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Biomedical subjects

A L Burnett

Publications and source records attributed to A L Burnett.

At least 19 recordsLinked to original sources
PubMed2006

Endothelial dysfunction in diabetic erectile dysfunction.

Erectile dysfunction (ED) is highly prevalent in diabetes mellitus. Pathophysiological mechanisms underlying diabetes-associated ED are in large part due to endothelial dysfunction, which functionally refers to the inability of the endothelium to produce vasorelaxing messengers and to maintain vasodilation and vascular homeostasis. The precise mechanisms leading to endothelial dysfunction in the diabetic vasculature, including the penis, are not yet fully understood. Hyperglycemia affects endothelial nitric oxide synthase activity and nitric oxide production/bioavailability, nitric oxide-independent relaxing factors, oxidative stress, production and/or action of hormones, growth factors and/or cytokines, and generation and activity of opposing vasoconstrictors. Considering recent advances in the field of vascular biology and diabetes, the emphasis in this review is placed on the mechanisms of hyperglycemia-induced endothelial dysfunction in the pathophysiology of diabetes-associated ED.

Diabetes Complications↗
PubMed2004

Novel nitric oxide signaling mechanisms regulate the erectile response.

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

Animals↗
PubMed2003

Priapism pathophysiology: clues to prevention.

Priapism, in which penile erection persists in the absence of sexual excitation, is an enigmatic yet devastating erectile disorder. Current endeavors to manage the disorder suffer from a poor fundamental knowledge of the etiology and pathogenesis of priapism. These endeavors have remained essentially reactive, which commonly fail to avert its pathological consequences of erectile tissue damage and erectile disability, not to mention its psychological toll. The role of preventative management seems paramount with respect to priapism. As a prerequisite to formulating prevention strategies, gaining understanding of its pathogenic features and likely pathophysiologic mechanisms is viewed to be quite important. This review combined an analysis of clinicopathologic reports as well as a summary of clinical and basic science investigations on the subject to date. These assessments support the basic classification of priapism into low-flow (ischemic) and high-flow (nonischemic) hemodynamic categories, resulting from venous outflow occlusion and unregulated arterial overflow of the penis, respectively. In addition, consistent with the hypothesis that dysregulative physiology of penile erection accounts for some presentations of priapism, several plausible molecular mechanisms influencing the functional state of the erectile tissue are discussed. Current progress in the field suggests prevention possibilities using androgenic suppressive therapy, adrenergic agonist therapies, and effectors of the nitric oxide-dependent erection regulatory pathway in the penis. New ideas for prevention may emerge from targeting molecular mechanisms involved in regulating erectile tissue function.

Humans↗
PubMed2003

Protein inhibitor of nitric oxide synthase (NOS) and the N-methyl-D-aspartate receptor are expressed in the rat and mouse penile nerves and colocalize with penile neuronal NOS.

Nitrergic neurotransmission triggering penile erection is mediated by nitric oxide (NO) synthesized in the cavernosal nerves of the penis by penile neuronal NO synthase (PnNOS). In the central nervous system, nNOS is activated by the N-methyl-D-aspartate receptor (NMDAR) and, presumably, is inhibited by the protein inhibitor of NOS (PIN). The PnNOS and NMDAR are expressed in the penis, and PnNOS has been localized in penile nerves. Both proteins colocalize with PIN in the hypothalamus and the spinal cord involved in the control of erection. The present study aimed to elucidate the relationship between PnNOS, PIN, and NMDAR in the penis. It was found that in the rat, PIN was expressed in the pelvic ganglion and the cavernosal nerve, and penile PIN cDNA was cloned, sequenced, and expressed. Immunohistochemistry localized PIN to the cavernosal and dorsal nerve of the penis, whereas NMDAR was not detected in the latter. Dual-fluorescence labeling showed that PnNOS colocalized with PIN in both nerves but with NMDAR only in the cavernosal nerve. Aging did not affect the mRNA levels of PnNOS, nNOS, NMDAR, and PIN. Both PIN and NMDAR were detected in penile nerves of the wild-type and nNOS(-/-) mouse. The PIN protein did not inhibit or bind NOS in penile extracts, and in vivo, PIN cDNA reduced the erectile response to electrical field stimulation. In conclusion, PIN and NMDAR colocalize with PnNOS in penile nerves, but the functional significance of these protein interactions for penile erection remains to be elucidated.

Aging↗
PubMed2002

FK506 binding protein 12 is expressed in rat penile innervation and upregulated after cavernous nerve injury.

To evaluate whether FK506 and other immunophilin ligands may have potential therapeutic efficacy for erectile function preservation after penile nerve injury, we demonstrated localizations of the immunophilin FK506 binding protein 12 (FKBP 12) in intact and injured rat penile nerves and correlated these findings with localizations of neuronal nitric oxide synthase (nNOS), which neuronally forms nitric oxide for mediation of penile erection, in response to systemically administered FK506. Adult male Sprague-Dawley rats were subjected to unilateral right cavernous nerve forceps crush injury and administered FK506 (1 mg/kg i.p.) or saline at the same time and daily up to 7 days. At 1, 3 and 7 days after injury, bilateral cavernous nerves and major pelvic ganglia were collected for nNOS immunohistochemistry, FKBP 12 immunohistochemistry, and FKBP 12 in situ hybridisation. Protein expressions of nNOS and FKBP 12 were observed in major pelvic ganglion, cavernous nerve and nerve terminals within the rat penis as well as mRNA expression of FKBP 12 observed in the rat major pelvic ganglion neuronal cell bodies to a minimal extent at baseline conditions. After cavernous nerve injury, nNOS immunoreactivity was observed to be slightly diminished in ipsilateral penile nerve structures at only one day following injury while both FKBP 12 protein and mRNA expressions were observed to be increased at each interval of study. FK506 treatment did not affect staining of intact or injured nerves. Our demonstration that FKBP 12 is localized to penile innervation in the rat and becomes upregulated following cavernous nerve crush injury, independent of FK506 treatment, suggests that this immunophilin mediates a neurotrophic mechanism. Whether FK506 affords neuroprotection that preserves penile erection through FKBP 12 upregulation is unclear.

Animals↗
PubMed2002

Simulated ischemia induces renal tubular cell apoptosis through a nuclear factor-kappaB dependent mechanism.

PURPOSE: Ischemia-reperfusion injury is a relatively common cause of renal tubular cell death and acute renal failure. While nuclear factor-kappaB has been implicated in the pathophysiology of renal ischemia-reperfusion injury, the effect of nuclear factor-kappaB inhibition on ischemia induced renal tubular cell death remains unknown. MATERIALS AND METHODS: Renal tubular cells (LLC-PK1) were exposed to simulated ischemia in the presence or absence of 10 microM. pyrrolidine dithiocarbamate (nuclear factor-kappaB inhibitor). Nuclear factor-kappaB activation (electrophoretic mobility shift assay and immunohistochemistry) and the effect of pyrrolidine dithiocarbamate on nuclear factor-kappaB activation (electrophoretic mobility shift assay) and ischemia induced apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling) were determined. RESULTS: Simulated ischemia induced nuclear factor-kappaB activation and renal tubular cell apoptosis versus controls (mean plus or minus standard error of mean 62 +/- 5.2 versus 0.4 +/- 0.3 apoptotic nuclei per high power field, p <0.05). In contrast, previous cellular exposure to pyrrolidine dithiocarbamate effectively inhibited nuclear factor-kappaB activation and prevented ischemia induced apoptosis (mean 14 +/- 6 apoptotic nuclei per high power field). CONCLUSIONS: Simulated ischemia induces nuclear factor-kappaB intranuclear translocation and activation in renal tubular cells. Furthermore, nuclear factor-kappaB mediates ischemia induced renal tubular cell apoptosis. Further elucidation of the complex role of nuclear factor-kappaB in inflammatory injury may lead to the development of targeted therapeutic strategies that ameliorate ischemic renal injury.

Animals↗
PubMed2001

A novel model of ischemia in renal tubular cells which closely parallels in vivo injury.

PURPOSE: Renal ischemia-reperfusion (IR) injury is a devastating clinical problem. While effective animal models have been developed to investigate this condition, they are limited by differential renal cell inflammatory mediator production and heterogeneous cell sensitivity to ischemia. We therefore developed an in vitro model of renal tubular cell ischemia that simulates the cellular injury observed in animal models of renal IR injury. MATERIALS AND METHODS: Using the established renal tubular cell line, LLC-PK1, simulated ischemia was induced by immersing the cellular monolayer in mineral oil. The effect of simulated ischemia on renal tubular cells was then determined by measuring the time course of TNF-alpha protein expression (ELISA), TNF-alpha mRNA induction (RT-PCR), and renal tubular cell apoptosis (TUNEL). RESULTS: Maximal TNF-alpha protein expression occurs following 60 min of simulated ischemia and 2 h of substrate replacement (reimmersion in media), and maximal TNF-alpha mRNA induction occurs following 60 min of simulated ischemia. Cellular apoptosis peaks following 60 min of simulated ischemia and 24 h of reperfusion. CONCLUSION: The time course of TNF-alpha production and apoptosis induction in this model closely parallels the time course for these markers in vivo. This study constitutes the initial demonstration that an in vitro oil immersion model of ischemia simulates the cellular injury (TNF-alpha production and apoptosis) observed in animal models of renal ischemia-reperfusion. This model may be used to study cellular mechanisms of IR in the absence of the systemic confounding variables.

Animals↗
PubMed2001

Novel pharmacological approaches in the treatment of erectile dysfunction.

The pharmacological treatment of erectile dysfunction has taken central importance among therapeutic approaches for this increasingly recognized, widespread disorder. In the past decade and a half, the specialty of erectile dysfunction management has witnessed an enormous growth in basic scientific interest which has been translated impressively to the clinical arena. Discoveries of regulatory mechanisms involved in penile erection have been garnered both at peripheral neurologic and end organ levels and at central brain and spinal cord levels. These discoveries along with ongoing investigations in the field provide a firm foundation for implementing exciting and effective erectile dysfunction pharmacotherapies both now and in the future. The purpose of this report is to review the current trends and new directions in the pharmacotherapy of erectile dysfunction.

Central Nervous System Agents↗
PubMed2001

Corporoplasty using pericardium allograft (tutoplast) with complex penile prosthesis surgery.

Penile prosthesis implantation can be challenging for such presentations as penile fibrosis and prosthesis erosion and conditions in which the corporal body is severely damaged or deficient. The technical complexity of some repairs and the infections associated with synthetic graft materials will sometimes pose limitations to using these materials. We offer a new role for Tutoplast processed pericardial allograft for complex corporoplasty during penile prosthesis surgery.

Aged↗
PubMed2001

General use of animal models for investigation of the physiology of erection.

In review, animal models have accounted significantly for the amazing strides made in the field of sexual dysfunction research. Fundamentally, they have offered a unique experimental approach to test many hypotheses regarding sexual function. Since their early use for sexual physiology research, there has been increasing sophistication using animals involving techniques for stimulating and monitoring sexual responses. One specific area that has been advanced is the use of conscious animal models to obtain a better sense of the natural contexts for sexual physiology and to avoid pharmacological interference associated with anesthetics. Another area of interest is the increasing use of simple but valid techniques to record and assess sexual responses. Efforts to develop and evaluate animal models that replicate disorders of sexual function have also been most advantageous. In the future, animal models will remain useful. The expanded applications of animal models include the study of predisposing disease states associated with sexual dysfunction and the study of all aspects of sexual dysfunction, in both male and female subjects. Continued judgment must be applied, understanding the advantages of one or another animal model, to explore questions and provide answers that are most scientifically relevant to the human condition. The promise of advancing therapies in this field indicates the additional prominent role for animals for the purposes of drug development.

Animals↗
PubMed2001

Endothelial nitric oxide synthase protein expression, localization, and activity in the penis of the alloxan-induced diabetic rat.

PURPOSE: To explore the possible relevance of endothelial nitric oxide synthase (eNOS) in the pathophysiology of erectile dysfunction (ED) associated with diabetes mellitus, we compared the catalytic activity, protein expression, and cellular localization of eNOS with those of neuronal nitric oxide synthase (nNOS) in the penis of rats with alloxan-induced diabetes. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were given alloxan or vehicle only and monitored weekly by Dextrostix for confirmation of glucosuria. Tail-flick immersion and penile reflex testing were used to evaluate sensory neuropathy and ED, respectively. At 4 to 5 weeks (early) and 10 to 11 weeks (late), animals were sacrificed, and their penes were subjected to nNOS and eNOS catalytic activity assay, Western immunoblotting, and immunohistochemistry examination. Masson's trichrome staining of penile tissue and serum testosterone measurements were performed for light microscopy and sex steroidogenic analysis, respectively. RESULTS: Confirmed diabetic rats showed significant reductions in penile nNOS expression and eNOS activity and expression early, prior to observed ED, and nNOS and eNOS activities and expressions late, synchronous with ED. Decreased intensities of both nNOS staining, localized to the dorsal and cavernosal nerves distributing to the penis, and eNOS staining, localized to penile vascular and sinusoidal endothelium, were assessed in diabetic animals. Penile vascular and cavernosal tissue appeared intact in diabetic rats. Testosterone levels were equivalent in nondiabetic and diabetic rats. CONCLUSIONS: In the penis of the alloxan-induced diabetic rat, eNOS protein expression and synthetic activity were reduced compared with the normal rat penis, independent of testosterone influence and in the absence of significant erectile tissue degenerative changes. These eNOS effects apparently preceded nNOS effects. Full elucidation of the possible mechanisms affecting eNOS function in the diabetic rat penis requires further investigation.

Alloxan↗
PubMed2001

Heat shock prevents simulated ischemia-induced apoptosis in renal tubular cells via a PKC-dependent mechanism.

Heat shock produces cellular tolerance to a variety of adverse conditions; however, the protective effect of heat shock on renal cell ischemic injury remains unclear. Protein kinase C (PKC) has been implicated in the signaling mechanisms of acute preconditioning, yet it remains unknown whether PKC mediates heat shock-induced delayed preconditioning in renal cells. To study this, renal tubular cells (LLC-PK1) were exposed to thermal stress (43 degrees C) for 1 h and heat shock protein (HSP) 72 induction was confirmed by Western blot analysis. Cells were subjected to simulated ischemia 24 h after thermal stress, and the effect of heat shock (delayed preconditioning) on ischemia-induced apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling) and B cell lymphoma 2 (Bcl(2)) expression (Western) was determined. Subsequently, the effect of PKC inhibition on HSP72 induction and heat stress-induced ischemic tolerance was evaluated. Thermal stress induced HSP72 production, increased Bcl(2) expression, and prevented simulated ischemia-induced renal tubular cell apoptosis. PKC inhibition abolished thermal induction of HSP72 and prevented heat stress-induced ischemic tolerance. These data demonstrate that thermal stress protects renal tubular cells from simulated ischemia-induced apoptosis through a PKC-dependent mechanism.

Alkaloids↗
PubMed2000

Use of intraoperative video documentation to improve sexual function after radical retropubic prostatectomy.

OBJECTIVES: To determine whether arbitrary minor variances in surgical technique can have a major impact on the recovery of sexual function after radical retropubic prostatectomy. METHODS: The surgical procedures of 62 potent men were videotaped prospectively. Eighteen months after the study was initiated, the videotapes were reviewed and specific steps in the surgical procedure correlated with patient-reported potency rates. RESULTS: Four steps were identified that appeared to correlate with the recovery of sexual function: over-sewing back-bleeders from the proximal dorsal vein on the anterior surface of the prostate, division of the striated sphincter when placing urethral sutures, division of the posterior striated sphincter, and hemostasis at the end of the case. CONCLUSIONS: We believe that retrospective review of intraoperative videotapes has great promise. Because many surgeons use different techniques, it is likely that each individual may be able to identify other important arbitrary variations that may improve their patients' outcomes. Similarly, for surgeons with less than optimal outcomes, the review of early successful cases may enable them to identify ways that modification of their surgical technique can improve the outcome of future patients. To the best of our knowledge, the use of retrospective review of intraoperative videotapes has not been commonly used in any other surgical field.

Adult↗
PubMed2000

Patient-reported urinary continence and sexual function after anatomic radical prostatectomy.

OBJECTIVES: After radical prostatectomy, the rates for recovery of urinary continence and sexual function reported by experienced surgeons are much higher than the patient-reported outcomes from other centers. It is uncertain whether this represents differences in surgical technique or in the collection of data. This study was performed to determine patient-reported rates of continence and potency after radical prostatectomy performed by an experienced surgeon at a high-volume referral center for the treatment of localized prostate cancer. METHODS: Sixty-four men with localized prostate cancer who were potent preoperatively and who had sexual partners underwent anatomic radical prostatectomy between March 1997 and January 1998. A validated disease-targeted quality-of-life survey that assesses function and bother in two organ systems (urinary and sexual) was administered preoperatively and at 3, 6, 12, and 18 months postoperatively. RESULTS: Urinary continence, which was defined as wearing no pads, gradually improved during the first 12 months after surgery, and at 1 2 and 18 months, 93% of the patients were dry. Throughout the study, 93% to 98% of the patients characterized their urinary bother as none or small. Potency, defined as the ability to have unassisted intercourse with or without the use of sildenafil, improved gradually, and by 18 months, 86% of patients were potent and 84% considered sexual bother as none or small. Although one third of patients at 18 months were using sildenafil intermittently, only 2 patients were not able to have intercourse without its use. CONCLUSIONS: Patient-reported rates of continence and potency after radical prostatectomy performed by an experienced surgeon are high.

Adult↗
PubMed2000

Near infrared spectrophotometry for the diagnosis of vasculogenic erectile dysfunction.

A specialized near infrared spectrophotometry instrument for noninvasive, continuous monitoring of the hemodynamic events of erection in the human penis has been developed. Its potential application for the diagnostic evaluation of erectile dysfunction was investigated. Thirty-eight patients and 18 volunteer subjects underwent penile near infrared spectrophotometry using an optical sensor probe with wavelength selectivity for hemoglobin absorption spectra. Penile blood volume changes and their time courses were measured following intracavernous pharmacostimulation in patients and visual sexual stimulation in volunteers. Spectrophotometric results were compared with results obtained simultaneously using color duplex ultrasonography, strain gauge penile circumference monitoring, penile tonometry, and clinical assessments. Spectrophotometric recordings of penile erection showed measurable blood volume changes consistent with the hemodynamic events of this biological function. Blood volume per cent (BV%) increase correlated with clinical ratings of erection quality (P < 0.001), penile rigidity measurements (P < 0.005), and penile circumference increases (P < 0.0001), and it correlated with mean peak systolic velocity measurements when BV% increase was restricted to values less than 50% (P < 0.001). The time to reach half the maximum blood volume change (BV T1) correlated directly with the time to reach half the maximum penile circumference size increase (P < 0.001), whereas BV T4 correlated inversely with mean resistive index measurements only when BV T(1/2) was restricted to values greater than 120 s (P < 0.05). Spectrophotometric criteria consisting of BV % less than 35% and BV T(1/2) greater than 120 s affirmed the diagnosis of severe erectile impairment with a similar degree of accuracy as standard ultrasonographic criteria (P < 0.002). Penile near infrared spectrophotometry is a safe, inexpensive and simply used biomedical optics technique that provides quantitative measurements of the vascular physiology of penile erection and appears to offer clinical utility in the diagnosis of vasculogenic erectile dysfunction.

Adult↗