Biomedical subjects

Nestor Gonzalez-Cadavid

Publications and source records attributed to Nestor Gonzalez-Cadavid.

10 recordsLinked to original sources

PubMed2006

Case report: Avoidance of palpable corporal fibrosis due to priapism with upregulators of nitric oxide.

INTRODUCTION: Recent evidence suggests that blocking inducible nitric oxide (NO) synthase in the penis may exacerbate fibrotic processes and that application of medications known to increase NO in tissues may prevent fibrosis. AIM: To report the use of an antifibrotic regimen consisting of medications known to upregulate NO production in two patients with refractory priapism. METHODS: Two patients presented with priapism of greater than 48-hour duration. After corporal aspiration/irrigation and shunting procedures failed, both were prescribed a daily antifibrotic regimen comprising the phosphodiesterase inhibitors pentoxifylline and sildenafil, and the NO precursor, L-arginine. RESULTS: At 1 year, both patients were found to have supple corpora without evidence of corporal fibrosis. CONCLUSIONS: An antifibrotic regimen consisting of upregulators of NO production may ameliorate the corporal fibrosis associated with recalcitrant priapism.

Arginine↗

PubMed2006

Phosphodiesterase type 5 is not upregulated by tadalafil in cultures of human penile cells.

OBJECTIVE: Tadalafil, a long-acting phosphodiesterase type 5 (PDE5) inhibitor, improves the erectile response by inhibiting cyclic guanosine monophosphate (cGMP) breakdown. Sustained higher levels of cGMP may hypothetically upregulate PDE5 expression and/or activity and lead to tachyphylaxis. We have investigated whether PDE5 upregulation occurs in vitro in cultures of human penile cells subjected to long-term incubation with increasing concentrations of tadalafil in the presence of a nitric oxide (NO) donor. METHODS: Human corpora cavernosa smooth muscle cells (CSMC) and tunica albuginea fibroblasts (TAF) primary cultures were characterized by immunocytochemistry and Western blot, and incubated with graded concentrations of tadalafil for 14 days, adding S-nitroso-N-acetyl penicillamine (SNAP) as an NO donor for the last 24 hours or at time zero, and cGMP levels were measured. Incubations were repeated for 7, 10, and 14 days, in the presence of SNAP, and PDE5 was estimated by Western blot, and at 14 days, by immunocytochemistry combined with quantitative image analysis, and by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Constructs of the human PDE5A promoter expressing luciferase were cloned and transfected into CSMC, and promoter activation by 8-deoxybromo-cGMP (8-Br-cGMP) was measured by luminometry. RESULTS: Incubations of CSMC with SNAP and tadalafil up to 14 days did not upregulate PDE5 mRNA or protein levels. With TAF, PDE5 protein was also not upregulated despite a slight increase in mRNA levels. PDE5 enzyme activity was unaffected by tadalafil in either CSMC or TAF. No upregulation of the PDE5 promoter was observed with up to 2 mM 8-Br-cGMP. CONCLUSIONS: Long-term incubation of human penile cells with tadalafil at concentrations above the in vitro IC50, and around the in vivo Cmax utilized in the clinical setting, did not upregulate PDE5A expression nor decrease cGMP levels. These data suggest that PDE5 upregulation is unlikely to occur in vivo on long-term tadalafil treatment.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2005

Conservative management options for Peyronie's disease.

Peyronie's disease is an acquired condition that presents clinically with a palpable induration, a distinct plaque, or a curvature of the erect penis. At times, the erections are painful. Erectile dysfunction (ED) often is associated with Peyronie's disease. The current era of phosphodiesterase therapy for the treatment of ED seems to have increased the number of patients presenting for treatment of Peyronie's disease. During the past decade, significant advances have been made in understanding the pathophysiology of the disease, resulting in numerous nonsurgical therapies proposed for the treatment of Peyronie's disease. These medical treatments can be administered systemically, locally, or intralesionally. Unfortunately, there are few randomized, placebo-controlled trials to evaluate most of these proposed therapies. In evaluating therapies for Peyronie's disease, it must be remembered that the natural disease history includes spontaneous resolution of pain and even a small improvement in penile curvature in some men. This article reviews the natural history, scientific understanding, and nonsurgical treatment options for the mild to moderate Peyronie's deformities. Surgical therapy remains the mainstay of treatment for severe and refractory cases of Peyronie's disease that result in a physical or psychologic dysfunction.

Humans↗

PubMed2004

Delta-4-androstene-3,17-dione binds androgen receptor, promotes myogenesis in vitro, and increases serum testosterone levels, fat-free mass, and muscle strength in hypogonadal men.

Previous studies of Delta 4-androstene-3,17-dione (4-androstenedione) administration in men have not demonstrated sustained increments in testosterone levels, fat-free mass (FFM), and muscle strength, and failure to demonstrate androstenedione's androgenic/anabolic effects has stifled efforts to regulate its sales. To determine whether 4-androstenedione has androgenic/anabolic properties, we evaluated its association with androgen receptor (AR) and its effects on myogenesis in vitro. Additionally, we studied the effects of a high dose of 4-androstenedione on testosterone levels, FFM, and muscle strength in hypogonadal men. We determined the dissociation constant (K(d)) for 4-androstenedione using fluorescence anisotropy measurement of competitive displacement of fluorescent androgen from AR ligand-binding domain. AR nuclear translocation and myogenic activity of androstenedione were evaluated in mesenchymal, pluripotent C3H10T1/2 cells, in which androgens stimulate myogenesis through an AR pathway. We determined effects of a high dose of androstenedione (500 mg thrice daily) given for 12 wk on FFM, muscle strength, and hormone levels in nine healthy, hypogonadal men. 4-Androstenedione competitively displaced fluorescent androgen from AR ligand-binding domain with a lower affinity than dihydrotestosterone (K(d), 648 +/- 21 and 10 +/- 0.4 nm, respectively). In C3H10T1/2 cells, 4-androstenedione caused nuclear translocation of AR and stimulated myogenesis, as indicated by a dose-dependent increase in myosin heavy chain II+ myotube area and up-regulation of MyoD protein. Stimulatory effects of 4-androstenedione on myosin heavy chain II+ myotubes and myogenic determination factor expression were attenuated by bicalutamide, an AR antagonist. Administration of 1500 mg 4-androstenedione daily to hypogonadal men significantly increased serum androstenedione, total and free testosterone, estradiol, and estrone levels and suppressed SHBG and high-density lipoprotein cholesterol levels. 4-androstenedione administration was associated with significant gains in FFM (+1.7 +/- 0.5 kg; P = 0.012) and muscle strength in bench press (+4.3 +/- 3.1 kg; P = 0.006) and leg press exercises (+18.8 +/- 17.3 kg; P = 0.045). 4-androstenedione is an androgen that binds AR, induces AR nuclear translocation, and promotes myogenesis in vitro, with substantially lower potency than dihydrotestosterone. 4-androstenedione administration in high doses to hypogonadal men increases testosterone levels, FFM, and muscle strength, although at the dose tested, the anabolic effects in hypogonadal men are likely because of its conversion to testosterone.

3T3 Cells↗

PubMed2004

New discoveries in the basic science understanding of Peyronie's disease.

Peyronie's disease is an acquired benign condition representing localized fibrosis of the penis. The disease is caused by microvascular trauma to the penis, with subsequent fibrin deposition resulting in aberrant wound healing and possibly other etiologies. Histopathologic studies of the Peyronie's plaque have demonstrated the role of transforming growth factor-beta 1 in the pathologic development of penile plaque. Animal models have been developed to test pathophysiology and therapeutics. The role of inducible nitric oxide synthase and nitric oxide has been established to limit and counteract fibrosis. Differential gene expression studies have identified candidate up-regulated or down-regulated genes that are involved in the pathophysiology of Peyronie's disease.

Animals↗

PubMed2003

Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression.

The mechanisms by which excessive glucocorticoids cause muscular atrophy remain unclear. We previously demonstrated that dexamethasone increases the expression of myostatin, a negative regulator of skeletal muscle mass, in vitro. In the present study, we tested the hypothesis that dexamethasone-induced muscle loss is associated with increased myostatin expression in vivo. Daily administration (60, 600, 1,200 micro g/kg body wt) of dexamethasone for 5 days resulted in rapid, dose-dependent loss of body weight (-4.0, -13.4, -17.2%, respectively, P < 0.05 for each comparison), and muscle atrophy (6.3, 15.0, 16.6% below controls, respectively). These changes were associated with dose-dependent, marked induction of intramuscular myostatin mRNA (66.3, 450, 527.6% increase above controls, P < 0.05 for each comparison) and protein expression (0.0, 260.5, 318.4% increase above controls, P < 0.05). We found that the effect of dexamethasone on body weight and muscle loss and upregulation of intramuscular myostatin expression was time dependent. When dexamethasone treatment (600 micro g. kg-1. day-1) was extended from 5 to 10 days, the rate of body weight loss was markedly reduced to approximately 2% within this extended period. The concentrations of intramuscular myosin heavy chain type II in dexamethasone-treated rats were significantly lower (-43% after 5-day treatment, -14% after 10-day treatment) than their respective corresponding controls. The intramuscular myostatin concentration in rats treated with dexamethasone for 10 days returned to basal level. Concurrent treatment with RU-486 blocked dexamethasone-induced myostatin expression and significantly attenuated body loss and muscle atrophy. We propose that dexamethasone-induced muscle loss is mediated, at least in part, by the upregulation of myostatin expression through a glucocorticoid receptor-mediated pathway.

Animals↗

PubMed2003

Myostatin is a skeletal muscle target of growth hormone anabolic action.

Myostatin is a cytokine that has recently been shown to selectively and potently inhibit myogenesis. To investigate the mechanisms of anabolic actions of GH on skeletal muscle growth, we examined the in vitro and in vivo effects of GH on myostatin regulation. Twelve GH-deficient hypopituitary adult subjects were treated with recombinant GH (5 micro g/kg.d) in a double-blind, placebo-controlled fashion. Body composition and physical function were assessed and skeletal muscle biopsies from the vastus lateralis performed at 6-monthly intervals during 18 months of treatment. Myostatin mRNA expression was significantly inhibited to 31 +/- 9% (P < 0.001) of control by GH but not by placebo administration (79 +/- 11%) as determined by quantitative real-time PCR normalized for the housekeeping glyceraldehyde-3-phosphate dehydrogenase gene. The inhibitory effect of GH on myostatin was sustained after 12 and 18 months of GH treatment. These effects were associated with increases in lean body mass and translated into enhanced aerobic performance as determined by maximal oxygen uptake and ventilation threshold. Parallel in vitro studies of skeletal muscle cells demonstrated significant reduction of myostatin expression by myotubes in response to GH, compared with vehicle treatment. Conversely, GH receptor antagonism resulted in up-regulation of myostatin in myoblasts. Given the potent catabolic actions of myostatin, our data suggest that myostatin represents a potential key target for GH-induced anabolism.

Adult↗

PubMed2003

Peyronie's Disease: A Review.

Peyronie's disease is an acquired benign condition without known systemic sequelae with presenting symptoms that include the presence of a plaque or induration of the penile shaft, penile curvature or deformity during erection, penile pain, and erectile dysfunction. This article reviews the natural history of the disease, discusses the disease's etiology (widely thought to involve minor penile trauma with subsequent aberrant wound healing), and outlines proper clinical evaluation of Peyronie's disease patients. Medical treatments can be systemic (colchicine, potassium aminobenzoate, vitamin E), intralesional (steroids, verapamil, collagenase, interferons), or topical. Surgical therapy for Peyronie's disease (plication, graft-based, and prosthetic techniques) should be reserved for the man who has failed conservative therapy and whose curvature, indentation, or erectile dysfunction precludes intercourse. Regardless of the surgical procedure, the patient should be made aware of the inherent risks of surgery.

Journal Article↗

PubMed2002

Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy.

Administration of replacement doses of testosterone to healthy hypogonadal men and supraphysiological doses to eugonadal men increases muscle size. To determine whether testosterone-induced increase in muscle size is due to muscle fiber hypertrophy, 61 healthy men, 18-35 yr of age, received monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist to suppress endogenous testosterone secretion and weekly injections of 25, 50, 125, 300, or 600 mg testosterone enanthate (TE) for 20 wk. Thigh muscle volume was measured by magnetic resonance imaging (MRI) scan, and muscle biopsies were obtained from vastus lateralis muscle in 39 men before and after 20 wk of combined treatment with GnRH agonist and testosterone. Administration of GnRH agonist plus TE resulted in mean nadir testosterone concentrations of 234, 289, 695, 1,344, and 2,435 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Graded doses of testosterone administration were associated with testosterone dose and concentration-dependent increase in muscle volume measured by MRI (changes in vastus lateralis volume, -4, +7, +15, +32, and +48 ml at 25-, 50-, 125-, 300-, and 600-mg doses, respectively). Changes in cross-sectional areas of both type I and II fibers were dependent on testosterone dose and significantly correlated with total (r = 0.35, and 0.44, P < 0.0001 for type I and II fibers, respectively) and free (r = 0.34 and 0.35, P < 0.005) testosterone concentrations during treatment. The men receiving 300 and 600 mg of TE weekly experienced significant increases from baseline in areas of type I (baseline vs. 20 wk, 3,176 +/- 186 vs. 4,201 +/- 252 microm(2), P < 0.05 at 300-mg dose, and 3,347 +/- 253 vs. 4,984 +/- 374 microm(2), P = 0.006 at 600-mg dose) muscle fibers; the men in the 600-mg group also had significant increments in cross-sectional area of type II (4,060 +/- 401 vs. 5,526 +/- 544 microm(2), P = 0.03) fibers. The relative proportions of type I and type II fibers did not change significantly after treatment in any group. The myonuclear number per fiber increased significantly in men receiving the 300- and 600-mg doses of TE and was significantly correlated with testosterone concentration and muscle fiber cross-sectional area. In conclusion, the increases in muscle volume in healthy eugonadal men treated with graded doses of testosterone are associated with concentration-dependent increases in cross-sectional areas of both type I and type II muscle fibers and myonuclear number. We conclude that the testosterone induced increase in muscle volume is due to muscle fiber hypertrophy.

Adolescent↗

PubMed2002

Future strategies for treating erectile dysfunction.

Erectile dysfunction affects over half of all men between 50 and 70 years of age, and by the age of 40, about 40% of men may suffer from some form of erectile dysfunction. Many disease states, such as diabetes, hypertension, depression, and vascular disease, are associated with the condition, which may occur many years prior to the onset of these disorders. The phenomenal success of sildenafil in improving erections in men with erectile dysfunction is due to the fact that the drug, as a phosphodiesterase inhibitor, improves the relaxation of smooth muscle cells, which become dysfunctional with the aging process. However, not everyone responds to this medication, mainly because the efficacy of the drug is directly dependent on the release of nitric oxide from the nerve terminals of the cavernosal nerve, and this may become defective with aging/certain disease states. The goal of gene therapy for organic impotence is to allow the patient to sustain physiologically elicited erections without resorting to pharmacological treatment immediately prior to the sexual act. Experimental efforts in gene therapy for erectile dysfunction are likely to continue intensively in a series of directions, some specific to the nature of the selected gene to be manipulated or the physiology of the corpora cavernosa itself, and others extrapolatable from the advancement of gene therapy in general.

Journal Article↗