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Biomedical subjects

G B Brock

Publications and source records attributed to G B Brock.

At least 19 recordsLinked to original sources
PubMed2003

Effect of PDE5 inhibition combined with free oxygen radical scavenger therapy on erectile function in a diabetic animal model.

Phosphodiesterase (PDE) inhibitors represent an important advance in the treatment of erectile dysfunction (ED). In spite of widespread use and generally good efficacy, as a class they remain ineffective in 15-57% of men. Specific cohorts of patients with severe vascular or neurogenic basis to their ED, such as diabetic men or those who have undergone radical pelvic surgery, demonstrate lower response rates with PDE inhibition treatment. We believe that circulating levels of nitric oxide (NO) may be enhanced through delivery of adequate concentrations of free oxygen radical scavenger molecules such as vitamin E. Higher levels of NO, theoretically, should produce increased penile blood flow with the potential for a synergistic effect when combined with a PDE5 inhibitor. With this hypothesis in mind, 20 adult male Sprague-Dawley streptozotocin-induced (60 mg/kg i.p.) diabetic rats were divided into four therapeutic groups (n=5). Group I--control animals received peanut oil, group II--vitamin E 20 IU/day, group III--sildenafil 5 mg/kg/day and group IV--vitamin E 20 IU/day plus sildenafil 5 mg/kg/day, by oral gavage daily for 3 weeks. Erectile function was assessed as a rise in intracavernous pressure following cavernous nerve electrostimulation. Penile tissue was harvested to determine the changes in tissue morphology including neuronal nitric oxide synthase, smooth muscle alpha-actin and endothelial cell integrity. PDE5 protein content and activity were measured. Significant increases in intracavernous pressure were measured in the animals receiving combined vitamin E plus sildenafil treatment. Immunohistochemical staining showed increases of neuronal nitric oxide synthase, endothelial cell and smooth muscle cell staining. Western blot analysis did not show significant differences of PDE5 protein between the groups. However, higher PDE5 activity was measured in the sildenafil group and lower activity of PDE5 was recorded in the cohort receiving vitamin E with sildenafil. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in a meaningful way in this animal model of diabetes. This study indicates a potential means of salvaging erectile function among patients who are refractory to sildenafil.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Priapism. From Priapus to the present time.

Advances in the pharmacotherapeutic options available to treat erectile dysfunction over the past decade have transformed the field of impotence. The initial foray into this field with intracavernous injections of papaverine rapidly expanded the number of men seeking attention for priapism, a previously rare clinical condition. The recent widespread use and acceptance of oral agents for the treatment of erectile dysfunction, with a reduced incidence of priapism has decreased the number of men at risk for injection-related prolonged erections. The use of recreational drugs (cocaine) and perineal trauma leading to presentations of priapism seem to be rising in incidence. The urologist remains the consultant-specialist ultimately responsible for these men and should be cognizant of the array of treatments described for this condition. Early determination of the state of corporal oxygenation is essential and will define the optimal management approach. A wide range of medical conditions and risk factors may be etiologic and should be elicited from the patient at the initial interview. Low-flow ischemic priapism requires a rapid resolution, often achieved through use of alpha-agonists orally or by direct injection into the penile circulation, whereas nonischemic priapism can be treated more conservatively. Research into this condition has only recently been initiated. Through greater understanding of the pathophysiology of priapism, the clinician may become armed with etiology-specific medical alternatives providing timely detumescence for men with prolonged erections.

Algorithms↗
PubMed2001

New insights into the role of endothelin-1 in radiation-associated impotence.

The objectives of this work were to: (1) Determine if prostate and penile tissue levels of endothelin-1 (ET-1) are increased in a rat following pelvic irradiation. (2) Determine if an ETa receptor antagonist (BQ-123) potentiates erectile function in these irradiated animals. Rats were divided into three study groups: control, 1000 cGy and 2000 cGy. The experimental groups received a single dose of radiation to the pelvic region. A time course was established to measure the effects of irradiation on prostate and penile tissue levels of endothelin-1 (ET-1)-like immunoreactivity. The effect of intracavernous injection of BQ-123 (25 microg/30 microl) was evaluated by measuring intracavernous pressure (ICP) following cavernous nerve electrical field stimulation. In the 2000 cGy group, a significant rise in ET-1-like immunoreactivity tissue levels was observed at 20 days. A significant decrease in ICP was recorded in the 1000 and 2000 cGy irradiated rats compared to the control group. Only the 2000 cGy group had a significant improvement in erectile function following BQ-123 administration. A significant improvement was observed 20 min post-administration, lasted 90 min, and was back to pre-administered levels at 120 min. The conclusion made was that radiation-induced impotence in irradiated rats is associated with an increased production of ET-1. Preliminary results are suggestive that ETa receptor antagonist may be of use to reverse such radiation-induced impotence in these irradiated animals.

Animals↗
PubMed2001

Modern pharmacotherapy for erectile dysfunction: evolving concepts with central and peripheral acting agents.

Pharmacotherapy for men experiencing erectile dysfunction has undergone dramatic advances over the past 5 years with the introduction of an effective oral agent. Sildenafil has increased the pool of couples seeking treatment for this important health issue as well as expanding the numbers of physicians treating it. Research into the growing field of erectile dysfunction is expanding at a rapid pace. Independent investigators worldwide now regularly contribute to our body of scientific knowledge. Novel oral therapies targeted at specific points along the erectile cascade are undergoing pre-clinical and early phase registration trials with the promise of rapid action, extended duration of responsiveness and an improved side effect profile. In this review, we have highlighted recent information on the next generation of phosphodiesterase inhibitors and summarized the evolving research into centrally acting agents, which may lead to effective combination therapy.

Erectile Dysfunction↗
PubMed2000

Current status of standardized questionnaires in the measurement of erectile dysfunction.

The evaluation and management of erectile dysfunction has evolved dramatically over the past decade. Clinicians now benefit from advances in the understanding of the physiologic pathways involved in the function of erections and from the availability of innovative and effective therapies. The clinical history remains the essential starting point in the evaluation of patients with erectile dysfunction. The standardized questionnaire has been used as a valuable complement to the clinical history and in the assessment of treatment efficacy.

Erectile Dysfunction↗
PubMed1999

Searching for an intrinsic neuroendocrine cell in the kidney. An immunohistochemical study of the fetal, infantile and adult kidney.

The pathogenesis of primary renal carcinoid tumor is unknown. One hypothesis has implied derivation from a yet unrecognized intrinsic neuroendocrine cell in the renal parenchyma/hilum either as a minute endocrineparacrine constituent or resulting from entrapped/misplaced progenitor cells of the so-called dispersed neuroendocrine system during organogenesis. Immunohistochemical staining for chromogranin and serotonin was systematically performed on a whole-mount and geographically mapped normal adult kidney, kidneys from 15 fetuses (age range: 15 to 38 weeks), and renal specimens from 18 infants/children (age range: 7 days to 123 months). Minute paraganglion nests (composed of chromogranin positive/serotonin negative chief cells and S-100 protein positive dendritic cells) were incidentally detected within the renal hilum primitive stroma (unilaterally) of two fetuses at 22 and 26 weeks. Sequestration and persistence of such paraganglion nests during renal growth and maturation would offer a basis for the rare occurrence of extra-adrenal paraganglioma involving the renal hilum/pedicle. Otherwise, no neuroendocrine cell was detected within the renal parenchyma or hilum, therefore not validating/sustaining the aforementioned hypothesis in the pathogenesis of renal carcinoid tumor.

Carcinoid Tumor↗
PubMed1999

Neuronal and endothelial nitric oxide synthase isoforms: quantification of protein and mRNA in the normal rat penis.

Nitric oxide synthase (NOS) is an important enzyme for erection. We evaluated the content of neuronal (nNOS) and endothelial (eNOS) isoforms and their mRNA in the penis and major pelvic ganglion (MPG) of adult male rats by Western and Northern blot analysis. The cerebellum was evaluated as a control. nNOS protein and its mRNA were detected in abundance in the MPG, cerebellum, pelvic urethra and within the crura of the penis. In contrast, the penile urethra, neurovascular bundle and the shaft of penis contained smaller amounts of this protein. eNOS protein was most abundant in the penile and pelvic parts of the urethra, whereas a moderate level was found in the penile shaft, crura, neurovascular bundle, MPG and cerebellum. Similarly eNOS mRNA was abundant in the penile and pelvic parts of the urethra, MPG and cerebellum. Penile shaft, crura and neurovascular bundle showed moderate amounts of eNOS mRNA. In conclusion, nNOS and its mRNA are most abundant in the MPG and crura of penis whereas eNOS is most abundant in the urethra and to a lesser extent present in the penis. Importantly eNOS protein and mRNA were demonstrated in the MPG, where eNOS function has to be studied.

Animals↗
PubMed1999

The impact of chronic renal failure on nitric oxide synthase isoforms gene expression in the penis and pelvic ganglia of rats.

PURPOSE: Patients with chronic renal failure experience a variety of physical and metabolic alterations. Uremia is often accompanied by erectile dysfunction (ED). Little information is available concerning the underlying pathophysiological mechanisms by which chronic renal failure can lead to erectile dysfunction. In this study, chronic renal failure was induced by 5/6 nephrectomy in a rat model. Cavernous nerve stimulation was used to measure the intracavernous pressure (ICP) rise. MATERIALS AND METHODS: Adult male Sprague-Dawley rats, aged between 10-12 weeks and weighing 200-250 gm. were divided into two groups. The first group (n = 20) served as a control (sham-operated) and underwent laparotomy with dissection of the perirenal fat around both kidneys. The second group (n = 40) were subjected to an excisional 5/6 nephrectomy (unilateral nephrectomy and contralateral upper and lower polar nephrectomy). Serum creatinine was measured 3 days post-operatively and at the end of the 12th week. Development of renal failure was considered if the animal had serum creatinine more than 120 microM/l. After 12 weeks, 10 animals per group were subjected to electric field stimulation (EFS) of the cavernous nerve with simultaneous recording of ICP-rise and systemic blood pressure. Northern and western blot analyses were used to determine the mRNA expression and protein contents of NOS isoforms (neuronal and endothelial) in the penile tissues and MPG. RESULTS: This remnant kidney model resulted in renal failure in 20 of 40 animals. The ICP-rise after cavernous nerve stimulation in the renal failure group was significantly impaired, 7.7+/-2.9 cm. H2O, as compared to control rats, 55.5+/-1.2 cm. H2O (p<0.001). The latency period after cavernous nerve stimulation was significantly increased in renal failure rats (6.9+/-0.95 sec.) in comparison to controls (2.4+/-0.25 sec.). Six of ten uremic animals had significantly lower testosterone (<1 nmol./l.) levels compared to non-uremic rats (3.6 nmol./l.) (p<0.005). Northern blot analysis revealed that renal failure rats had significantly higher levels of nNOS mRNA in the MPG and penile tissues than controls. There was no change in eNOS mRNA in either group. Western blot analysis demonstrated that eNOS and nNOS protein contents in the MPG and penile tissues of renal failure rats were significantly higher than those of controls. CONCLUSION: This report demonstrates that impairment of erection in renal failure rats, as determined by ICP-rise, was present in spite of elevated neuronal nitric oxide synthase mRNA and its protein in the MPG and penile tissues. Further studies are needed to determine whether erectile dysfunction is a result of post-translational changes, circulating inhibitory substances or other factors.

Animals↗
PubMed1998

Reduction of ventral prostate weight by finasteride is associated with suppression of insulin-like growth factor I (IGF-I) and IGF-I receptor genes and with an increase in IGF binding protein 3.

Finasteride, a competitive and specific inhibitor of 5alpha-reductase, is widely used in the treatment of symptomatic benign prostatic hyperplasia. We demonstrate here that finasteride, when administered in an in vivo experimental system, caused ventral prostate regression. Intraprostatic dihydrotestosterone levels decreased, whereas testosterone levels increased in a dose-dependent manner following finasteride treatment. Finasteride also inhibited the expression of insulin-like growth factor (IGF)-I and IGF-I receptor genes in the ventral prostate. Finasteride significantly increased IGF binding protein-3 and slightly decreased IGF binding protein-2, -4, and -5 gene expression. Because IGFs are potent mitogens for prostate epithelial cells, this newly described activity of finasteride may contribute to its antiproliferative properties, particularly with regard to the inhibition of prostate growth seen clinically and in animal models.

5-alpha Reductase Inhibitors↗
PubMed1998

Priapism secondary to penile metastasis: a report of two cases and a review of the literature.

Malignancy metastasis to the penis is an uncommon clinicopathological entity. We present two cases of malignant priapism following penile metastasis, in which the diagnosis was established by core needle biopsy of the corpus cavernosum. Primary tumors were urothelial carcinoma of the urinary bladder in one case (the patient having concomitant high-grade prostatic adenocarcinoma) and prostatic adenocarcinoma in the other. The clinicopathological features of 51 previously reported cases of penile metastasis in the recent literature are reviewed.

Adenocarcinoma↗
PubMed1998

The latissimus dorsi bladder myoplasty to assist detrusor function.

The objective of this study was to evaluate whether an innervated skeletal muscle might augment detrusor function. In four dogs we performed the latissimus dorsi myoplasty, a transfer of the latissimus muscle as an innervated free flap wrapped around the bladder. Stimulation of the latissimus dorsi free flap initially achieved an average bladder pressure of 45.8 +/- 8.41 cm H2O, sufficient for partial evacuation. After 4 months the muscle generated a maximal pressure of 82 cm H2O, resulting in an evacuation of 27.7%. For selected patients, the latissimus dorsi bladder myoplasty may provide an alternative to intermittent catheterization in the future.

Animals↗
PubMed1998

Improvement of erectile function in diabetic rats by insulin: possible role of the insulin-like growth factor system.

Erectile dysfunction is commonly experienced in men with diabetes mellitus. We report that the intracavernous pressure (ICP) rise in diabetic rats was 55% of the control and returned to normal following insulin (I) or insulin plus free oxygen scavenger (I + S) treatment. Insulin-like growth factor (IGF) binding protein (IGFBP) -3, -4, and -5 messenger RNA (mRNA) levels in the major pelvic ganglia (MPG) of diabetic rats were elevated by 2-fold, 2.6-fold, and 2.5-fold, respectively. Both I and I + S returned IGFBP-4 and 5 mRNA levels to normal, whereas IGFBP-3 gene expression was severely inhibited. IGFBP-2 gene expression was greatly inhibited by diabetes and was unresponsive to treatment. In the penis of diabetic rats, IGFBP-2 and -4 mRNA levels were low, whereas IGFBP-3 mRNA levels were elevated 10-fold. These effects were reversed by I and I + S. I and I + S also corrected the IGFBP-3 expression pattern. IGF-I gene expression in the penis and MPG was not significantly increased (P < 0.05) by diabetes and returned to normal levels following I or I + S treatment. Because IGFs are potent regulatory factors in vascular tone, this newly described activity of insulin may play an important role in the improvement of erectile function seen clinically and in animal models.

Animals↗
PubMed1997

Evaluation of a no-needle penile injector: a preliminary study evaluating tissue penetration and its hemodynamic consequences in the rat.

OBJECTIVES: Intracavernous needle injection is an effective delivery method for pharmacotherapy of erectile dysfunction. Needle phobia, pain, and concern about local tissue injury have stimulated the search for new, less invasive means of inducing penile erection. In this preliminary communication, we evaluate a jet injector as an alternative to needle injection for intracavernous delivery of vasoactive drugs. METHODS: Jet injection was evaluated in three groups of rats receiving either India ink, saline, or papaverine into the penis. The ability of the jet injection to penetrate through the tunica albuginea and deliver liquid to the corpora cavernosa smooth muscle was assessed by the degree of staining within the corpus cavernosum (ink group), histologic change (saline group), and rise in intracavernous pressure (papaverine group). Erectile capacity following cavernous nerve electric stimulation was compared before and 1 hour after injection of saline or papaverine. RESULTS: Ink traversed the skin and tunica albuginea with extensive deposition noted within the cavernous spaces. Varying degree of subcutaneous hemorrhage were seen with saline jet injection; however, the corpus cavernous smooth muscles showed no evidence of injury. Jet injection of papaverine 3250 micrograms significantly increased cavernous pressure (39.4 +/- 4.6 cm H2O) compared with saline injection (2.8 +/- 1.3 cm H2O). CONCLUSIONS: We conclude that acute jet injection is an effective method for intracavernous delivery of drugs. Long-term effects should be evaluated prior to clinical use.

Animals↗
PubMed1996

7-Nitroindazole: a selective inhibitor of penile erection: an in vivo study in a rat animal model.

OBJECTIVES: The neuronal isoform of nitric oxide synthase (nNOS) has been localized in neurons innervating the penis and is believed to be an important mediator of erection. Using the selective inhibitor 7-nitroindazole (7-NI), we evaluated the possible role of nNOS in penile erection using a rat animal model. METHODS: Eighteen Sprague-Dawley rats were divided into three study groups. A sham group (n = 6) received the vehicle arachis oil, a low-dose group received 5 mg/kg (n = 6), and a high-dose group received 50 mg/kg (n = 6) of 7-NI prior to measurement of blood pressure and cavernous nerve stimulation-induced rise in intracavernous pressure. RESULTS: A dose-dependent inhibition of erection by 7-NI was seen. Control animals had an intracavernous pressure rise of 55.5 +/- 4.0 cm H2O, whereas the low-dose group had 26.5 +/- 2.8 cm H2O and the high-dose group had 6.2 +/- 2.1 cm H2O. A partial recovery of erection was seen in the low- and high-dose groups after 3 hours. Blood pressure was unaffected by 7-NI administration. CONCLUSIONS: 7-NI induced a reversible, dose-dependent inhibition of erection without affecting blood pressure. This in vivo study provides further evidence of the role played by nNOS in erection.

Analysis of Variance↗
PubMed1996

Neurogenic erectile dysfunction: the course of nicotinamide adenine dinucleotide phosphate diaphorase-positive nerve fibers on the surface of the prostate.

OBJECTIVES: Nitric oxide (NO) plays an important role as a neurotransmitter in the peripheral neural regulation of erection. A histochemical stain able to localize fibers releasing NO in combination with an in vivo study were used to evaluate the course and physiologic significance of the nerve fibers innervating the cavernous smooth muscle. METHODS: Morphologic studies in 6 rats and 6 human cadavers were performed, tracing the course of branches of the cavernous nerve branches using a nicotinamide adenine dinucleotide phosphate diaphorase staining technique. Electrostimulations in rats were performed before and after transection of the anterolateral part of the prostate capsule. RESULTS: Multiple nerve fibers were documented running on the lateral and ventral surfaces of the prostate distinct from the classically described dorsolateral neurovascular bundle. Transection of these fibers resulted in a loss of electrically induced intracavernous pressure (59.4 +/- 5.6 cm H2O versus 27.0 +/- 4.6 cm H2O). CONCLUSIONS: These preliminary morphologic and physiologic studies support a significant role for these nerve fibers in erection.

Animals↗
PubMed1996

Intracavernous injection of linsidomine chlorhydrate in monkeys: lack of toxic effect with long-term use.

OBJECTIVE: We sought to investigate whether linsidomine chlorhydrate (SIN1, the active metabolite of molsidomine and a nitric oxide donor) has a toxic effect when used chronically for the treatment of impotence. METHODS: We gave 50 intracavernous injection of 1.5 mg SIN1 over 25 weeks to each of 5 monkeys. RESULTS: Four monkeys consistently responded with erections of sufficient rigidity and duration (mean 47.5 +/- 3.3 min), and none of the five evidenced histopathologic changes of the cavernous tissue. CONCLUSION: SIN1 appears to be a safe option for the pharmacotherapy of erectile dysfunction.

Animals↗