| 1. |
- Fry, Christopher H., et al.
(författare)
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Fibrosis and the bladder, implications for function ICI-RS 2017
- 2018
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Ingår i: Neurourology and Urodynamics. - : Wiley. - 0733-2467. ; 37, s. 7-12
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Most benign bladder pathologies are associated with an increase of extracellular matrix (ECM—fibrosis) and may progress from formation of stiffer matrix to a more compliant structure. The aims were to summarize current knowledge of the origins of bladder fibrosis and consequences in bladder function. Methods: A meeting at the International Consultation on Incontinence Research Society 2017 congress discussed the above aims and considered paradigms to reduce the extent of fibrosis. Discussants based their arguments on the basis of their own expertise, supplemented by review of the literature through PubMed. Proposals for future work were derived from the discussion. Results: Altered urodynamic compliance when ECM deposition is increased is mirrored by changes in the elastic modulus of isolated tissue, whether compliance is decreased or increased. No changes to compliance or fibrosis have been reported after botulinum toxin injections. Several paracrine and autocrine agents increase ECM deposition, the role of TGF-β was particularly emphasized. None of these agents has a net long-term effect on detrusor contractility and the reduction of contractile performance with increased ECM is due solely to a loss of detrusor mass. Several strategies to reduce fibrosis were described, ranging from potential therapeutic roles for vitamin-D or endostatin, manipulation of intracellular pathways that mediate myofibroblast differentiation and the potential role of the anti-fibrotic hormone relaxin. An understanding of epigenetic regulation of ECM deposition was also considered. Conclusions: The conclusion that reduced bladder contractile function with increased fibrosis is due largely to the replacement of detrusor with ECM offers a way forward for future research to consider approaches that will restore bladder function by reducing ECM deposition.
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| 3. |
- Andersson, Karl Erik, et al.
(författare)
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Acute Intravesical Capsaicin for the Study of TRPV1 in the Lower Urinary Tract : Clinical Relevance and Potential for Innovation
- 2022
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Ingår i: Medical Sciences. - : MDPI AG. - 2076-3271. ; 10:3
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Forskningsöversikt (refereegranskat)abstract
- Capsaicin acts on sensory nerves via vanilloid receptors. TRPV1 has been extensively studied with respect to functional lower urinary tract (LUT) conditions in rodents and humans. We aimed to (1) provide background information on capsaicin and TRPV1 and its mechanisms of action and basis for clinical use, (2) review the use of acute intravesical capsaicin instillation (AICI) in rodents to mimic various LUT disorders in which capsaicin sensitive C-fibers are involved and (3) discuss future innovative treatments. A comprehensive search of the major literature databases until June 2022 was conducted. Both capsaicin-sensitive and resistant unmyelinated bladder afferent C-fibers are involved in non-neurogenic overactive bladder/detrusor overactivity (OAB/DO). AICI is a suitable model to study afferent hyperactivity mimicking human OAB. Capsaicin-sensitive C-fibers are also involved in neurogenic DO (NDO) and potential targets for NDO treatment. AICI has been successfully tested for NDO treatment in humans. Capsaicin-sensitive bladder afferents are targets for NDO treatment. TRPV1-immunoreactive nerve fibers are involved in the pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS). The AICI experimental model appears relevant for the preclinical study of treatments targeting bladder afferents for refractory IC/BPS. The activity of capsaicin-sensitive bladder afferents is increased in experimental bladder outlet obstruction (BOO). The AICI model may also be relevant for bladder disorders resulting from C-fiber hyperexcitabilities related to BOO. In conclusion, there is a rationale for the selective blockade of TRPV1 channels for various bladder disorders. The AICI model is clinically relevant for the investigation of pathophysiological conditions in which bladder C-fiber afferents are overexcited and for assessing innovative treatments for bladder disorders based on their pathophysiology.
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| 4. |
- Andersson, Karl-Erik
(författare)
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Alpha-adrenoceptors and benign prostatic hyperplasia: basic principles for treatment with alpha-adrenoceptor antagonists.
- 2002
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Ingår i: World Journal of Urology. - : Springer Science and Business Media LLC. - 1433-8726 .- 0724-4983. ; 19:6, s. 390-396
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Tidskriftsartikel (refereegranskat)abstract
- The selective blockade of alpha1-adrenoceptors (ARs) is now a well-accepted and widely used treatment for patients presenting with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and bladder outlet obstruction. The sites of action of the currently used alpha1-AR antagonists when relieving LUTS have not yet been established, but it seems clear that effects on prostatic as well as non-prostatic tissues are important. Alpha1-ARs in the bladder, urethra, and vas deferens, on ganglia and nerve terminals, and in the central nervous system (CNS) may all influence LUTS and the clinical effects of alpha1-AR antagonists. The relevance of alpha1-AR subtype selectivity for the clinical usefulness of existing drug therapy has still not been clarified, but it cannot be dismissed that blockading both alpha1A- and alpha1D-ARs is necessary for optimal clinical effect. Despite the above uncertainties, there seems to be a consensus that clinically available alpha1-AR antagonists provide a safe, effective and generally well-tolerated therapy for patients with LUTS.
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| 7. |
- Andersson, Karl Erik, et al.
(författare)
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Are there relevant animal models to set research priorities in LUTD? ICI-RS 2019
- 2020
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Ingår i: Neurourology and Urodynamics. - : Wiley. - 0733-2467 .- 1520-6777. ; 39:S3, s. 9-15
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Forskningsöversikt (refereegranskat)abstract
- Aim: To discuss animal models of lower urinary tract disorders (LUTD) and their translational impact. Methods: Report of discussions based on presented literature-search based reviews relevant for the purpose. Results: Animal models can be used to investigate fundamental biological mechanisms, but also as tools to elucidate aspects of the pathogenesis of disease and to provide early evidence of any safety risk. Several different models may be required to obtain information that can have a translational impact. The term “translational research” covers not only the process of directly transferring knowledge from basic sciences to human trials to produce new drugs, devices, and treatment options for patients (T1 type translation) but also the implementation of early clinical research findings (phases I-III) into practice to improve care for patients (T2 type). Direct transfer of animal data to T2 is rarely possible, and the process often does not continue after the first trials in humans (phase I). It should be emphasized that many preclinical observations do not have (and do not need to have) immediate translational impact. Conclusions: No single animal model can mimic the complexity of the human disease. Still, animal models can be useful for gaining information on LUT function in humans, for elucidating pathophysiological mechanisms, and for the definition of targets for future drugs to treat LUT disorders.
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| 8. |
- Andersson, Karl-Erik
(författare)
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Bladder activation: afferent mechanisms.
- 2002
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Ingår i: Urology. - 1527-9995. ; 59:5 Suppl 1, s. 43-50
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Tidskriftsartikel (refereegranskat)abstract
- The major function of the lower urinary tract is to store and periodically evacuate urine from the bladder. This requires coordination of the smooth muscles of the bladder and urethra, and of the striated muscles of the outflow region and pelvic floor by a complex neural control system. Lumbosacral afferent fibers (pelvic afferents), but also afferents in the hypogastric and pudendal nerves, are of major importance for the regulation of the mechanisms for continence and micturition. In the bladder, afferent nerves have been identified suburothelially as well as in the detrusor muscle. Suburothelially, they form a plexus that lies immediately beneath the epithelial lining. This plexus is particularly dense in the bladder neck and the trigone. The most important afferents for the micturition process are myelinated Adelta-fibers and unmyelinated C-fibers. Immunocytochemical and tracing studies have revealed that numerous peptides, including substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide, enkephalins, and cholecystokinin are localized either alone, or in combination, in afferent pathways of the bladder and urethra. The receptors on these nerves include: vanilloid receptors, purinoceptors, tachykinin, and prostanoid receptors. Extracellular adenosine triphosphate (ATP) has been found to mediate excitation of small-diameter sensory neurons via P2X3 receptors, and it has been proposed that in the bladder, distention causes release of ATP from the urothelium. ATP, in turn, can activate P2X3 receptors on suburothelial afferent nerve terminals to evoke a neural discharge. However, it is most likely that a cascade of inhibitory and stimulatory transmitters/mediators, as well as ATP, are involved in the transduction mechanisms underlying the activation of afferent fibers during bladder filling.
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| 9. |
- Andersson, Karl Erik, et al.
(författare)
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Changes in the rat urinary bladder after the relief of outflow obstruction – tracing targets for treatment of persistent symptoms in patients
- 2022
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Ingår i: Frontiers in Urology. - : Frontiers Media SA. - 2673-9828. ; 2
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Forskningsöversikt (refereegranskat)abstract
- Studies on patients with bladder outflow obstruction who have undergone surgery for benign prostatic hyperplasia, successfully relieving the obstruction, have revealed a persistence of storage symptoms associated with detrusor overactivity (DO) in 20% to 40% of patients. To study the underlying mechanisms, we have used a common rat model of obstruction/de-obstruction, assuming that non-voiding contractions can be used as a surrogate parameter for DO in humans. Using microarray analysis and electron microscopic images from obstructed and de-obstructed bladder tissue we have tried to identify changes that could serve as a basis for the search of new targets for drugs. Even if voiding function is rapidly normalized after release of outflow obstruction and many of the morphological changes are reversed, the microarray analysis revealed that the de-obstructed rat bladder has gene expressions, structural, and functional properties that make it distinctly different from both control and obstructed bladders. We suggest that whole bladder arrays can be used for identifying cellular mechanisms that could be targets for drugs meant for treatment of persistent DO and LUTS after de-obstruction. Based on available array information for some membrane receptors and morphologic structures with corresponding changes in bladder function, it seems worthwhile to re-assess the development potential for e.g., endothelin receptor antagonists, purinergic receptor antagonists and Rho-kinase inhibitors.
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