RESUMO
The large-conductance calcium-activated potassium channel (BKCa channel) is expressed on various tissues and is involved in smooth muscle relaxation. The channel is highly expressed on urinary bladder smooth muscle cells and regulates the repolarization phase of the spontaneous action potentials that control muscle contraction. To discover novel chemical activators of the BKCa channel, we screened a chemical library containing 8364 chemical compounds using a cell-based fluorescence assay. A chemical compound containing an isoxazolyl benzene skeleton (compound 1) was identified as a potent activator of the BKCa channel and was structurally optimized through a structure-activity relationship study to obtain 4-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol (CTIBD). When CTIBD was applied to the treated extracellular side of the channel, the conductance-voltage relationship of the channel shifted toward a negative value, and the maximum conductance increased in a concentration-dependent manner. CTIBD altered the gating kinetics of the channel by dramatically slowing channel closing without effecting channel opening. The effects of CTIBD on bladder muscle relaxation and micturition function were tested in rat tissue and in vivo. CTIBD concentration-dependently reduced acetylcholine-induced contraction of urinary bladder smooth muscle strips. In an acetic acid-induced overactive bladder (OAB) model, intraperitoneal injection of 20 mg/kg CTIBD effectively restored frequent voiding contraction and lowered voiding volume without affecting other bladder function parameters. Thus, our results indicate that CTIBD and its derivatives are novel chemical activators of the bladder BKCa channel and potential candidates for OAB therapeutics. SIGNIFICANCE STATEMENT: The novel BKCa channel activator CTIBD was identified and characterized in this study. CTIBD directly activates the BKCa channel and relaxes urinary bladder smooth muscle of rat, so CTIBD can be a potential candidate for overactive bladder therapeutics.
Assuntos
Fluorbenzenos/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Músculo Liso/fisiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Bexiga Urinária/fisiologia , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Fluorbenzenos/química , Masculino , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Ratos , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Micção/efeitos dos fármacos , Xenopus laevisRESUMO
As the regenerative mechanisms of biological organisms, self-healing provides useful functions for soft electronics or associated systems. However, there have been few examples of soft electronics where all components have self-healing properties while also ensuring compatibility between components to achieve multifunctional and resilient bio-integrated electronics. Here, we introduce a stretchable, biodegradable, self-healing conductor constructed by combination of two layers: (i) synthetic self-healing elastomer and (ii) self-healing conductive composite with additives. Abundant dynamic disulfide and hydrogen bonds of the elastomer and conductive composite enable rapid and complete recovery of electrical conductivity (~1000 siemens per centimeter) and stretchability (~500%) in response to repetitive damages, and chemical interactions of interpenetrated polymer chains of these components facilitate robust adhesion strength, even under extreme mechanical stress. System-level demonstration of soft, self-healing electronics with diagnostic/therapeutic functions for the urinary bladder validates the possibility for versatile, practical uses in biomedical research areas.
Assuntos
Elastômeros , Condutividade Elétrica , Eletrônica , Elastômeros/química , Materiais Biocompatíveis/química , Humanos , Polímeros/químicaRESUMO
Current standard clinical options for patients with detrusor underactivity (DUA) or underactive bladderâthe inability to release urine naturallyâinclude the use of medications, voiding techniques, and intermittent catheterization, for which the patient inserts a tube directly into the urethra to eliminate urine. Although those are life-saving techniques, there are still unfavorable side effects, including urinary tract infection (UTI), urethritis, irritation, and discomfort. Here, we report a wireless, fully implantable, and expandable electronic complex that enables elaborate management of abnormal bladder function via seamless integrations with the urinary bladder. Such electronics can not only record multiple physiological parameters simultaneously but also provide direct electrical stimulation based on a feedback control system. Uniform distribution of multiple stimulation electrodes via mesh-type geometry realizes low-impedance characteristics, which improves voiding/urination efficiency at the desired times. In vivo evaluations using live, free-moving animal models demonstrate system-level functionality.
Assuntos
Bexiga Inativa , Bexiga Urinária , AnimaisRESUMO
The lifetime of transient electronic components can be programmed via the use of encapsulation/passivation layers or of on-demand, stimuli-responsive polymers (heat, light, or chemicals), but yet most research is limited to slow dissolution rate, hazardous constituents, or byproducts, or complicated synthesis of reactants. Here we present a physicochemical destruction system with dissolvable, nontoxic materials as an efficient, multipurpose platform, where chemically produced bubbles rapidly collapse device structures and acidic molecules accelerate dissolution of functional traces. Extensive studies of composites based on biodegradable polymers (gelatin and poly(lactic-co-glycolic acid)) and harmless blowing agents (organic acid and bicarbonate salt) validate the capability for the desired system. Integration with wearable/recyclable electronic components, fast-degradable device layouts, and wireless microfluidic devices highlights potential applicability toward versatile/multifunctional transient systems. In vivo toxicity tests demonstrate biological safety of the proposed system.
Assuntos
Eletrônica , PolímerosRESUMO
Underactive bladder or detrusor underactivity (DUA), that is, not being able to micturate, has received less attention with little research and remains unknown or limited on pathological causes and treatments as opposed to overactive bladder, although the syndrome may pose a risk of urinary infections or life-threatening kidney damage. Here, we present an integrated expandable electronic and optoelectronic complex that behaves as a single body with the elastic, time-dynamic urinary bladder with substantial volume changes up to ~300%. The system configuration of the electronics validated by the theoretical model allows conformal, seamless integration onto the urinary bladder without a glue or suture, enabling precise monitoring with various electrical components for real-time status and efficient optogenetic manipulation for urination at the desired time. In vivo experiments using diabetic DUA models demonstrate the possibility for practical uses of high-fidelity electronics in clinical trials associated with the bladder and other elastic organs.
RESUMO
OBJECTIVES: The present study aimed to evaluate changes in mRNA and protein expression levels of α1-AR before and after doxazosin treatment. METHODS: This 12-month, prospective study included males aged 50 or older who had lower urinary tract symptoms (LUTS) (International Prostate Symptom Score [IPSS] ≥ 8) with benign prostatic hyperplasia (BPH). All patients underwent transrectal ultrasound-guided prostate biopsy before and after doxazosin 4 mg medication for 12 months. The mRNA and protein expression of prostate α1-AR were analyzed using real-time quantitative reverse transcription-polymerase chain and Western blotting, respectively, before and after treatment. The clinical efficacy of doxazosin was evaluated according to changes in prostate volume, serum prostate-specific antigen (PSA) level, IPSS, quality of life (QoL) index, maximum flow rate, parameters in a voiding diary, and a Patient's Perception of Bladder Condition (PPBC) questionnaire. RESULTS: Twenty patients aged 50-72 (median age 66) with LUTS secondary to BPH completed this study. Administering doxazosin for 12 months significantly increased α1-AR protein expression in the prostate. α1-AR mRNA expression did not change significantly after doxazosin administration. IPSS, QoL index, and PPBC scores significantly improved after 12 months of doxazosin treatment. Maximal flow rate, postvoid residual urine volume (PVR), prostate volume and the parameters from the voiding diary did not change significantly after 12 months. The change of IPSS total score and LUTS were maintained until 12 months after starting treatment with doxazosin. CONCLUSION: Doxazosin treatment was able to increase α1-AR protein expression in the prostate. Despite increased α1-AR expression, doxazosin provides sustained, significant relief of LUTS for up to one year without a decrease in efficacy.
RESUMO
NAD(P)H oxidase plays an important role in hypertension and its complication in aldosterone-salt rat. We questioned whether NAD(P)H oxidase subunit expression and activity are modulated by aldosterone and whether this is associated with target-organ damage. Rats were infused with aldosterone (0.75 microg/hr/day) for 6 weeks and were given 0.9% NaCl+/-losartan (30 mg/kg/day), spironolactone (200 mg/kg/day), and apocynin (1.5 mM/L). Aldosterone-salt hypertension was prevented completely by spironolactone and modestly by losartan and apocynin. Aldosterone increased aortic NAD(P)H oxidase activity by 34% and spironolactone and losartan inhibited the activity. Aortic expression of the subunits p47(phox), gp91(phox), and p22(phox) increased in aldosterone-infused rats by 5.5, 4.7, and 3.2-fold, respectively, which was decreased completely by spironolactone and partially by losartan and apocynin. Therefore, the increased expression of NAD(P)H oxidase may contribute to cardiovascular damage in aldosterone-salt hypertension through the increased expression of each subunit.