International Index of Erectile Function questionnaire was completed by 14 of 21 men to assess severity of erectile dysfunction (ED) before and after treatment. Improvements of 20% or more in penile curvature occurred in 14 (67%) of 21 men. Penile pain decreased in eight (80%) of 10, and plaque size decreased subjectively in 15 (71%) of 21 participants. The International Index of Erectile Function questionnaire showed significant improvement of ED in five (71%) of seven men with baseline moderate to severe ED. Peak systolic blood flow improved in three (43%) of seven men with baseline hemodynamic impairment, and veno-occlusive disease resolved in three (18%) of 17 individuals. IFN-alpha-2B injections led to significant improvements in penile pain and curvature caused by PD. CONCLUSION: Results of intralesional IFN-alpha-2B injections in improving ED are encouraging. The study findings warrant further investigation of the effectiveness of IFN-alpha-2B injections for treatment of PD.

Adult↗
PubMed2004

The protective effect of aminoguanidine on erectile function in diabetic rats is not related to the timing of treatment.

OBJECTIVE: To assess the accumulation of advanced glycation end products (AGEs) in streptozotocin (STZ)-induced diabetic rat cavernosal tissue, and to determine whether the protective effect of aminoguanidine (AG) on erectile function is related to the timing of treatment, as the accumulation of AGEs in the penis may be important in the pathogenesis of diabetes mellitus-induced erectile dysfunction, and prolonged treatment with AG (a selective AGE inhibitor), prevents erectile dysfunction in this situation. MATERIALS AND METHODS: Harlan Sprague-Dawley rats were divided into groups 1-4, i.e. age-matched controls; STZ diabetic rats (60 mg/kg intraperitoneal) given free access to water; STZ diabetic rats treated with AG (1 g/L per day in the drinking water) immediately after inducing diabetes; and STZ-diabetic rats treated with AG 1 month after inducing diabetes, respectively. Two months after inducing diabetes the intracavernosal pressure was measured after cavernosal nerve stimulation, and cavernosal AGE (5-hydroxy methyl furfural, 5-HMF) levels assessed. RESULTS: Cavernosal tissue 5-HMF levels from groups 2 and 4 were significantly higher than in group 1 (control). The expression of 5-HMF in group 3 was similar to that in group 1. Diabetic rats had significantly lower erectile function than controls, while groups 3 and 4 (treated with AG) had normal erectile function, as measured by cavernosal nerve stimulation. CONCLUSIONS: The effect of AG on AGE levels seems to be time-dependent; that the 1-month treatment with AG improved erectile function with no change in AGEs suggests that AG has protective effects on the penile vasculature through alternative pathways.

Animals↗
PubMed2004

Gene therapy techniques for the delivery of endothelial nitric oxide synthase to the corpora cavernosa for erectile dysfunction.

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual intercourse. In the last decade, significant advancements in the pathophysiology of male ED have occurred. Basic science research on erectile physiology has been devoted to investigating the pathogenesis of ED and has led to the conclusion that ED is predominately a disease of vascular origin. Nitric oxide (NO) is the principal mediator of penile erection. NO is synthesized by endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) in the penis. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED. This chapter reviews the use of two gene transfer techniques: adenoviral gene transfer of eNOS and eNOS gene-modified rat marrow stromal cells (rMSCs) to the penis of aged rats for the potential application of gene therapy for the treatment of ED.

Adenoviridae↗
PubMed2004

Vardenafil: a novel type 5 phosphodiesterase inhibitor for the treatment of erectile dysfunction.

Orally administered phosphodiesterase type 5 (PDE5) inhibitors have become the first-line treatment option for erectile dysfunction (ED). Vardenafil is a potent and highly selective PDE5 inhibitor developed as an oral therapy for ED. Two pivotal, randomised, double-blind, multi-centre studies have evaluated the use of vardenafil in men with ED. Vardenafil improved the rate of achieving and maintaining an erection during sexual intercourse. Improvement was also noted in other aspects of sexual function, including confidence, orgasmic function and overall satisfaction. Vardenafil produces clinically and statistically significant improvements in erectile function regardless of age, baseline severity and aetiology and is efficacious for the treatment of ED in diabetic and postradical prostatectomy patients. Vardenafil has a rapid onset of action, in which erections sufficiently rigid for eventual intercourse completion can be achieved as early as 16 min after ingestion. Vardenafil 20 mg has sustained long-term efficacy by providing up to 92% of patients with improved erections during > 2 years of treatment. Vardenafil is well-tolerated, with an adverse event profile typical of this class of PDE5 inhibitors. The most common adverse events were headache, flushing, rhinitis and dyspepsia, which were mild-to-moderate in severity and they generally attenuated with continued use. Vardenafil may be associated with transient reductions in blood pressure and commensurate increases in heart rate, with the overall incidence of cardiovascular-related adverse events similar to that of placebo. Although claims can be made about potential features of benefit for each of the currently marketed PDE5 inhibitors, there are at present, no non-pharmaceutical company sponsored, peer-reviewed, head-to-head trials that have been published.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Engineering ex vivo-expanded marrow stromal cells to secrete calcitonin gene-related peptide using adenoviral vector.

Calcitonin gene-related peptide (CGRP) is a target for cardiovascular gene therapy. Marrow stromal cells (MSCs) hold promise for use in adult stem cell-based cell and gene therapy. To determine the feasibility of adenoviral-mediated CGRP gene transfer into ex vivo-expanded MSCs, rat MSCs were isolated, ex vivo expanded, and transduced with adenoviruses. Adprepro-CGRP and AdntlacZ, adenoviral vectors containing prepro-CGRP or nuclear-targeted beta-galactosidase reporter gene ntlacZ under the control of Rous sarcoma virus promoter, were used. In this study, it can be shown that transduction efficiency of adenoviral-mediated gene transfer into ex vivo-expanded MSCs is dose dependent, transgene expression persists for more than 21 days in culture, and adenoviral transduction does not alter the proliferation or viability of MSCs. Transduced MSCs retain multipotentiality and transgene expression after cell differentiation. The expression and secretion of CGRP by Adprepro- CGRP-transduced MSCs was confirmed by Western blot analysis and enzyme immunoassay. The secretion of CGRP by Adprepro-CGRP-transduced MSCs is dose dependent, and the transduced cells release as much as 9.5 +/- 0.4 pmol CGRP/1 x 10(6) cells/48 hours (mean +/- standard error of mean, n = 3) into culture medium at a multiplicity of infection of 300. Furthermore, culture supernatant from Adprepro-CGRP-transduced MSCs increases intracellular cyclic AMP levels in pulmonary artery smooth muscle cells in culture. These findings suggest that replication-deficient recombinant adenovirus can be used to gene engineer ex vivo-expanded MSCs and that high-level secretion of biologically active CGRP can be achieved, underscoring the clinical potential of using this novel adult stem cell-based cell and gene therapy strategy for the treatment of cardiovascular diseases.

Adenoviridae↗
PubMed2003

Role of cyclooxygenase-2 in the generation of vasoactive prostanoids in the rat pulmonary and systemic vascular beds.

BACKGROUND: Prostanoid synthesis by the cyclooxygenase (COX)-2 pathway plays an important role in inflammation, and recent studies have shown the presence of COX-2 in the normal rat lung. However, the role of COX-2 in the generation of vasoactive prostanoids in the rat is uncertain. In the present study, the hypothesis that synthesis of vasoactive prostanoids via the COX-2 pathway can alter pulmonary and systemic vascular resistance was investigated, and the effects of selective COX-2 inhibitors on pulmonary and systemic responses to the prostanoid precursor arachidonic acid were examined in the anesthetized rat with a recently developed right-heart catheterization technique. METHODS AND RESULTS: Injections of arachidonic acid caused dose-related increases in pulmonary vascular resistance and decreases in systemic vascular resistance. These responses were attenuated by selective COX-2 inhibitors and a selective COX-1 inhibitor, whereas responses to exogenous prostanoids were not altered. Nimesulide or NS-398 did not alter arachidonic acid-induced platelet aggregation in rat platelet-rich plasma. Western blot analysis and immunostaining showed the expression of both COX isoforms in the rat lung. CONCLUSIONS: The results of these experiments suggest that arachidonic acid is converted into vasoactive prostanoids by the COX-2 and COX-1 pathway in the pulmonary and peripheral vascular beds in the rat and that TXA2 is a major prostanoid formed in the normal rat lung.

Animals↗
PubMed2003

Adenoviral gene transfer of eNOS: high-level expression in ex vivo expanded marrow stromal cells.

Endothelial nitric oxide synthase (eNOS) is an attractive target for cardiovascular gene therapy. Marrow stromal cells (MSCs), also known as mesenchymal stem cells, hold great promise for use in adult stem cell-based cell and gene therapy. To determine the feasibility of adenoviral-mediated eNOS gene transfer into ex vivo expanded MSCs, rat MSCs (rMSCs) were isolated, expanded ex vivo, and transduced with Ad5RSVeNOS, an adenoviral vector containing the eNOS gene under the control of the Rous sarcoma virus promoter. The presence of eNOS protein in Ad5RSVeNOS-transduced rMSCs was confirmed by immunohistochemical and Western blot analysis. Transduction efficiency was dose dependent, and eNOS transgene expression in rMSCs persisted for > or =21 days in culture. The rMSCs retained multipotential differentiation capability after adenoviral-mediated eNOS gene transfer. Furthermore, intracavernosal injection of Ad5RSVeNOS-transduced rMSCs increased the expression of eNOS in the corpus cavernosum, and stem cells were identified within corporal sinusoids. These findings demonstrate that replication-deficient recombinant adenovirus can be used to engineer ex vivo expanded rMSCs and that high-level eNOS transgene expression can be achieved, pointing out the clinical potential of using this novel adult stem cell-based gene therapy method for the treatment of cardiovascular diseases.

Adenoviridae↗
PubMed2003

Patient and partner satisfaction and long-term results after surgical treatment for Peyronie's disease.

OBJECTIVES: To assess the long-term functional outcome, patient and partner satisfaction, and predictive factors for unfavorable results in men treated with a surgical approach for severe Peyronie's disease. METHODS: Sixty-one patients underwent surgical treatment for Peyronie's disease between 1997 and 2001 and were retrospectively evaluated. All patients were assessed preoperatively with a detailed sexual and medical history, focused physical examination, and penile duplex ultrasonography. Nineteen patients underwent penile plaque excision/incision and grafting with Tutoplast cadaveric pericardial grafting material (group 1). Penile prosthesis implantation and manual modeling was performed in 31 patients (group 2a), and 11 men were treated with penile prosthesis implantation and pericardial grafting (group 2b). RESULTS: The mean follow-up of the patients was 21.9 +/- 13.6 months (range 12 to 48). Complete penile straightening was achieved in 15 patients (78.9%) in the excision/incision and grafting group. In the 42 men who underwent reconstruction using penile prosthesis implantation (group 2a,b), penile curvature resolved completely in 37 patients (88%). Long-term postoperative residual curvatures greater than 30 degrees occurred in 3 patients (15.7%) and 2 patients (4.8%) in groups 1 and 2a,b, respectively. One penile prosthesis (2.3%) was explanted in the second group for erosion. Patient responses to our questionnaire showed that overall 83.6% of the patients and 76.9% of the partners were satisfied with the surgical result. CONCLUSIONS: According to the results of this long-term, retrospective study, pericardial grafting can be used successfully after plaque excision/incision procedures in men undergoing surgical treatment for severe Peyronie's disease. In patients with Peyronie's disease and erectile dysfunction, implantation of a penile prosthesis and correction of the curvature with a graft can provide an acceptable, functionally straight penis without any increased risk of complications compared with penile prosthesis implantation alone.

Adult↗
PubMed2003

Gene transfer of endothelial nitric oxide synthase partially restores nitric oxide synthesis and erectile function in streptozotocin diabetic rats.

PURPOSE: We determined whether adenoviral gene transfer of endothelial nitric oxide synthase (eNOS) to the penis of streptozotocin induced diabetic rats could improve the impaired erectile response. MATERIALS AND METHODS: Two experimental groups of animals were transfected with adenoviruses, including streptozotocin (Sigma Chemical Company, St. Louis, Missouri) diabetic rats with AdCMVbetagal and streptozotocin diabetic rats with AdCMVeNOS. At 1 to 2 days after transfection these study animals underwent cavernous nerve stimulation to assess erectile function and their responses were compared with those of age matched control rats. In control and transfected streptozotocin diabetic rats eNOS and neuronal NOS (nNOS) were examined by Western blot analysis. Constitutive and inducible NOS activities were evaluated in the presence and absence of calcium by L-arginine to L-citrulline conversion and nitrate plus nitrite levels were measured. In control and streptozotocin diabetic penes beta-galactosidase activity and localization were determined. RESULTS: After transfection with AdCMVbetagal beta-galactosidase was localized to the endothelium and smooth muscle cells of the streptozotocin diabetic rat penis. Streptozotocin diabetic rats had a significant decrease in erectile function, as determined by peak and total intracavernous pressure (area under the curve) after cavernous nerve stimulation compared with control rats. Streptozotocin diabetic rats transfected with AdCMVeNOS had peak intracavernous pressure and area under the curve similar to those in control animals. This change in erectile function was a result of eNOS over expression with an increase in eNOS protein expression and constitutive NOS activity as well as an increase in nitric oxide biosynthesis, as reflected by an increase in cavernous nitrate plus nitrite formation. There was no change in nNOS protein expression or calcium independent conversion of NOS (inducible NOS activity). CONCLUSIONS: Adenoviral gene transfer of eNOS significantly increased peak and total intracavernous pressure to cavernous nerve stimulation in streptozotocin diabetic rats to a value similar to the response observed in control rats. Our results suggest that eNOS contributes significantly to the physiology of penile erection. These data demonstrate that in vivo adenoviral gene transfer of eNOS can physiologically improve erectile function in the streptozotocin diabetic rat.

Animals↗
PubMed2003

The protective effect of aminoguanidine on erectile function in streptozotocin diabetic rats.

PURPOSE: Erectile dysfunction (ED) is frequently associated with diabetes mellitus. We determined if advanced glycation end products (AGEs) are involved in ED and investigated if the selective AGE and inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (AG) could protect against the development of ED in a diabetic rat model. MATERIALS AND METHODS: Harlan Sprague-Dawley rats were divided into 3 groups. The 9 nondiabetic rats in group 1 served as age matched controls. Diabetes was induced in the 9 rats in groups 2 and 3, respectively, by intraperitoneal injection of streptozocin (60 mg/kg). While group 2 was given free access to water and a standard diet, group 3 was treated with AG added to drinking water (1 gm/l daily). Two months after diabetes induction in vivo intracavernous pressure measurements were determined. Penile tissue glycation (furosine on high performance liquid chromatography), AGEs (pentosidine on high performance liquid chromatography and immunohistochemistry), AGE receptor (galectin-3 on immunohistochemistry and Western blot) and iNOS (Western blot) levels were measured in control and diabetic penises. RESULTS: Cavernous tissue furosine, pentosidine, galectin-3 and iNOS protein levels were significantly elevated in the diabetic group compared with controls (p <0.05). On the other hand, cavernous tissue furosine, pentosidine, galectin-3 and iNOS expression were lower in diabetic rats treated with AG despite an unchanged glycemia level. Diabetic rats had a significant decrease in erectile function compared with control rats (p <0.05), while AG treated diabetic rats showed erectile function similar to that in control animals. CONCLUSIONS: Glycation, AGEs, galectin-3 and iNOS levels are elevated in diabetic rat penile tissue and significantly decreased by AG treatment. Furthermore, erectile function was preserved in AG treated animals. The observation that AG improved glycation despite no effect on glycemia suggests that AG may improve penile collagen turnover.

Animals↗
PubMed2003

Responses to human CGRP, ADM, and PAMP in human thymic arteries.

Responses to human CGRP, adrenomedullin (ADM), and proadrenomedullin NH2-terminal 20 peptide (PAMP) were studied in small human thymic arteries. CGRP, ADM, and PAMP produced concentration-dependent vasodilator responses in arteries preconstricted with the thromboxane mimic U-46619. Responses to ADM and PAMP were attenuated, whereas responses to CGRP were not altered by endothelial denudation. Inhibitors of nitric oxide synthase and guanylyl cyclase attenuated responses to ADM and PAMP but not to CGRP. The CGRP1 receptor antagonist CGRP(8-37) attenuated responses to CGRP and ADM but not to PAMP. Responses to CGRP were reduced by SQ-22536 and Rp-cAMPS, inhibitors of adenylyl cyclase and PKA. These data suggest that responses to CGRP and ADM are mediated by CGRP(8-37)-sensitive receptors and that the endothelial ADM receptor induces vasodilation by a nitric oxide-guanylyl cyclase mechanism, whereas a smooth muscle CGRP receptor signals by a cAMP-dependent mechanism. A different endothelial receptor recognizes PAMP and signals by a nitric oxide-dependent mechanism.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2002

Gene transfer of extracellular SOD to the penis reduces O2-* and improves erectile function in aged rats.

Increased superoxide anion (O(2)(-).) may contribute to vascular dysfunction in aging. In aged cavernosal tissue, lucigenin-enhanced chemiluminescence demonstrated a threefold increase in superoxide formation, and the oxidative fluorescent probe hydroethidine indicated higher superoxide levels throughout the aged penis. This increase in superoxide was associated with impaired cavernosal nerve-mediated and agonist-induced erectile responses, increased nitrotyrosine staining, and lower cGMP levels, but no compensatory change in cavernosal extracellular (EC)-superoxide dismutase (EC-SOD) mRNA or protein. In vivo adenoviral (Ad) gene transfer of EC-SOD to the penis resulted in higher expression of EC-SOD mRNA, protein, SOD activity, cGMP levels, and lower nitrotyrosine staining. Transfection with AdCMVEC-SOD resulted in a significant increase in erectile response to cavernosal nerve stimulation, ACh, and zaprinast to a magnitude similar to young rats. These data provide evidence in support of the hypothesis that erectile dysfunction associated with aging is related in part to an increase in cavernosal O(2)(-). formation. Gene-transfer of EC-SOD reduces superoxide formation and restores age-associated erectile function and may represent a novel therapeutic target for the treatment of erectile dysfunction.

Adenoviridae↗
PubMed2002

Adeno-associated viral gene transfer of dominant negative RhoA enhances erectile function in rats.

We previously reported the inhibition of Rho-kinase to result in increased intracavernosal pressure (ICP) in an in vivo rat model of erection. Expression of an upstream activator of Rho-kinase, RhoA, has been demonstrated in the penile vasculature; however, the functional role of RhoA in the regulation of erection remains unknown. We used adeno-associated viral gene transfer of a dominant negative RhoA mutant (T19NRhoA) into rat cavernosum to test the hypothesis that RhoA activation is physiologically important for maintenance of the non-erect state and inhibition of this pathway leads to erection. Anesthetized, male, Sprague-Dawley rats transfected with the T19NRhoA mutant exhibited an elevated baseline ICP/mean arterial pressure (MAP) and nerve stimulation-induced ICP/MAP as compared with beta-galactosidase-transfected controls. The novel findings of this study demonstrate a functional role of RhoA in maintaining the flaccid penis and provide support for the inhibition of RhoA as a potential therapy for the enhancement of erectile function.

Animals↗
PubMed2002

Role of calcitonin gene-related peptide (CGRP) in chronic hypoxia-induced pulmonary hypertension in the mouse. Influence of gene transfer in vivo.

Calcitonin gene-related peptide (CGRP) is believed to play an important role in maintaining low pulmonary vascular resistance (PVR) and may be involved in modulating the pulmonary vascular response to chronic hypoxia. In the present study, an adenoviral vector encoding CGRP (AdRSVCGRP) was used to examine the effects of in vivo gene transfer of CGRP to the lung on increases in PVR, right ventricular mass, and pulmonary vascular remodeling that occurs in chronic hypoxia in the mouse. Following intratracheal administration of AdRSVCGRP or reporter gene mice were exposed to 16 days of chronic hypoxia (FIO(2) 0.10). The increase in pulmonary arterial pressure (PAP), PVR, right ventricular mass, and pulmonary vascular remodeling in response to chronic hypoxia was attenuated in animals overexpressing CGRP, whereas systemic arterial pressure was not altered. Following exposure to hypoxia, a subgroup of mice were treated with capsaicin, which did not significantly alter CGRP expression in the mouse lung. These data show that in vivo transfer of the CGRP gene to the lung attenuates the increase in PVR, right ventricular mass, and pulmonary vascular remodeling in chronically hypoxic mice with little effect on the systemic circulation. Moreover, these data suggest that adenoviral gene transfer of CGRP to the lung results in expression of the gene product in non-neural tissue.

Animals↗