Biomedical subjects

Peter Zvara

Publications and source records attributed to Peter Zvara.

11 recordsLinked to original sources

PubMed2006

Oral treatment with a vitamin D3 analogue (BXL628) has anti-inflammatory effects in rodent model of interstitial cystitis.

OBJECTIVE: To investigate the effects of a vitamin D3 analogue (BXL628) in a model of chronic cystitis, as calcitriol analogues might be an interesting new therapeutic option for interstitial cystitis, for although the cause of the disease remains unclear, the increase in mast cells in the mucosa and detrusor muscle are significant. MATERIALS AND METHODS: We devised a mouse model of allergen-induced allergic cystitis that is associated with the up-regulation of genes for interleukin-13, FcepsilonRIalpha and mast cells-derived proteases, a massive inflammatory reaction in the bladder tissue, and augmented levels of mast cell-derived protease 1 (MMCP1) detected in mouse sera. RESULTS: Oral administration of BXL628 significantly reduced the expression of interleukin-13, FcepsilonRIalpha and MMCP1 in the bladder. Furthermore, histological analysis showed a decrease in oedema and leukocyte infiltration in the bladder wall. BXL628 treatment reduced serum MMCP1 levels, indicating an effect on mast cell degranulation in vivo. CONCLUSIONS: Vitamin D3 analogues may successfully be used as anti-inflammatory agents in allergen-mediated inflammatory reactions. Moreover, the modulatory effect shown on mast cell activation by the BXL628 analogue strongly supports its potential therapeutic use in a possibly mast cell-dependent disease such as human interstitial cystitis.

Animals↗

PubMed2006

A role for pituitary adenylate cyclase activating polypeptide (PACAP) in detrusor hyperreflexia after spinal cord injury (SCI).

Intrathecal administration of the PAC1 receptor antagonist, PACAP6-38 (10 nM), significantly (P < or = 0.05) reduced intermicturition, threshold and micturition pressures in chronic (3-6 weeks) spinal cord injured rats but intravesical administration (100-300 nM) was without effect. Intrathecal PACAP6-38 reduced the number and amplitude of nonvoiding bladder contractions observed after spinal cord injury (SCI). PACAP may contribute to detrusor hyperreflexia induced by SCI and PACAP antagonists may be a novel approach to reduce detrusor hyperreflexia after SCI.

Animals↗

PubMed2005

Role for pituitary adenylate cyclase activating polypeptide in cystitis-induced plasticity of micturition reflexes.

Pituitary adenylate cyclase activating polypeptide (PACAP) peptides are expressed and regulated in sensory afferents of the micturition pathway. Although these studies have implicated PACAP in bladder control, the physiological significance of these observations has not been firmly established. To clarify these issues, the roles of PACAP and PACAP signaling in micturition and cystitis were examined in receptor characterization and physiological assays. PACAP receptors were identified in various tissues of the micturition pathway, including bladder detrusor smooth muscle and urothelium. Bladder smooth muscle expressed heterogeneously PAC(1)null, PAC(1)HOP1, and VPAC(2) receptors; the urothelium was more restricted in expressing preferentially the PAC(1) receptor subtype only. Immunocytochemical studies for PAC(1) receptors were consistent with these tissue distributions. Furthermore, the addition of 50-100 nM PACAP27 or PACAP38 to isolated bladder strips elicited transient contractions and sustained increases in the amplitude of spontaneous phasic contractions. Treatment of the bladder strips with tetrodotoxin (1 muM) did not alter the spontaneous phasic contractions suggesting direct PACAP effects on bladder smooth muscle. PACAP also increased the amplitude of nerve-evoked contractions. By contrast, vasoactive intestinal polypeptide had no direct effects on bladder smooth muscle. In a rat cyclophosphamide (CYP)-induced cystitis paradigm, intrathecal or intravesical administration of PAC(1) receptor antagonist, PACAP6-38, reduced cystitis-induced bladder overactivity. In summary, these studies support roles for PACAP in micturition and suggest that inflammation-induced plasticity in PACAP expression in peripheral and central micturition pathways contribute to bladder dysfunction with cystitis.

Animals↗

PubMed2005

Erectile dysfunction in mice lacking the large-conductance calcium-activated potassium (BK) channel.

Penile erection is dependent on the nitric oxide (NO)/cGMP-dependent protein kinase I (PKGI) pathway. One important target of PKGI in smooth muscle is the large-conductance, calcium-activated potassium (BK) channel, which upon activation hyperpolarizes the smooth muscle cell membrane, causing relaxation. Relaxation of arterial and corpus cavernosum smooth muscle (CCSM) is necessary to increase blood flow into the corpora cavernosa that leads to penile tumescence. We investigated the functional role of BK channels in the corpus cavernosum utilizing a knock-out mouse lacking the Slo gene (Slo-/-) responsible for the pore-forming subunit of the BK channel. Whole-cell currents were recorded from isolated CCSM cells of Slo+/+ and Slo-/- mice. Iberiotoxin-sensitive voltage- and [Ca2+]-activated K+ currents, the latter activated by local transient calcium releases (calcium sparks), were present in Slo+/+ CCSM cells, but absent in Slo-/- cells. CCSM strips from Slo-/- mice demonstrated a four-fold increase in phasic contractions, in the presence of phenylephrine. Nerve-evoked relaxations of precontracted strips were reduced by 50%, both in strips from Slo-/- mice and by blocking BK channels with iberiotoxin in the Slo+/+ strips. Consistent with the in vitro results, in vivo intracavernous pressure exhibited pronounced oscillations in Slo-/- mice, but not in Slo+/+ mice. Furthermore, intracavernous pressure increases to nerve stimulation, in vivo, were reduced by 22% in Slo-/- mice. These results indicate that the BK channel has an important role in erectile function, and loss of the BK channel leads to erectile dysfunction.

Animals↗

PubMed2005

Decrease in bladder overactivity with REN1820 in rats with cyclophosphamide induced cystitis.

PURPOSE: Studies suggest that nerve growth factor (NGF) contributes to bladder overactivity stemming from bladder inflammation. Studies were performed to determine the NGF dependence of cyclophosphamide (CYP) induced changes in bladder function using the recombinant NGF sequestering protein REN1820. MATERIALS AND METHODS: Urodynamic testing and behavioral observations were made in female rats treated with CYP (4 or 48 hours) and REN1820 or vehicle. RESULTS: Rats examined 4 or 48 hours after CYP treatment plus REN1820 showed significantly fewer nonvoiding contractions with smaller amplitude (p </=0.01). Rats examined 48 hours after CYP treatment plus REN1820 showed decreased voiding frequency (p </=0.01). No changes in filling, threshold or micturition pressure were observed with REN1820 treatment. Rats treated with CYP plus REN1820 showed greater mobility and normal resting postures compared with rats treated with CYP plus vehicle. CONCLUSIONS: These studies demonstrate that the use of the NGF sequestering protein REN1820 in rats with CYP induced cystitis decreases bladder overactivity. This is characterized by 1) a decrease in the number and amplitude of nonvoiding contractions and 2) decreased voiding frequency. Rats treated with REN1820 showed greater mobility and normal resting postures, which may reflect improved overall health or well-being. REN1820 may prove to be a novel therapeutic in individuals with the chronic inflammatory bladder syndrome interstitial cystitis.

Animals↗

PubMed2004

Increased expression of neuronal nitric oxide synthase in bladder afferent cells in the lumbosacral dorsal root ganglia after chronic bladder outflow obstruction.

Nitric oxide (NO), a neurotransmitter in autonomic reflex pathways, plays a role in functional neuroregulation of the lower urinary tract. Upregulation of the levels of neuronal nitric oxide synthase (nNOS), the enzyme system responsible for NO synthesis, has been documented in the peripheral, spinal and supraspinal segments of the micturition reflex in diseases such as cystitis, bladder/sphincter dyssynergia following spinal cord injury and bladder overactivity after cerebral infarction. These observations suggest that NO might play a role in the development of bladder overactivity. In this study, nNOS-immunoreactivity (IR) was evaluated in bladder afferent and spinal neurons following bladder outflow obstruction (BOO) in male and female rats. Chronic BOO was induced by placing lumen reducing ligatures around the proximal urethra. Six weeks following the obstructive or sham surgery, bladder function was evaluated by awake cystometry. Bladder afferent neurons in L1, L2, L6 and S1 dorsal root ganglia (DRG) were identified by retrograde neuronal labeling with injection of Fast Blue into the bladder smooth muscle. A differential distribution of nNOS-IR was subsequently evaluated in bladder afferent neurons in the DRG and in the associated spinal cord segments. The percentage of bladder afferent neurons expressing nNOS-IR was increased in L6 (1.8-fold in males and 1.9-fold in females) and S1 (2.8-fold in males and 5.3-fold in females) DRG. In contrast, no changes in nNOS-IR in neurons or fiber distribution were observed in any spinal cord segments examined.

Animals↗

PubMed2004

Minimally invasive therapies for prostatitis.

A plethora of reports describe a number of promising new minimally invasive treatment modalities available to patients with chronic prostatitis. This article reviews these studies, with most evaluating treatments using heat or intraprostatic injection. The results are difficult to compare because of the inconsistencies in study design, modalities of treatment, and outcome measures. Standard criteria for assessing symptom severity in chronic prostatitis recently have been developed and prospective clinical trials are underway to evaluate minimally invasive therapies for this debilitating condition. Until definitive data from these trials are available, minimally invasive therapies most likely will continue to be empirical and not a standard of care.

Anti-Bacterial Agents↗

PubMed2004

Prostatic tissue ablation by injection: a literature review.

PURPOSE: Most men 50 to 80 years old will have development of some degree of benign prostatic hyperplasia (BPH). Many who experience lower urinary tract symptoms (LUTS) will be treated medically. However, significant numbers will have more severe and progressive disease requiring surgery. Transurethral resection of the prostate is the current gold standard of treatment for BPH. Minimally invasive therapies for symptomatic BPH emerge and fade continuously. However, intraprostatic injection for BPH has been used for more than 100 years and may be on the verge of a rebirth. The goal of this review is to familiarize the reader with the origins and history of intraprostatic injection, and its evolution using transperineal, transrectal and transurethral routes with multiple injectants. Initially used to treat urinary retention in men with BPH, its primary indication is now for LUTS. MATERIALS AND METHODS: We performed a structured MEDLINE review of the literature on intraprostatic injections from 1966 to 2003, augmented with relevant articles from select journals and documents dating to 1832. RESULTS: In patients with BPH transperineal and transurethral injections have the most systematic evaluation. Most injectants will cause localized prostatic necrosis and gland volume reduction with varying degrees of LUTS relief. Anhydrous ethanol is the most widely studied injectable to date. There are advantages and disadvantages associated with each route of injection. CONCLUSIONS: Examined for more than a century, the potential for using injectables for prostatic tissue ablation remains significant. More systematic laboratory research and clinical trials, currently ongoing, need to be completed.

Animals↗

PubMed2004

Diffusion properties of transurethral intraprostatic injection.

OBJECTIVES: To evaluate the location and extent of diffusion that occurs when liquid is injected transurethrally into the prostate gland, by correlating real-time fluoroscopy and gross pathology, and to quantify the variables that influence intraprostatic diffusion during chemoablation of the prostate. MATERIALS AND METHODS: A solution of diatrizoate meglumine (Hypaque, Nycomed, Princeton, NJ) gentamicin and methylene-blue dye (HGM) was injected transurethrally into the prostate in six dogs, using a passive-deflection needle injection system. The intraprostatic diffusion characteristics were evaluated during each injection using real-time C-arm fluoroscopy, and following each injection by gross examination of methylene blue staining within the prostatic tissues. HGM back-flow into the urethra at the time of injection was assessed by measuring gentamicin levels in the collected bladder irrigant after each injection, using a standard dilution formula. RESULTS: There was variability in the intraprostatic diffusion both fluoroscopically and grossly. The needle occasionally assumed a straighter trajectory than its intended curve. Intraprostatic diffusion was detected in 12 of 36 injections (33%). Using standard manipulations of various devices increased the intraprostatic diffusion in these injections to almost 80%. There was less intraprostatic diffusion when the injection resistance was either extremely high or absent. There was no extraprostatic extravasation of HGM beyond the prostatic capsule. CONCLUSION: Current methods of transurethral intraprostatic injection are variable for both the diffusion of HGM solution and in needle deployment. The gross diffusion patterns with the HGM solution were consistent with the diffusion patterns documented in our previous research using absolute ethanol. These and other factors may partly explain the variability of the lesions produced with ethanol injection. Therefore, more research is needed to further elucidate the diffusion characteristics of solutions injected intraprostatically using the transurethral approach.

Animals↗

PubMed2003

Urinary bladder instability induced by selective suppression of the murine small conductance calcium-activated potassium (SK3) channel.

Small conductance, calcium-activated potassium (SK) channels have an important role in determining the excitability and contractility of urinary bladder smooth muscle. Here, the role of the SK isoform SK3 was examined by altering expression levels of the SK3 gene using a mouse model that conditionally overexpresses SK3 channels (SK3T/T). Prominent SK3 immunostaining was found in both the smooth muscle (detrusor) and urothelium layers of the urinary bladder. SK currents were elevated 2.4-fold in isolated myocytes from SK3T/T mice. Selective suppression of SK3 expression by dietary doxycycline (DOX) decreased SK current density in isolated myocytes, increased phasic contractions of isolated urinary bladder smooth muscle strips and exposed high affinity effects of the blocker apamin of the SK isoforms (SK1-3), suggesting an additional participation from SK2 channels. The role of SK3 channels in urinary bladder function was assessed using cystometry in conscious, freely moving mice. The urinary bladders of SK3T/T had significantly greater bladder capacity, and urine output exceeded the infused saline volume. Suppression of SK3 channel expression did not alter filling pressure, threshold pressure or bladder capacity, but micturition pressure was elevated compared to control mice. However, SK3 suppression did eliminate excess urine production and caused a marked increase in non-voiding contractions. The ability to examine bladder function in mice in which SK3 channel expression is selectively altered reveals that these channels have a significant role in the control of non-voiding contractions in vivo. Activation of these channels may be a therapeutic approach for management of non-voiding contractions, a condition which characterizes many types of urinary bladder dysfunctions including urinary incontinence.

Animals↗

PubMed2002

Differential expression of bladder neurotrophic factor mRNA in male and female rats after bladder outflow obstruction.

PURPOSE: We validated a male rat model of bladder outflow obstruction and compared the expression of bladder neurotrophic factor mRNA in male and female rats 6 weeks after bladder outlet obstruction. MATERIALS AND METHODS: We examined the proximal urethra in male Wistar rats. Urethral lumen reducing ligatures were placed in 15 females and 19 males, while 10 male and 10 female controls underwent sham surgery. Awake cystometry was performed 6 weeks after surgery. Ribonuclease protection assay was used to measure changes in bladder neurotrophic factor mRNA expression in the 2 sexes. RESULTS: Average bladder capacity in rats with bladder outlet obstruction increased 3-fold in males and 4.4-fold in females compared with controls, while bladder weight increased 2.2 and 4.3-fold, respectively. Filling and threshold pressure increased significantly and nonvoiding bladder contractions were recorded in 100% of female and 80% of male rats with bladder outlet obstruction. An 8-fold increase in bladder brain derived neurotrophic factor mRNA was noted in each sex after obstruction. A 2-fold increase in bladder nerve growth factor mRNA after obstruction was only observed in females. CONCLUSIONS: This male rat model of bladder outlet obstruction was created by placing lumen reducing ligatures at the urethrovesical junction. The dramatic increase in bladder brain derived neurotrophic factor mRNA expression and differential expression of nerve growth factor mRNA in male and female rats with bladder outlet obstruction suggest that additional neurotrophic factors may contribute to the lower urinary tract neuroplasticity associated with bladder outlet obstruction and this contribution may be gender dependent.

Animals↗