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1.
Acta Cir Bras ; 35(3): e202000305, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520081

RESUMO

PURPOSE: To evaluate the effect of chronic alcoholism on morphometry and apoptosis mechanism and correlate with miRNA-21 expression in the corpus cavernosum of rats. METHODS: Twenty-four rats were divided into two experimental groups: Control (C) and Alcoholic group (A). After two weeks of an adaptive phase, rats from group A received only ethanol solution (20%) during 7 weeks. The morphometric and caspase-3 immunohistochemistry analysis were performed in the corpus cavernosum. The miRNA-21 expression was analyzed in blood and cavernous tissue. RESULTS: Chronic ethanol consumption decreased cavernosal smooth muscle area of alcoholic rats. The protein expression of caspase 3 in the corpus cavernosum was higher in A compared to the C group. There was no difference in the expression of miRNA-21 in serum and cavernous tissue between the groups. CONCLUSION: Chronic ethanol consumption reduced smooth muscle area and increased caspase 3 in the corpus cavernosum of rats, without altered serum and cavernosal miR-21 gene expression.


Assuntos
Alcoolismo/complicações , Apoptose/efeitos dos fármacos , Pênis/efeitos dos fármacos , Pênis/patologia , Animais , Caspase 3/análise , Modelos Animais de Doenças , Disfunção Erétil/induzido quimicamente , Disfunção Erétil/patologia , Expressão Gênica , Imuno-Histoquímica , Masculino , MicroRNAs/análise , Músculo Liso/efeitos dos fármacos , Ratos Wistar , Valores de Referência
2.
Am J Physiol Renal Physiol ; 318(2): F496-F505, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31904286

RESUMO

Urethral smooth muscle (USM) generates tone to prevent urine leakage from the bladder during filling. USM tone has been thought to be a voltage-dependent process, relying on Ca2+ influx via voltage-dependent Ca2+ channels in USM cells, modulated by the activation of Ca2+-activated Cl- channels encoded by Ano1. However, recent findings in the mouse have suggested that USM tone is voltage independent, relying on Ca2+ influx through Orai channels via store-operated Ca2+ entry (SOCE). We explored if this pathway also occurred in the pig using isometric tension recordings of USM tone. Pig USM strips generated myogenic tone, which was nearly abolished by the Cav1.2 channel antagonist nifedipine and the ATP-dependent K+ channel agonist pinacidil. Pig USM tone was reduced by the Orai channel blocker GSK-7975A. Electrical field stimulation (EFS) led to phentolamine-sensitive contractions of USM strips. Contractions of pig USM were also induced by phenylephrine. Phenylephrine-evoked and EFS-evoked contractions of pig USM were reduced by ~50-75% by nifedipine and ~30% by GSK-7975A. Inhibition of Ano1 channels had no effect on tone or EFS-evoked contractions of pig USM. In conclusion, unlike the mouse, pig USM exhibited voltage-dependent tone and agonist/EFS-evoked contractions. Whereas SOCE plays a role in generating tone and agonist/neural-evoked contractions in both species, this dominates in the mouse. Tone and agonist/EFS-evoked contractions of pig USM are the result of Ca2+ influx primarily through Cav1.2 channels, and no evidence was found supporting a role of Ano1 channels in modulating these mechanisms.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Sinalização do Cálcio , Contração Isométrica , Músculo Liso/metabolismo , Uretra/metabolismo , Animais , Benzamidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Sinalização do Cálcio/efeitos dos fármacos , Estimulação Elétrica , Feminino , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Masculino , Músculo Liso/efeitos dos fármacos , Nifedipino/farmacologia , Fenilefrina/farmacologia , Pirazóis/farmacologia , Sus scrofa , Uretra/efeitos dos fármacos
3.
Res Vet Sci ; 128: 43-48, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31710963

RESUMO

ß2-adrenoceptor agonists are considered the most effective drugs to counteract bronchoconstriction in horses with asthma, but only clenbuterol is commonly employed in clinical practice. We evaluated the effects of different selective ß2 agonists: clenbuterol, ritodrine, salbutamol, and fenoterol on the contractions of isolated bronchial muscle of horses induced by electrical field stimulation (EFS), carbachol, histamine, and KCl. All ß2 agonists reduced the amplitude of contraction induced by the different stimuli but with variable efficacy and potency. Fenoterol and salbutamol were more effective than clenbuterol in relaxing the bronchial contractions induced by EFS and histamine, and were able to completely abolish carbachol-induced contractions, unlike clenbuterol and ritodrine. The respective potency values (pEC50) of clenbuterol, ritodrine, salbutamol, and fenoterol were 7.74 ±â€¯0.20, 7.77 ±â€¯0.17, 7.30 ±â€¯0.23, 8.01 ±â€¯0.13, for EFS-induced contractions; 8.39 ±â€¯0.26, 5.49 ±â€¯0.28, 6.63 ±â€¯0.14, 7.68 ±â€¯0.11, for carbachol-induced contraction; 7.39 ±â€¯0.27, 7.04 ±â€¯0.28, 6.45 ±â€¯0.34, 7.34 ±â€¯0.22, for histamine-induced contraction; 7.15 ±â€¯0.06, 6.07 ±â€¯0.20, 6.48 ±â€¯0.14, 6.70 ±â€¯0.18, for KCl-induced contraction. Salbutamol and fenoterol showed a higher efficacy than clenbuterol in relaxing horse bronchial muscle pre-contracted by most stimuli. Clenbuterol displayed a good potency but a rather low efficacy, and this may be due to its partial agonist nature; ritodrine showed lower or not significantly different efficacy and potency compared to the other agonists. An evaluation of the clinical efficacy by fenoterol and salbutamol in horses with asthma could be of great interest to assess if they could represent more effective bronchodilators compared to clenbuterol.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Brônquios/efeitos dos fármacos , Broncodilatadores/farmacologia , Cavalos/fisiologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Albuterol/farmacologia , Animais , Brônquios/fisiologia , Clembuterol/farmacologia , Fenoterol/farmacologia , Masculino , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Ritodrina/farmacologia
4.
Anesth Analg ; 130(4): 1077-1084, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31490256

RESUMO

BACKGROUND: Neuromodulation, as a therapeutic modality for pain treatment, is an alternative to opioid therapies and therefore receiving increased interest and use. Neuromodulation at a peripheral nerve target, in the form of bilateral electrical pudendal nerve stimulation (bPNS), has been shown to reduce bladder hypersensitivity in rats and anecdotally reduces pain in humans with pelvic pain of urological origin. Recent studies have identified a role for spinal γ-aminobutyric acid (GABA) receptors in this effect. Concomitant medication use, such as benzodiazepines, could alter responses to neuromodulation, and so before the development of a clinical trial to confirm translation of this potential therapy, the potential interactions between acute and chronic use of benzodiazepines and bPNS were examined in a preclinical model. METHODS: Bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Diazepam (1-5 mg/kg intraperitoneal [i.p.]) or vehicle was administered acutely (with or without bPNS) and chronically (5 mg/kg subcutaneous [s.c.] daily for 2 weeks before the final experiment). bPNS was delivered as bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Visceromotor responses (VMRs; abdominal muscle contractile responses to urinary bladder distension [UBD]) were used as nociceptive end points. Due to the profound effects of diazepam, the effect of midazolam (0.5-1.0 mg/kg i.p.) on VMRs and bPNS effects was also studied. RESULTS: Diazepam and midazolam both produced a dose-dependent, flumazenil-reversible inhibition of VMRs to UBD. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that had received vehicle injections. Select doses of diazepam and midazolam suppressed the inhibitory effect of bPNS on VMRs. CONCLUSIONS: This study suggests that inhibitory effects of bPNS on bladder pain could be suppressed in subjects receiving benzodiazepine therapy, suggesting that potential clinical testing of pudendal nerve stimulation for the treatment of painful bladder syndromes may be confounded by the use of benzodiazepines. Clinical assessment of other forms of neuromodulation should also be screened for impacts of benzodiazepines.


Assuntos
Benzodiazepinas/farmacologia , Nociceptividade/efeitos dos fármacos , Nervo Pudendo/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Animais , Diazepam/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Feminino , Flumazenil/farmacologia , Moduladores GABAérgicos/farmacologia , Midazolam/farmacologia , Neurônios Motores/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos
5.
Am J Respir Cell Mol Biol ; 62(1): 43-48, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31340135

RESUMO

The soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate signaling pathway evokes vascular smooth muscle relaxation; whether this pathway mediates airway smooth muscle relaxation remains controversial. We posit that sGC activators are equi-effective as ß-agonists in reversing contractile agonist-induced airway smooth muscle shortening. To provide clarity, we tested the efficacy of sGC stimulator and activator drugs, BAY 41-2272 and BAY 60-2270, respectively, in reversing bronchoconstriction of human small airways using human precision-cut lung slices (hPCLS). Both BAY drugs reversed carbachol-induced bronchoconstriction to a maximal degree comparable to that of formoterol. Moreover, the sGC drugs remained effective bronchodilators despite formoterol-induced desensitization of the airways. Analysis of the hPCLS after their activation by sGC or ß2-adrenergic receptor agonist showed distinct cyclic nucleotide accumulation in the hPCLS. Collectively, these data suggest that cAMP and cyclic guanosine monophosphate pathways are equi-effective for reversing carbachol-induced bronchoconstriction in the human airway via separate and distinct second messenger pathways. This should open the door for future studies to test whether sGC-targeted drugs alone or in combination can serve as effective bronchodilators in asthma and chronic obstructive pulmonary disease.


Assuntos
Broncodilatadores/farmacologia , Músculo Liso/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , Guanilil Ciclase Solúvel/metabolismo , Asma/tratamento farmacológico , Asma/metabolismo , Broncoconstrição/efeitos dos fármacos , GMP Cíclico/metabolismo , Humanos , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Sistema Respiratório/metabolismo , Transdução de Sinais/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Traqueia/metabolismo
6.
Am J Physiol Lung Cell Mol Physiol ; 318(2): L345-L355, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31747297

RESUMO

The nongenomic mechanisms by which glucocorticoids modulate ß2 agonist-induced-bronchodilation remain elusive. Our studies aimed to elucidate mechanisms mediating the beneficial effects of glucocorticoids on agonist-induced bronchodilation. Utilizing human precision-cut lung slices (hPCLS), we measured bronchodilation to formoterol, prostaglandin E2 (PGE2), cholera toxin (CTX), or forskolin in the presence and absence of budesonide. Using cultured human airway smooth muscle (HASM), intracellular cAMP was measured in live cells following exposure to formoterol, PGE2, or forskolin in the presence or absence of budesonide. We showed that simultaneous budesonide administration amplified formoterol-induced bronchodilation and attenuated agonist-induced phosphorylation of myosin light chain, a necessary signaling event mediating force generation. In parallel studies, cAMP levels were augmented by simultaneous exposure of HASM cells to formoterol and budesonide. Budesonide, fluticasone, and prednisone alone rapidly increased cAMP levels, but steroids alone had little effect on bronchodilation in hPCLS. Bronchodilation induced by PGE2, CTX, or forskolin was also augmented by simultaneous exposure to budesonide in hPCLS. Furthermore, HASM cells expressed membrane-bound glucocorticoid receptors that failed to translocate with glucocorticoid stimulation and that potentially mediated the rapid effects of steroids on ß2 agonist-induced bronchodilation. Knockdown of glucocorticoid receptor-α had little effect on budesonide-induced and steroid-dependent augmentation of formoterol-induced cAMP generation in HASM. Collectively, these studies suggest that glucocorticoids amplify cAMP-dependent bronchodilation by directly increasing cAMP levels. These studies identify a molecular mechanism by which the combination of glucocorticoids and ß2 agonists may augment bronchodilation in diseases such as asthma or chronic obstructive pulmonary disease.


Assuntos
Brônquios/fisiologia , Broncodilatadores/farmacologia , Budesonida/farmacologia , AMP Cíclico/biossíntese , Músculo Liso/fisiologia , Brônquios/efeitos dos fármacos , Carbacol/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Toxina da Cólera/farmacologia , Colforsina/farmacologia , Dinoprostona/farmacologia , Fluticasona/farmacologia , Fumarato de Formoterol/farmacologia , Humanos , Músculo Liso/efeitos dos fármacos , Cadeias Leves de Miosina/metabolismo , Fosforilação/efeitos dos fármacos , Prednisona/farmacologia , Receptores de Glucocorticoides/metabolismo
7.
Am J Physiol Gastrointest Liver Physiol ; 318(2): G244-G253, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31790272

RESUMO

The mechanisms underlying electrical rhythmicity in smooth muscle of the proximal colon are incompletely understood. Our aim was to identify patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated whole mouse colon and characterize their mechanisms of origin. Two independent extracellular recording electrodes were used to record the patterns of electrical activity in smooth muscle of the proximal region of whole isolated mouse colon. Cross-correlation analysis was used to quantify spatial coordination of these electrical activities over increasing electrode separation distances. Four distinct neurogenic patterns of electrical rhythmicity were identified in smooth muscle of the proximal colon, three of which have not been identified and consisted of bursts of rhythmic action potentials at 1-2 Hz that were abolished by hexamethonium. These neurogenic patterns of electrical rhythmicity in smooth muscle were spatially and temporally synchronized over large separation distances (≥2 mm rosto-caudal axis). Myogenic slow waves could be recorded from the same preparations, but they showed poor spatial and temporal coordination over even short distances (≤1 mm rostro-caudal axis). It is not commonly thought that electrical rhythmicity in gastrointestinal smooth muscle is dependent upon the enteric nervous system. Here, we identified neurogenic patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated mouse colon, which are dependent on synaptic transmission in the enteric nervous system. If the whole colon is studied in vitro, recordings can preserve novel neurogenic patterns of electrical rhythmicity in smooth muscle.NEW & NOTEWORTHY Previously, it has not often been thought that electrical rhythmicity in smooth muscle of the gastrointestinal tract is dependent upon the enteric nervous system. We identified patterns of electrical rhythmicity in smooth muscle of the mouse proximal colon that were abolished by hexamethonium and involved the temporal synchronization of smooth muscle membrane potential over large spatial fields. We reveal different patterns of electrical rhythmicity in colonic smooth muscle that are dependent on the ENS.


Assuntos
Colo/inervação , Colo/fisiologia , Motilidade Gastrointestinal/fisiologia , Músculo Liso/inervação , Músculo Liso/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Colo/efeitos dos fármacos , Eletrodos Implantados , Fenômenos Eletrofisiológicos/fisiologia , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/fisiologia , Feminino , Bloqueadores Ganglionares/farmacologia , Hexametônio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
8.
Am J Physiol Cell Physiol ; 318(2): C406-C421, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851526

RESUMO

Nonselective cation channels, consistent with transient receptor potential melastatin-4 (TRPM4), regulate detrusor smooth muscle (DSM) function. TRPM4 channels can exist as homomers or assemble with sulfonylurea receptors (SURs) as complexes. We evaluated contributions of TRPM4/SUR-TRPM4 channels to DSM excitability and contractility by examining the effects of TRPM4/SUR-TRPM4 channel modulators 9-phenanthrol, glibenclamide, and diazoxide on freshly-isolated guinea pig DSM cells (amphotericin-B perforated patch-clamp electrophysiology) and mucosa-free DSM strips (isometric tension recordings). In DSM cells, complete removal of extracellular Na+ decreased voltage-step-induced cation (non-K+ selective) currents. At high positive membrane potentials, 9-phenanthrol at 100 µM attenuated voltage step-induced currents more effectively than at 30 µM, revealing concentration-dependent, voltage-sensitive inhibition. In comparison to 9-phenanthrol, glibenclamide (100 µM) displayed lower inhibition of cation currents. In the presence of glibenclamide (100 µM), 9-phenanthrol (100 µM) further decreased the currents. The SUR-TRPM4 complex activator diazoxide (100-300 µM) weakly inhibited the currents. 9-Phenanthrol, but not glibenclamide or diazoxide, increased cell capacitance (a cell surface area indicator). In contractility studies, glibenclamide displayed lower potencies than 9-phenanthrol attenuating spontaneous and 20 mM KCl-induced DSM phasic contractions. While both compounds showed similar maximum inhibitions on DSM spontaneous phasic contractions, glibenclamide was generally less efficacious on 20 mM KCl-induced phasic contractions. In summary, the observed differential effects of 9-phenanthrol and glibenclamide on DSM excitability and contractility support unique mechanisms for the two compounds. The data suggest that SUR-TRPM4 complexes do not contribute to DSM function. This study advances our understanding of pharmacological effects of glibenclamide and 9-phenanthrol on DSM cell cation currents.


Assuntos
Cátions/metabolismo , Glibureto/farmacologia , Músculo Liso/efeitos dos fármacos , Fenantrenos/farmacologia , Canais de Cátion TRPM/antagonistas & inibidores , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cobaias , Masculino , Potenciais da Membrana/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Técnicas de Patch-Clamp/métodos
9.
Zhongguo Zhong Yao Za Zhi ; 44(18): 3924-3934, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31872726

RESUMO

Lotus( Nelumbo nucifera) is a traditional medicinal plant,and nowadays it is regarded both as medicine and food. It is widespread across China and rich in natural resources. Almost every part of N. nucifera could be used for medical or edible purpose,including seeds( Lianzi),black ripe fruits( Shilianzi),seed coats( Lianyi),green embryos of mature seed( Lianzixin),flowers( Lianhua),stamens( Lianxu),receptacles( Lianfang),leaves( Heye),leaf or flower stalks( Hegeng),leaf bases( Heyedi),rhizomes( Ou) and rhizome nodes( Oujie). Therefore,this plant is praised as a commercial crop with great economic values. Isoquinoline type alkaloids are the main chemical components of lotus. Smooth muscles usually exist in the digestive tract,respiratory tract and vascular,urinary,reproductive and other human systems. Dysfunction of smooth muscle contraction will induce many diseases including hypertension,asthma and gastrointestinal disorder,etc.,and most of current therapeutic strategies rely on relaxation of smooth muscle by drugs.Previous studies have shown that alkaloids of lotus have strong relaxation activity on smooth muscle. The present paper reviews phytochemistry and smooth muscle relaxation activity of 59 isoquinoline alkaloids from N. nucifera through accessing CNKI,PubMed and multiple databases for biomedical sciences.


Assuntos
Alcaloides/farmacologia , Isoquinolinas/farmacologia , Relaxamento Muscular , Músculo Liso/efeitos dos fármacos , Nelumbo/química , China , Humanos , Compostos Fitoquímicos/farmacologia , Extratos Vegetais
10.
Sheng Li Xue Bao ; 71(6): 863-873, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31879742

RESUMO

The aim of this study was to investigate the inhibitory effect and the underlying mechanism of ethacrynic acid (EA) on the contraction in mice. BL-420S force measuring system was used to measure the tension of mouse tracheal rings. The whole cell patch clamp technique was utilized to record the channel currents of airway smooth muscle (ASM) cells. The calcium imaging system was used to determine the intracellular Ca2+ concentration ([Ca2+]i) in ASM cells. The results showed that EA significantly inhibited the high K+ (80 mmol/L) and acetylcholine (ACh, 100 µmol/L)-induced contraction of mouse tracheal rings in a dose-dependent manner. The maximal relaxation percentages were (97.02 ± 1.56)% and (85.21 ± 0.03)%, and the median effective concentrations were (40.28 ± 2.20) µmol/L and (56.22 ± 7.62) µmol/L, respectively. EA decreased the K+ and ACh-induced elevation of [Ca2+]i from 0.40 ± 0.04 to 0.16 ± 0.01 and from 0.50 ± 0.01 to 0.39 ± 0.01, respectively. In addition, EA inhibited L-type voltage-dependent calcium channel (LVDCC) and store-operated calcium channel (SOCC) currents in ASM cells, and Ca2+ influx. Moreover, EA decreased the resistance of the respiratory system (Rrs) in vivo in mice. These results indicated that EA inhibits LVDCC and SOCC, which results in termination of Ca2+ influx and decreases of [Ca2+]i, leading to relaxation of ASM. Taken together, EA might be a potential bronchodilator.


Assuntos
Ácido Etacrínico , Contração Muscular , Músculo Liso , Sistema Respiratório , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L , Inibidores Enzimáticos/farmacologia , Ácido Etacrínico/farmacologia , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Sistema Respiratório/citologia , Sistema Respiratório/efeitos dos fármacos
11.
Bull Exp Biol Med ; 168(1): 55-57, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31741246

RESUMO

We studied the effect of endomorphin-1 on isolated mesenteric lymphatic vessels in rats. It was found that endomorphin-1 caused a dose-dependent increase in the contractile activity of lymphangions, which was associated with stimulation of intracellular calcium depots. The observed effect of endomorphin-1 in isolated lymphatic vessels has a complex mechanism; it depends on the concentration of the applied peptide and is probably determined by its interaction with non-opioid receptors.


Assuntos
Cálcio/metabolismo , Vasos Linfáticos/efeitos dos fármacos , Vasos Linfáticos/metabolismo , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Oligopeptídeos/farmacologia , Receptores Opioides mu/metabolismo , Animais , Masculino , Ratos
12.
BMC Urol ; 19(1): 103, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660941

RESUMO

BACKGROUND: Competent detrusor muscles with coordinated contraction and relaxation are crucial for normal urinary bladder storage and emptying functions. Hence, detrusor instability, and subsequently bladder overactivity, may lead to undesirable outcomes including incontinence. Multiple mechanisms may underlie the pathogenesis of detrusor overactivity including inflammation and oxidative stress. Herein, we tested the possibility that CoQ10 may have a potential therapeutic role in detrusor overactivity. METHODS: Forty adult male Wistar albino rats weighing 100-150 g were used in the present study. Rats were divided (10/group) into control (receiving vehicles), monosodium glutamate (MSG)-treated (receiving 5 mg/kg MSG daily for 15 consecutive days), MSG + OO-treated (receiving concomitantly 5 mg/kg MSG and olive oil for 15 consecutive days), MSG + CoQ10-treated (receiving concomitantly 5 mg/kg MSG and 100 mg/kg CoQ10 daily for 15 consecutive days) groups. RESULTS: MSG resulted in significant increase in bladder weight and sensitised the bladder smooth muscles to acetylcholine. MSG has also resulted in significant increase in bladder TNF-α, IL-6, malondialdehyde, nerve growth factor and connexion 43, with significant decrease in the antioxidant enzymes superoxide dismutase and catalase. Olive oil had no effect on MSG induced alterations of different parameters. Treatment with CoQ10 has resulted in a significant restoration of all the altered parameters. CONCLUSION: Taken together, our results suggest that CoQ10 antagonizes the deleterious effects of MSG on detrusor activity. We propose that CoQ10 could be a therapeutic strategy targeting urinary bladder dysfunction.


Assuntos
Músculo Liso/efeitos dos fármacos , Ubiquinona/análogos & derivados , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Animais , Junções Comunicantes/efeitos dos fármacos , Inflamação/tratamento farmacológico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Glutamato de Sódio/administração & dosagem , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Bexiga Urinária Hiperativa/induzido quimicamente
13.
Fitoterapia ; 139: 104367, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629045

RESUMO

Ca2+-activated Cl- channels (CaCCs) wildly exist in many tissues which play an important role in ion transport and excitation conduction, especially fluid secretion and smooth muscle contraction in epithelial tissues. TMEM16A as a classic CaCC expresses in the intestine, and has become a potential target of intestinal physiological and pathological researches and therapeutic drug screening. In this study, we identified trans-δ-viniferin (TVN), a resveratrol dimmer, could inhibit TMEM16A activity in TMEM16A expressed FRT cells with IC50 of 19.7 µM, it also prevented Ca2+-activated Cl- current in HT-29 cells with IC50 of 4.65 µM and in colonic mucosa. In the mechanism studies, TVN showed no significant inhibition on CFTR and basal Na+/K+-ATPase in both intestinal epithelial cells and colonic tissues, except for inhibition of calcium concentration and Ca2+-activated K+ channel to some degree. In anti-diarrheal studies, TVN could effectively prevent diarrhea caused by rotavirus infection and reduce the pellet number in IBS-D mice. These physiological effects are at least partially attributed to the inhibitory effect of TVN on CaCC-mediated intestinal fluid secretion and the reduction of smooth muscle contraction force by inhibiting TMEM16A. Collectively, the present study identified a new pharmacological target of TVN which provided the theoretical basis for the application of TVN in the treatment of rotavirus-infected diarrhea and IBS-D.


Assuntos
Benzofuranos/farmacologia , Canais de Cloreto/antagonistas & inibidores , Diarreia/tratamento farmacológico , Células Epiteliais/efeitos dos fármacos , Resorcinóis/farmacologia , Estilbenos/farmacologia , Animais , Cálcio/análise , Diarreia/virologia , Motilidade Gastrointestinal/efeitos dos fármacos , Células HT29 , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal/citologia , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Ratos , Rotavirus
14.
Life Sci ; 238: 116953, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626793

RESUMO

AIMS: This study focused on investigating whether NS8593 reverses airway smooth muscle (ASM) contraction and the underlying mechanism. MAIN METHODS: ASM contraction in mouse tracheal rings and lung slices was measured. Currents mediated by voltage dependent Ca2+ channels (VDCCs) and ACH-activated channels were measured using the whole-cell patch-clamp technique in single tracheal smooth muscle cells (TSMCs). Intracellular Ca2+ level and cell length were measured using an LSM 700 laser confocal microscope and a Zen 2010 software. Mouse respiratory system resistance (Rrs) was assessed using a FlexiVent FX system. KEY FINDINGS: High K+ (80 mM K+) and ACH induced ASM contraction in mouse tracheal rings and lung slices, which was partially relaxed by nifedipine (blocker of L-type VDCCs, LVDCCs), YM-58483 (blocker of store-operated Ca2+ entry (SOCE), transient receptor potential C3 (TRPC3) and TRPC5 channels), respectively. However, the contraction was completely reversed by NS8593, whereas, slightly relaxed by formoterol. ACH activated inward currents, which displayed linear and reversed around 0 mV, indicating the currents were mediated by non-selective cation channels (NSCCs). Moreover, these currents were blocked by YM-58483. In addition, such currents were abolished by NS8593, implicating that NS8593 inhibits the same channels. Besides, NS8593 inhibited increases of intracellular Ca2+ and the associated cell shortening. Finally, NS8593 inhibited ACH-induced increases of mouse respirator system resistance (Rrs). SIGNIFICANCE: Our results indicate that NS8593 inhibits LVDCCs and NSCCs, resulting in decreases of intracellular Ca2+ and then leading to ASM relaxation. These data suggest that NS8593 might be a new bronchodilator.


Assuntos
1-Naftilamina/análogos & derivados , Asma/tratamento farmacológico , Canais de Cálcio Tipo L/química , Cálcio/metabolismo , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , 1-Naftilamina/farmacologia , Animais , Antialérgicos/farmacologia , Asma/induzido quimicamente , Asma/patologia , Canais de Cálcio Tipo L/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso/metabolismo , Músculo Liso/patologia , Ovalbumina/toxicidade
15.
Iran J Allergy Asthma Immunol ; 18(3): 320-331, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31522439

RESUMO

In this study we aimed to examine the relaxant effect of berberine, a compound extracted from a variety of herbs, on rat tracheal smooth muscle (TSM) and its possible mechanism(s). Cumulative concentrations of berberine (20, 65, 200 and 600 µg/mL) were added on pre-contracted TSM by methacholine or KCl in non-incubated or incubated tissues with atropine, chlorpheniramine, propranolol, diltiazem, glibenclamide, indomethacin, L-NG-nitro arginine methyl ester (L-NAME) and papaverine. The relaxant effects of theophylline (0.2, 0.4, 0.6 and 0.8 mM) as positive control and saline (1 mL) as negative control were also examined in non-incubated tissues. Berberine showed significant and concentration-dependent relaxant effects in non-incubated tissues contracted by KCl and methacholine (p<0.01 to p<0.001). There was no significant difference in the relaxant effects of berberine between non-incubated and incubated tissues with atropine, propranolol, diltiazem, glibenclamide, and papaverine. The relaxant effects of second concentrations of berberine in incubated tissues with L-NAME, its three lower concentration in incubated tissues with chlorpheniramine and its all concentrations in incubated tissues with indomethacin were significantly lower than non-incubated tissues (p<0.05 to p<0.001). The EC50 values of berberine in incubated tissues with chlorpheniramine was significantly higher than the non-incubated condition (p<0.05). Our findings reveal a relatively potent relaxant effect of berberine that is lower than the effect of theophylline. Proposed mechanisms for the relaxant effect of berberine are histamine (H1) receptor blockade, inhibition of cyclooxygenase pathways and/or nitric oxide formation.


Assuntos
Berberina/farmacologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores Histamínicos H1/metabolismo , Transdução de Sinais , Animais , Berberina/química , Broncodilatadores/química , Broncodilatadores/farmacologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Modelos Biológicos , Cloreto de Potássio/farmacologia , Ratos , Traqueia/efeitos dos fármacos , Traqueia/metabolismo
16.
Surgery ; 166(6): 1048-1054, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31543322

RESUMO

BACKGROUND: Intestinal inflammation is the predominant contributor to the genesis of postoperative ileus. Janus kinase 1 plays an important role during inflammation. Here, we investigated the role of Janus kinase 1 in postoperative ileus and whether inhibition of Janus kinase 1 could mitigate postoperative ileus. METHODS: A mouse model of postoperative ileus was induced by intestinal manipulation. Janus kinase 1 inhibitor GLPG0634 or placebo was administered orally before intestinal manipulation. At the indicated time points post operation, neutrophil infiltration was assessed by immunohistochemistry and enzyme-linked immunosorbent assay; proinflammatory gene expression was quantified by quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay; and Janus kinase 1 activation was detected by Western blot. Functional studies were conducted to evaluate intestinal motility. RESULTS: We found that intestinal manipulation led to marked activation of Janus kinase 1, with increased proinflammatory gene expression and upregulated myeloperoxidase level. Moreover, intestinal manipulation resulted in an impairment of intestinal transit in vivo and inhibition of smooth muscle contractility in vitro. Preoperative administration of GLPG0634 markedly lowered the expression of proinflammatory cytokines, the myeloperoxidase level in the muscularis layer after bowel manipulation, and significantly ameliorated smooth muscle contractile function and intestinal transit ability. CONCLUSION: Our data showed that Janus kinase 1 activation mediated intestinal manipulation-induced resident macrophage activation after intestinal manipulation, and subsequent complex inflammatory cascade and gut dysmotility. Janus kinase 1 inhibition appears to be a prospective and convenient approach for the prevention of postoperative ileus.


Assuntos
Íleus/prevenção & controle , Janus Quinase 1/antagonistas & inibidores , Jejuno/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Piridinas/administração & dosagem , Triazóis/administração & dosagem , Animais , Modelos Animais de Doenças , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/imunologia , Humanos , Íleus/etiologia , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/cirurgia , Janus Quinase 1/metabolismo , Jejuno/efeitos dos fármacos , Jejuno/imunologia , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Contração Muscular/imunologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/imunologia , Peroxidase/metabolismo , Complicações Pós-Operatórias/etiologia , Cuidados Pré-Operatórios/métodos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Regulação para Cima/efeitos dos fármacos
17.
Drug Des Devel Ther ; 13: 2799-2809, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496656

RESUMO

Purpose: Eukaryotic initiation factor 2α (eIF2α) plays important roles in the proliferation and survival of pulmonary artery smooth muscle cells (PASMCs) in animal hypoxia-induced pulmonary hypertension models. However, the underlying mechanism remains unknown at large. Autophagy has been reported to play a key role in the vascular remodeling in pulmonary arterial hypertension (PAH). The purposes of this study are to determine the functions of eIF2α and autophagy in the vascular remodeling of the monocrotaline-induced PAH rats and to clarify the correlation between eIF2α and autophagy. Methods: We established a rat model of monocrotaline-induced PAH, and we established a cell model of platelet derived growth factor (PDGF)-induced PASMCs proliferation. The vascular morphology and the expression of eIF2α, LC3B, and p62 were assessed in the pulmonary arterial tissue of Sprague-Dawleyrats and PDGF-induced PASMCs. Results: Autophagy was significantly active in monocrotaline model group (MCT)-induced PAH rats, which obviously promotes vascular remodeling in MCT-induced PAH rats. Furthermore, the proliferation of PASMCs was induced by PDGF in vitro. The expression of LC3B, eIF2α was increased in the PDGF-induced PASMCs proliferation, and the expression of p62 was reduced in the PDGF-induced PASMCs proliferation. Moreover, eIF2α siRNA downregulated the expression of eIF2α and LC3B, and upregulated the expression of p62 in PDGF-induced PASMCs proliferation. eIF2α siRNA inhibited the PDGF-induced PASMCs proliferation. Finally, chloroquine can upregulate the protein expression of LC3B and p62, it also can inhibit proliferation in PDGF-induced PASMCs. Conclusion: Based on these observations, we conclude that eIF2α promotes the proliferation of PASMCs and vascular remodeling in monocrotaline-induced PAH rats through accelerating autophagy pathway.


Assuntos
Apoptose , Hipertensão Arterial Pulmonar/patologia , Remodelação Vascular , eIF-2 Quinase/metabolismo , Animais , Proliferação de Células , Masculino , Monocrotalina , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Músculo Liso/patologia , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley
18.
Am J Physiol Lung Cell Mol Physiol ; 317(4): L466-L474, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31411061

RESUMO

The transient receptor potential polycystin-2 (TRPP2) is encoded by the Pkd2 gene, and mutation of this gene can cause autosomal dominant polycystic kidney disease (ADPKD). Some patients with ADPKD experience extrarenal manifestations, including radiologic and clinical bronchiectasis. We hypothesized that TRPP2 may regulate airway smooth muscle (ASM) tension. Thus, we used smooth muscle-Pkd2 conditional knockout (Pkd2SM-CKO) mice to investigate whether TRPP2 regulated ASM tension and whether TRPP2 deficiency contributed to bronchiectasis associated with ADPKD. Compared with wild-type mice, Pkd2SM-CKO mice breathed more shallowly and faster, and their cross-sectional area ratio of bronchi to accompanying pulmonary arteries was higher, suggesting that TRPP2 may regulate ASM tension and contribute to the occurrence of bronchiectasis in ADPKD. In a bioassay examining isolated tracheal ring tension, no significant difference was found for high-potassium-induced depolarization of the ASM between the two groups, indicating that TRPP2 does not regulate depolarization-induced ASM contraction. By contrast, carbachol-induced contraction of the ASM derived from Pkd2SM-CKO mice was significantly reduced compared with that in wild-type mice. In addition, relaxation of the carbachol-precontracted ASM by isoprenaline, a ß-adrenergic receptor agonist that acts through the cAMP/adenylyl cyclase pathway, was also significantly attenuated in Pkd2SM-CKO mice compared with that in wild-type mice. Thus, TRPP2 deficiency suppressed both contraction and relaxation of the ASM. These results provide a potential target for regulating ASM tension and for developing therapeutic alternatives for some ADPKD complications of the respiratory system or for independent respiratory disease, especially bronchiectasis.


Assuntos
Brônquios/metabolismo , Bronquiectasia/genética , Músculo Liso/metabolismo , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genética , Animais , Brônquios/efeitos dos fármacos , Brônquios/fisiopatologia , Bronquiectasia/metabolismo , Bronquiectasia/fisiopatologia , Broncodilatadores/antagonistas & inibidores , Broncodilatadores/farmacologia , Cálcio/metabolismo , Carbacol/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Contração Isométrica/efeitos dos fármacos , Contração Isométrica/fisiologia , Isoproterenol/antagonistas & inibidores , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Knockout , Mióticos/farmacologia , Tono Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Respiração/efeitos dos fármacos , Transdução de Sinais , Canais de Cátion TRPP/deficiência , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Traqueia/fisiopatologia
19.
Ann Vasc Surg ; 61: 416-426, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31449943

RESUMO

BACKGROUND: The aim of the present study was to investigate the effect of resveratrol on cytokine levels and oxidative stress in intestinal ischemia/reperfusion (I/R) injuries. METHODS: To induce intestinal I/R, the superior mesenteric artery was occluded for 30 min and then reperfused for 150 min or 24 h. The therapeutic effects of resveratrol on the damage from intestinal I/R were investigated using an isolated organ bath, along with oxidant/antioxidant and inflammatory factors such as glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-(IL)-1ß, and tumor necrosis factor alpha (TNF-α). RESULTS: I/R control animals demonstrated severe deterioration of smooth muscle motor function as a significant decrease in potassium chloride- and acetylcholine-induced a contractile responses; high oxidative stress as an increase in lipid peroxidation and a decrease in GSH level; and an increase of MPO, IL-1ß, and TNF-α activity. Pretreatment of animals with resveratrol restored intestinal dysfunction; reduced elevated MDA, MPO, IL-1ß, and TNF-α levels; and reversed the depleted intestine GSH levels after both 150 min and 24 h reperfusion periods. CONCLUSIONS: The results indicated that resveratrol can reverse the effects of disrupted smooth muscle contractility, probably because of its antioxidant and anti-inflammatory effects on MPO, IL-1ß, and TNF-α activities.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Intestino Delgado/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Resveratrol/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Modelos Animais de Doenças , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/fisiopatologia , Masculino , Malondialdeído/metabolismo , Músculo Liso/metabolismo , Músculo Liso/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais
20.
Int J Mol Sci ; 20(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438481

RESUMO

A-type K+ channels contribute to regulating the propagation and frequency of action potentials in smooth muscle cells (SMCs). The present study (i) identified the molecular components of A-type K+ channels in rat vas deferens SMs (VDSMs) and (ii) showed the long-term, genomic effects of testosterone on their expression in VDSMs. Transcripts of the A-type K+ channel α subunit, Kv4.3L and its regulatory ß subunits, KChIP3, NCS1, and DPP6-S were predominantly expressed in rat VDSMs over the other related subtypes (Kv4.2, KChIP1, KChIP2, KChIP4, and DPP10). A-type K+ current (IA) density in VDSM cells (VDSMCs) was decreased by castration without changes in IA kinetics, and decreased IA density was compensated for by an oral treatment with 17α-methyltestosterone (MET). Correspondingly, in the VDSMs of castrated rats, Kv4.3L and KChIP3 were down-regulated at both the transcript and protein expression levels. Changes in Kv4.3L and KChIP3 expression levels were compensated for by the treatment with MET. These results suggest that testosterone level changes in testosterone disorders and growth processes control the functional expression of A-type K+ channels in VDSMCs.


Assuntos
Castração/efeitos adversos , Regulação para Baixo , Proteínas Interatuantes com Canais de Kv/genética , Proteínas Interatuantes com Canais de Kv/metabolismo , Ducto Deferente/metabolismo , Animais , Western Blotting , Eletrofisiologia , Masculino , Metiltestosterona/farmacologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Ratos , Ratos Wistar , Testosterona/metabolismo , Ducto Deferente/efeitos dos fármacos
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