Biomedical subjects

Trinity J Bivalacqua

Publications and source records attributed to Trinity J Bivalacqua.

At least 19 recordsLinked to original sources

PubMed2007

Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability.

Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiologic mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By microcardiac catheterization, all mice expressing exclusively human sickle hemoglobin had pulmonary hypertension, profound pulmonary and systemic endothelial dysfunction, and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors, and endothelium-dependent vasodilators and enhanced responses to vasoconstrictors. However, endothelium-independent vasodilation in sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO axis: impaired constitutive nitric oxide synthase activity (NOS) with loss of endothelial NOS (eNOS) dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Light microscopy and computed tomography revealed no plexogenic arterial remodeling or thrombi/ emboli. Transplanting sickle marrow into wild-type mice conferred the same phenotype, and similar pathobiology was observed in a nonsickle mouse model of acute alloimmune hemolysis. Although the time course is shorter than typical pulmonary hypertension in human sickle cell disease, these results demonstrate that hemolytic anemia is sufficient to produce endothelial dysfunction and global dysregulation of NO.

Anemia, Sickle Cell↗

PubMed2006

Endothelial nitric oxide synthase keeps erection regulatory function balance in the penis.

OBJECTIVES: We evaluated the regulatory influence of endothelial nitric oxide (NO) on the basal functional states of the NO and RhoA/Rho-kinase signaling pathways in the penis using endothelial NO synthase (eNOS) mutant mice and eNOS gene transfer technology. METHODS: Four groups of mice were used: wild type (WT), eNOS gene deleted (eNOS-/-), eNOS and neuronal NOS gene deleted (dNOS-/-), and eNOS-/- mutant mice transfected intracavernosally with eNOS. Cyclic guanosine monophosphate (cGMP) concentration, protein kinase G (PKG) activity, activated RhoA, and Rho-kinase activity were determined in penes of WT and both mutant mouse groups. Constitutive NOS and PKG activities, RhoA, Rho-kinase-alpha and -beta isoforms, and phosphorylated myosin light-chain phosphatase target subunit (p-MYPT-1) expressions and Rho-kinase activity were determined in penes of eNOS-/- mice after eNOS gene transfer. RESULTS: Compared with results in the WT penis, eNOS-/- and dNOS-/- mutant mouse penes had significant reductions in NOS activity, cGMP concentration, PKG activity, Rho-kinase activity, and p-MYPT-1 expression (p<0.05) with no significant changes in activated RhoA or in RhoA and Rho-kinase-alpha and -beta protein expressions. After eNOS gene transfer to penes of eNOS-/- mice, Rho-kinase-beta and p-MYPT-1 expressions and total Rho-kinase activity were significantly increased from baseline levels (p<0.05). CONCLUSIONS: These data suggest that endothelial NO has a role in the penis as a regulator of the basal signaling functions of the NO and RhoA/Rho-kinase erection mediatory pathways. These data offer new insight into the homeostasis of erection regulatory biology.

Analysis of Variance↗

PubMed2006

Overexpression of arginase in the aged mouse penis impairs erectile function and decreases eNOS activity: influence of in vivo gene therapy of anti-arginase.

Since both increased nitric oxide (NO) synthase (NOS) abundance and diminished NO signaling have been reported in the aging penis, the role of NO in the adaptations of aging remains controversial. Here we tested the hypothesis that arginase, an enzyme that competes with NOS for the substrate l-arginine, contributes to erectile dysfunction with advanced age in the B6/129 mouse strain. Arginase protein abundance, mRNA expression, and enzyme activity were elevated in aged compared with young penile endothelial cells. In addition, endothelial NOS (NOS3) protein abundance was greater in aged versus young penile endothelial cells, whereas NOS activity and cGMP levels were reduced. Calcium-dependent l-arginine-to-l-citrulline conversion and cGMP formation increased significantly in aged mouse penes in the presence of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH). However, there was no effect on l-arginine-to-l-citrulline conversion or cGMP accumulation in the endothelium from young mouse penes. To assess the functional role of arginase in the inhibition of NOS pathway responsiveness in the penis, we evaluated the effects of ABH and an adeno-associated virus encoding an antisense sequence to arginase I (AAVanti-arginase) on erectile function in vivo. ABH and AAVanti-arginase enhanced endothelium-dependent erectile responses in the aged mice without altering endothelium-independent responses. Paralleling our in vitro observations, ABH or AAVanti-arginase did not affect vascular responses in the young mice. Inhibition of the arginase pathway improves endothelial function in the aging penile circulation, suggesting that the arginase pathway may be exploited to improve erectile dysfunction associated with aging.

Aging↗

PubMed2006

Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age-associated erectile dysfunction.

Mesenchymal stem cells (MSCs) can be used in adult stem cell-based gene therapy for vascular diseases. To test the hypothesis that MSCs alone or endothelial nitric oxide synthase (eNOS)-modified MSCs can be used for treatment of erectile dysfunction (ED), syngeneic rat MSCs (rMSCs) were isolated, ex vivo expanded, transduced with adenovirus containing eNOS, and injected into the penis of aged rats. Histological analysis demonstrated that rMSCs survived for at least 21 days in corporal tissue after intracavernous injection, and an inflammatory response was not induced. Intracavernous administration of eNOS-modified rMSCs improved the erectile response in aged rats at 7 and 21 days after injection. The increase in erectile function was associated with increased eNOS protein, NOS activity, and cGMP levels. rMSCs alone increased erectile function of aged rats at day 21, but not at day 7, with the transplanted cells exhibiting positive immunostaining for several endothelial and smooth muscle cell markers. This change in rMSC phenotype was accompanied by upregulation of penile eNOS protein expression/activity and elevated cGMP levels. These findings demonstrate that an adenovirus can be used to transduce ex vivo expanded rMSCs to express eNOS and that eNOS-modified rMSCs improve erectile function in the aged rat. Intracavernous injection of unmodified wildtype rMSCs improved erectile function 21 days after injection through mechanisms involving improved endothelium-derived NO/cGMP signaling and rMSC differentiation into penile cells expressing endothelial and smooth muscle markers. These data highlight the potential clinical use of adult stem cell-based therapy for the treatment of ED.

Aging↗

PubMed2006

Gene therapy for erectile dysfunction: fact or fiction?

OBJECTIVES: Erectile dysfunction (ED) is a major health problem that seriously affects the quality of life of patients and their partners. Although all three selective phosphodiesterase type 5 inhibitors (PDE5-Is) are effective in the majority of ED cases, PDE5-I therapy is less efficacious in some hard-to-treat populations (diabetics, men after radical prostatectomy), prompting the development of new approaches, including gene therapy strategies for ED. METHODS: Gene therapy approaches are discussed in terms of the possible role of gene therapy for the treatment of ED, potential targets for gene transfer, vectors to carry targeted genes, and gene strategies for ED in certain disease states, such as diabetes, ageing, arterial and venogenic insufficiency, and cavernous nerve injury. RESULTS: The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial-lined spaces, and low level of blood flow, especially in the flaccid state. Gene therapy approaches have focused on a number of signaling pathways that are crucial for penile erection, such as nitric oxide/cyclic guanosine monophosphate, RhoA/Rho-kinase, growth factors, ion channels, peptides, and control of oxidative stress. CONCLUSIONS: The need for effective ED therapies in difficult-to-treat patients has encouraged investigators to seek novel modalities for the treatment of ED. Recent preclinical and clinical trials have demonstrated that gene therapy strategies may be feasible for these purposes.

Endothelium, Vascular↗

PubMed2006

Elevated RhoA/Rho-kinase activity in the aged rat penis: mechanism for age-associated erectile dysfunction.

Epidemiologic studies have shown that aging accounts significantly for the prevalence of erectile dysfunction (ED). The pathophysiology of ED during aging and its underlying molecular mechanisms are largely unknown. We hypothesized that increased RhoA/Rho-kinase signaling is a major factor in the pathogenesis of age-associated ED and the mechanism involves increased penile smooth muscle contractility through inhibition of myosin light chain phosphatase. Male Fischer 344 young (4 month old) and aged (20-22 month old) rats underwent erectile function testing in vivo by measuring intracavernosal pressure (ICP) and mean arterial blood pressure (MAP) upon electrical stimulation of the cavernous nerve. The data demonstrated that erectile function was significantly lower in aged rats than that in young rats at all voltages tested (P<0.05). Western blot analysis results showed that there were no significant changes in protein expressions of RhoA, Rho-kinase-alpha and -beta isoforms, and myosin light chain phosphatase target subunit (MYPT1); however, membrane-bound RhoA and phosphorylated MYPT1 were increased in aged rat penes by 95 +/- 15 and 56 +/- 8% (P<0.05), respectively, indicating enhanced RhoA and Rho-kinase activity. Inhibition of Rho-kinase with Y27632 maximally increased ICP/MAP to 0.72 +/- 0.05 in aged rats vs. 0.47 +/- 0.06 in young rats (P<0.05). Gene transfer of adeno-associated virus (AAV) encoding dominant negative RhoA (T19NRhoA) to penes of aged and young rats for 7 days markedly improved erectile function in aged rats when compared with that in young rats (P<0.05). These observations were also supported by Rho-kinase activity assay results showing that basal Rho-kinase activity in aged rat penes receiving AAV vehicle treatment was twofold greater than that in young rat penes receiving AAV vehicle treatment, while it was reduced to a level similar to that in young rat penes after gene therapy of T19NRhoA (P<0.05). Taken together, these data suggest that impaired erectile function during the aging process involves increased RhoA/Rho-kinase signaling, and this pathway may be exploited for the treatment of age-associated ED.

Aging↗

PubMed2006

Priapism: new concepts in the pathophysiology and new treatment strategies.

Priapism is defined as prolonged and persistent erection of the penis without sexual stimulation. This is a poorly understood disease process, and we have little information on the etiology and pathophysiology of this erectile disorder. Two main types of priapism exist: low-flow (ischemic) and high-flow (nonischemic) priapism. When the physician first diagnoses which type of priapism exists, distinguishing the type of priapic event is paramount in order to choose the correct treatment options. Until recently, we had not sufficiently understood the pathogenesis of this erectile disorder and therefore, could not effectively manage its pathologic consequences of erectile tissue damage and erectile dysfunction. In this review, the proposed pathogenesis of ischemic priapism is reviewed, and a survey regarding novel treatment modalities is given.

Humans↗

PubMed2006

Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism.

OBJECTIVES: Recurrent ischemic priapism describes a disorder of repeated episodes of prolonged penile erection that frequently leads to devastating complications of erectile tissue damage and erectile dysfunction. A mechanistic role for dysregulated phosphodiesterase 5 (PDE5) in the deranged smooth muscle response of the corpus cavernosum of the penis offers new understanding about the pathogenesis of the disorder and suggests that PDE5 may serve as a molecular target for its treatment and prevention. We explored the use of PDE5 inhibitors to treat recurrent priapism, based on the hypothesis that the erection regulatory function of PDE5 would be regularized by this treatment and protect against further episodes. METHODS: We administered PDE5 inhibitors using a long-term therapeutic regimen to 3 men with sickle cell disease-associated priapism recurrences and 1 man with idiopathic priapism recurrences. RESULTS: Long-term PDE5 inhibitor treatment alleviated priapism recurrences. CONCLUSIONS: These observations support the hypothesis that PDE5 dysregulation exerts a pathogenic role for priapism associated with hematologic dyscrasias, as well as idiopathic priapism. Although these preliminary findings suggest that continuous, long-term PDE5 inhibitor therapy may be useful as a preventative strategy for priapism, additional evaluation in the form of a controlled clinical trial is needed.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2006

The breakdown of preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-induced diabetic rats: preventive versus curative treatment.

OBJECTIVES: Accumulation of advanced glycation end products (AGEs) has been linked to many of the complications of diabetes mellitus, including erectile dysfunction (ED). Furthermore, it has been demonstrated that inhibitors of AGE formation, such as aminoguanidine, can prevent ED in diabetic animals. However, it is unknown whether late administration of a putative cross-link breaker, ALT-711, can reverse diabetic ED. We therefore compared ALT-711 and aminoguanidine in their ability to reverse ED in diabetic rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly divided into four groups: (i) age-matched controls; (ii) streptozotocin (STZ)-induced diabetic rats (60 mg/kg; intraperitoneal injection); (iii) STZ diabetic rats treated with ALT-711 (3 mg/kg/day, intraperitoneal injection); and (iv) STZ diabetic rats treated with aminoguanidine (1 gm/L in drinking water) during the final 6 weeks of 12 weeks of induced diabetes. At the end of 12 weeks, erectile response to cavernous nerve stimulation (CNS) was determined. Neuronal nitric oxide synthase (nNOS) contents were measured in all penises, and AGE levels were determined both in penile tissues and in serum samples. RESULTS: Erectile responses to CNS and penile nNOS protein content were significantly reduced, while AGE levels were elevated in the penises and serum of untreated diabetic animals. Treatment with ALT-711, but not with aminoguanidine, reversed ED and nNOS depletion and reduced serum and penile tissue AGE levels. CONCLUSIONS: These results suggest that cross-link breakers, such as ALT-711, are the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in the reversal of diabetes-related ED.

Animals↗

PubMed2006

Feasibility of the use of phosphodiesterase type 5 inhibitors in a pharmacologic prevention program for recurrent priapism.

INTRODUCTION: Recurrent ischemic priapism is an enigmatic erectile disorder in need of improved clinical interventions to avert its known, potentially serious complications. AIM: To evaluate the use of a long-term, continuous phosphodiesterase type 5 (PDE5) inhibitor therapeutic regimen in controlling recurrent ischemic priapism and its feasibility in a clinical management program for the disorder. MAIN OUTCOME MEASURES: The main outcome measure was reduction in frequency or duration of priapism episodes. A secondary outcome measure was preservation of erectile ability. METHODS: We retrospectively evaluated the clinical progress of seven patients (age 22-37 years) with sickle cell disease-associated "stuttering" priapism (N = 4) and idiopathic recurrent priapism (N = 3), who were counseled and consented to the "off-label" use of the PDE5 inhibitors sildenafil citrate and tadalafil. The medications were administered according to a specified therapeutic regimen based on scientific evidence that chronic PDE5 inhibitor administration in priapism contexts effectively reconditions PDE5 regulatory function in the penis. The duration of clinical follow-up extended through 2 years. RESULTS: All seven patients were confirmed to have recurrent ischemic priapism without identifiable pharmacologic, traumatic, or neoplastic disease associations based on clinical history, physical examination, laboratory testing, and penile diagnostics. PDE5 inhibitor treatment was successful in alleviating or resolving priapism recurrences in six of the seven patients. Erectile function was unchanged in six patients and improved in one patient at last follow-up compared with baseline status. All the patients reported that PDE5 inhibitor therapy was well tolerated and did not cause any adverse effects limiting their continued use of the medication. CONCLUSIONS: Because of their efficacy, safety, and tolerability as shown in this case series, PDE5 inhibitors would appear to have a possible role in a rigorously implemented clinical management program to control recurrent priapism. However, completion of a controlled clinical trial is necessary to confirm the utility of this treatment.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2006

Nitric oxide/redox-based signalling as a therapeutic target for penile disorders.

Oxidative and/or nitrosative stress is implicated in the pathogeneses of assorted penile disorders of clinical significance, notably erectile dysfunction, priapism and penile fibrosis. It is becoming increasingly recognised that the generation and activity of reactive oxygen and nitrogen species in the penis influence vascular homeostasis of this organ, with adverse effects exerted at cellular and molecular levels. Furthermore, these elements may interact with molecular signalling pathways operating in the penis, modulating their functional roles. This interaction in particular suggests that by accessing molecular targets associated with oxidative/nitrosative stress in the penis, new pharmacotherapeutic approaches may be developed to promote normal erectile ability and preserve erectile tissue health. This notion pertains to, but also extends beyond, interventions which predictably target components of the nitric oxide-based signal transduction pathway for the on-demand treatment of erectile dysfunction. The next line of pharmaceuticals for disorders of the penis, in general, may well spawn from an integrative understanding of the complex regulatory interactions influenced by, as well as influencing nitric oxide signalling in this organ.

Animals↗

PubMed2005

Vasoactive prostanoids are generated from arachidonic acid by COX-1 and COX-2 in the mouse.

Generation of vasoactive prostanoids from arachidonic acid by cyclooxygenase (COX)-1 and COX-2 was investigated in anesthetized mice. Intravenous injections of the prostanoid precursor arachidonic acid increased pulmonary arterial pressure and decreased systemic arterial pressure. Pulmonary pressor and systemic depressor responses were attenuated by SC-560 and nimesulide, inhibitors of COX-1 and COX-2, in doses that did not alter responses to injected prostanoids. Pulmonary pressor responses to arachidonic acid were blocked and a depressor response was unmasked, whereas systemic depressor responses were not altered, by a thromboxane receptor antagonist. Pulmonary and systemic pressor responses to angiotensin II injections and systemic pressor responses to angiotensin II infusion were not modified by COX-1 or COX-2 inhibitors but were attenuated by losartan. Systemic depressor responses to arachidonic acid were smaller in COX-1 and COX-2 knockout mice, whereas responses to angiotensin II, norepinephrine, U-46619, endothelin-1, and PGE(1) were not different in COX-1 and COX-2 knockout and wild-type control mice. These results suggest that vasoactive prostanoids with pulmonary pressor and systemic vasodepressor activity are formed by COX-1 and COX-2 and are consistent with Western blot analysis and immunostaining showing the presence of COX-1 and COX-2. These data suggest that thromboxane A(2) (TxA(2)) is formed from the precursor by COX-1 and COX-2 in the lung and are in agreement with immunofluorescence studies showing thromboxane synthase. The present data suggest that COX-1- or COX-2-derived prostanoids do not modulate responses to angiotensin II or other vasoactive agents and that prostanoid responses are similar in CD-1 and C57BL/6 and in male and female mice.

Angiotensin II↗

PubMed2005

Neurohumoral features of myocardial stunning due to sudden emotional stress.

BACKGROUND: Reversible left ventricular dysfunction precipitated by emotional stress has been reported, but the mechanism remains unknown. METHODS: We evaluated 19 patients who presented with left ventricular dysfunction after sudden emotional stress. All patients underwent coronary angiography and serial echocardiography; five underwent endomyocardial biopsy. Plasma catecholamine levels in 13 patients with stress-related myocardial dysfunction were compared with those in 7 patients with Killip class III myocardial infarction. RESULTS: The median age of patients with stress-induced cardiomyopathy was 63 years, and 95 percent were women. Clinical presentations included chest pain, pulmonary edema, and cardiogenic shock. Diffuse T-wave inversion and a prolonged QT interval occurred in most patients. Seventeen patients had mildly elevated serum troponin I levels, but only 1 of 19 had angiographic evidence of clinically significant coronary disease. Severe left ventricular dysfunction was present on admission (median ejection fraction, 0.20; interquartile range, 0.15 to 0.30) and rapidly resolved in all patients (ejection fraction at two to four weeks, 0.60; interquartile range, 0.55 to 0.65; P<0.001). Endomyocardial biopsy showed mononuclear infiltrates and contraction-band necrosis. Plasma catecholamine levels at presentation were markedly higher among patients with stress-induced cardiomyopathy than among those with Killip class III myocardial infarction (median epinephrine level, 1264 pg per milliliter [interquartile range, 916 to 1374] vs. 376 pg per milliliter [interquartile range, 275 to 476]; norepinephrine level, 2284 pg per milliliter [interquartile range, 1709 to 2910] vs. 1100 pg per milliliter [interquartile range, 914 to 1320]; and dopamine level, 111 pg per milliliter [interquartile range, 106 to 146] vs. 61 pg per milliliter [interquartile range, 46 to 77]; P<0.005 for all comparisons). CONCLUSIONS: Emotional stress can precipitate severe, reversible left ventricular dysfunction in patients without coronary disease. Exaggerated sympathetic stimulation is probably central to the cause of this syndrome.

Adult↗

PubMed2005

Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism.

The molecular mechanism for priapism is not well characterized. Although the nitric oxide (NO) pathway is known to mediate penile erection under normal conditions, we hypothesized that the mechanism of priapism rests in aberrant downstream signaling of this pathway based on our previous findings that mice lacking the gene for endothelial nitric oxide synthase (eNOS-/-) and mice lacking both neuronal NOS (nNOS) and eNOS (nNOS-/-, eNOS-/-) have a tendency for priapic activity. We investigated the role of downstream guanylate cyclase and phosphodiesterase type 5 (PDE5A) expression and function in mediating these responses in eNOS-/- and nNOS-/-, eNOS-/- mice. Erectile responses to both cavernous nerve stimulation and intracavernosal injection of the NO donor diethylamine-NONOate were augmented in eNOS-/- and nNOS-/-, eNOS-/- mice but not in WT or nNOS-/- mice. PDE5A protein expression and activity and cGMP levels were significantly lower in eNOS-/- and nNOS-/-, eNOS-/- mice, and this effect was reproduced in WT corpus cavernosum exposed to NOS inhibitors. Moreover, cavernous nerve stimulation was associated with a marked augmentation of cavernosal cGMP levels, suggesting that, although lower at baseline, the production of cGMP is unchecked in eNOS-/- and nNOS-/-, eNOS-/- mice upon neurostimulation. Transfection of eNOS-/- mice with an adenovirus encoding eNOS resulted in a normalization of PDE5A protein and activity as well as a correction of priapic activity. Coupled with the observation that sickle cell disease mice (which show a priapism phenotype) evince dysregulated PDE5A expression/activity, these data suggest that PDE5A dysregulation is a fundamental mechanism for priapism.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2005

Poly(Adenosine diphosphate-ribose) polymerase inhibition preserves erectile function in rats after cavernous nerve injury.

PURPOSE: We investigated the involvement of poly(adenosine diphosphate-ribose) (PAR) polymerase (PARP) activation in the development of erectile dysfunction and the therapeutic benefit of the potent PARP inhibitor INO-1001 (Inotek Pharmaceuticals Corp., Beverly, Massachusetts) in a bilateral cavernous nerve crush injury (BCNCI) model in rats. MATERIALS AND METHODS: Sprague-Dawley rats were divided into 3 groups, namely sham treated, BCNCI plus vehicle and BCNCI plus the PARP inhibitor INO-1001. One week after surgical intervention all groups underwent in vivo cavernous nerve stimulation. PAR activation, nitrotyrosine and inducible nitric oxide synthase were evaluated by immunohistochemistry and serum levels of INO-1001 were measured by high performance liquid chromatography. Penile tissues were analyzed for levels of malondialdehyde and myeloperoxidase. Data sets were statistically compared in all groups. RESULTS: Neurogenic mediated erectile responses were evaluated. Mean intracavernous pressure (ICP), the ICP-to-blood-pressure ratio and total ICP were significantly decreased in BCNCI plus vehicle rats. These values were not statistically different between the sham and PARP inhibitor treated groups. There was a marked decrease in PAR staining in the treatment group. There was a substantial increase in malondialdehyde tissue levels but not myeloperoxidase in response to BCNCI, which was unchanged with PARP inhibitor treatment. There was a marked increase in tyrosine nitration in the treatment group. Up-regulation of nitric oxide synthase and increased tyrosine nitration were not observed in the penile tissues of the treatment group. CONCLUSIONS: These data demonstrate that BCNCI in a rat model causes increased PARP activation, resulting in severe erectile dysfunction. Treatment with the PARP inhibitor INO-1001 decreases the degree of nitrosative stress, prevents PARP activation and provides significant cavernous neuroprotection, which in turn preserves erectile function.

Adenosine Diphosphate Ribose↗

PubMed2005

Superoxide anion production in the rat penis impairs erectile function in diabetes: influence of in vivo extracellular superoxide dismutase gene therapy.

INTRODUCTION: Superoxide anion may contribute to erectile dysfunction (ED) in diabetes mellitus by reducing cavernosal nitric oxide (NO) bioavailability. The purpose of this study was to determine if gene transfer of extracellular superoxide dismutase (EC-SOD) can reduce superoxide anion formation and determine if this reactive oxygen species may contribute to diabetes-related ED in an experimental model of diabetes. METHODS: Three groups of animals were utilized: (1) control; (2) streptozotocin (STZ)-diabetic rats [60 mg/kg intraperitoneally (ip)] intracavernosally injected with AdCMVbetagal (negative control); and (3) STZ-rats intracavernosally injected with AdCMVEC-SOD. Two months after ip injection of STZ, groups 2 and 3 were transfected with the adenoviruses and 2 days after transfection, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Confocal microscopy for superoxide anion and von Willebrand Factor (vWF) was performed in the STZ-diabetic rat. Superoxide anion production, total SOD activity, and cyclic guanosine monophosphate (cGMP) levels were measured in each experimental group of rats. RESULTS: Confocal microscopy demonstrated superoxide in smooth muscle and endothelial cells of the STZ-rat cavernosum and colocalized with vWF in the endothelium. Higher superoxide anion levels and decreased cGMP levels were found in the penis of STZ-rats at a time when erectile function was reduced. Two days after administration of AdCMVEC-SOD, superoxide anion levels were significantly lower in the penis of STZ-rats. Total SOD activity and cavernosal cGMP was increased in the penis of EC-SOD-transfected rats. STZ-rats transfected with AdCMVEC-SOD had a peak intracavernosal pressure (ICP) and total ICP to CNS that was similar to control rats. CONCLUSIONS: These data demonstrate that in vivo adenoviral gene transfer of EC-SOD can reduce corporal superoxide anion levels and raise cavernosal cGMP levels by increasing NO bioavailability thus restoring erectile function in the STZ-diabetic rat.

Adenoviridae↗

PubMed2005

Potential application for mesenchymal stem cells in the treatment of cardiovascular diseases.

Stem cells isolated from various sources have been shown to vary in their differentiation capacity or pluripotentiality. Two groups of stem cells, embryonic and adult stem cells, may be capable of differentiating into any desired tissue or cell type, which offers hope for the development of therapeutic applications for a large number of disorders. However, major limitations with the use of embryonic stem cells for human disease have led researchers to focus on adult stem cells as therapeutic agents. Investigators have begun to examine postnatal sources of pluripotent stem cells, such as bone marrow stroma or adipose tissue, as sources of mesenchymal stem cells. The following review focuses on recent research on the use of stem cells for the treatment of cardiovascular and pulmonary diseases and the future application of mesenchymal stem cells for the treatment of a variety of cardiovascular disorders.

Animals↗

PubMed2005

Endothelial nitric oxide synthase gene therapy for erectile dysfunction.

Basic science research on erectile physiology has been devoted to investigating the pathogenesis of erectile dysfunction (ED) and has led to the conclusion that ED is predominately a disease of vascular origin. It is well recognized that the incidence of ED dramatically increases in men who suffer from diabetes mellitus, hypercholesterolemia, and cardiovascular disease. Endothelial nitric oxide synthase (eNOS) is an important factor in cardiovascular homeostasis, angiogenesis, and erectile function. Given the impact of endothelial-derived nitric oxide (NO) in vascular biology, a great deal of research over the past decade has focused on the role of NO synthesis from the endothelium in normal erectile physiology as well as in disease states. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED. Therefore, a likely target of gene therapy for the treatment of ED is eNOS. This communication reviews the role of eNOS in erectile physiology and discusses the alterations in eNOS expression in various vascular diseases of the penis. Putative gene therapy interventions to restore eNOS expression and subsequent endothelial function may represent an exciting new therapeutic strategy for the future treatment of ED.

Erectile Dysfunction↗