RESUMO
INTRODUCTION: Sacral neuromodulation has been considered as an effective treatment option for various types of chronic voiding dysfunction, but the mechanism of action has not been well understood. The aim of this study was to evaluate the effect of chronic sacral neuromodulation on isolated bladder functions in a rat model of spinal cord injury. MATERIALS AND METHODS: Female Sprague-Dawley rats (250-300 g; N = 20) were assigned to four groups as follows: 1) control group (N = 6); 2) spinal cord transection group (SCT; N = 5); 3) spinal cord transection + sacral neuromodulation group (SCT + SNM; N = 5); 4) sham (spinal cord transection + electrode wire implantation without sacral neuromodulation; N = 4). The rats in the SCT, SCT + SNM, and sham groups were anesthetized with ketamine (60 mg/kg, i.p.) and xylazine (7 mg/kg, i.p.). The spinal cord was completely transected at T8-T9 level in SCT and SCT + SNM groups. Electrode wires were implanted into S3 dorsal foramina in both sham and SNM groups, but only the SNM group was subjected to electrical stimulation for four hours a day for three weeks. Twenty-one days later, the rats were sacrificed via anesthetic overdose, and isolated longitudinal bladder strip preparations were placed in organ baths for the investigation of their isometric responses to pharmacological agents. RESULTS: In isometric contraction experiments, SCT was found to increase the contraction responses of the bladder strips to muscarinic stimulation, and SNM could not prevent this increase. In isometric relaxation experiments, SCT caused a decrease in ß-adrenergic relaxation responses, and SNM augmented the bladder's ß-adrenergic relaxation responses. Nitric oxide did not affect the relaxation responses. CONCLUSION: In our rat model of SCT, SNM seemed to alter adrenergic receptor function in the urinary bladder. Further studies are required to clarify the mechanism of these alterations at the level of bladder receptors following sacral neuromodulation.
Assuntos
Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/fisiopatologia , Estimulação da Medula Espinal/métodos , Bexiga Urinária/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Contração Muscular/fisiologia , Ratos , Ratos Sprague-Dawley , Sacro , Bexiga Urinária/inervaçãoRESUMO
CONTEXT: Propranolol, atenolol, and ICI118,551 are non-selective ß-adrenergic receptor (AR), ß1-AR, and ß2-AR antagonists, respectively. OBJECTIVE: We investigated the efficacy of propranolol, atenolol, and ICI118,551 on proliferation, migration, and invasion of non-stimulated breast (MCF7), colon (HT-29), and hepatocellular (HepG2) cancer cells. MATERIALS AND METHODS: ß-AR expression profiling of cells was performed by real time PCR. Cell proliferation was determined by MTT. Boyden chamber and scratch assays were performed to evaluate invasion and migration. RESULTS AND DISCUSSION: All cell lines expressed ß-ARs. ICI118,551 was the most cytotoxic, whereas atenolol was the least effective ß-AR antagonist for 24, 48, and 72 h. Cell invasion was inhibited by ICI118,551 (45, 46, and 50% for MCF7, HT29, and HepG2, respectively) and propranolol (72, 65, and 90% for MCF7, HT29, and HepG2, respectively). Propranolol, atenolol, and ICI118,551 reduced migration of MCF7, HT-29, and HepG2 cells to varying extents depending on the application concentration and duration. Propranolol and atenolol reduced migration of MCF7 and HT-29 in a concentration-dependent manner, whereas migration of these cells decreased after 48 and 72 h of ICI118,551 applications. CONCLUSION: Beta2-AR antagonist seemed to be the most cytotoxic ß-blocker on non-stimulated cancer cells. Propranolol and ICI118,551 were more effective than atenolol in inhibiting invasion and migration of non-stimulated MCF7 and HT-29 cells; ICI118,551 being the most potent. Concordantly, ß2-selective blockage seemed to be more effective for non-stimulated cells. Effect of the selective ß-AR antagonists showed variation depending on the concentration, incubation time, and histological origin of cells.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Antagonistas Adrenérgicos beta/uso terapêutico , Células HT29 , Células Hep G2 , HumanosRESUMO
Hydrogen sulfide (H2S) has been shown to be effective against kidney ischemia-reperfusion injury (IRI) in animal studies. We aimed to evaluate the current evidence from in vivo animal studies for the protective effects of H2S against kidney IRI by systematically reviewing the literature and performing a meta-analysis. Based on the preregistered protocol (PROSPERO: CRD42021295469); PubMed, Medline, Embase, Web of Science, and Scopus were searched to identify in vivo animal studies evaluating the effect of H2S against kidney IRI. Standardized mean difference (SMD) with 95% confidence interval (CI) was calculated and pooled using random-effects meta-analysis. Twenty-two articles complied with eligibility criteria, from which the creatinine levels of 152 control animals and 182 animals treated with H2S from 27 individual experiments were pooled. H2S treatment significantly decreased serum creatinine (SMD = -1.82 [95% CI -1.12, -2.51], p < 0.0001), blood urea nitrogen (-2.50 [-1.46, -3.54], p < 0.0001), tissue malondialdehyde (-2.59 [-3.30, -1.88], p < 0.0001), tunel positive cells (-3.16 [-4.38, -1.94], p < 0.0001), and tubular damage score (-2.01 [-3.03, -0.99], p < 0.0001). There was a high heterogeneity across studies (I2 = 83.5% for serum creatinine level). In meta-regression analysis, the type of H2S donor and its application time accounted for 11.3% (p = 0.025) and 16.6% (p = 0.039) of heterogeneity, respectively. Accordingly, H2S protects the kidney against IRI only if it is given as GYY4137 before or during ischemia. Although H2S is a potential candidate against kidney IRI, further well-designed preclinical studies focusing on GYY4137 are warranted before clinical implication.
Assuntos
Sulfeto de Hidrogênio , Traumatismo por Reperfusão , Animais , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Creatinina , Rim , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controleRESUMO
OBJECTIVES: Organ damage due to long cold ischemia time remains a hurdle in transplantation. In this preliminary animal study, we compared the new Baskent University Preservation Solution (BUPS) with the University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions. MATERIALS AND METHODS: BUPS composition included electrolytes, raffinose, mannitol, N-acetylcysteine, taurine, adenosine, and ascorbic acid. In experiment 1, kidneys from 50 male Sprague-Dawley rats were placed into BUPS, HTK, or UW solution to assess cold ischemia injury, with biopsies taken at different time points for pathologic evaluation. In experiment 2, to investigate ischemia-reperfusion injury, 5 rats were renal transplant donors to 10 rats and 6 pigs were used as transplant donors-recipients among each other. RESULTS: In experiment 1, no significant cellular injury was shown at up to 3 hours of perfusion with any solution. At 6- to 48-hour perfusion, tubular injury was shown, with lowest injury in BUPS and HTK versus UW and control groups (P < .01). The BUPS group showed more moderate degree of tubular apoptosis and cytoskeletal rearrangement than the HTK and UW groups at 12-, 24-, and 48-hour perfusion (P < .01). In experiment 2, after ischemia-reperfusion injury, no significant differences were found between HTK and BUPS groups regarding tubular damage. Although no significant differences were shown regarding tubular cytoskeletal rearrangment and apoptosis in pig reperfusion group with BUPS versus HTK, significant differences were shown with these solutions in other groups. CONCLUSIONS: Tubular damage during ischemia-reperfusion injury (cytoskeletal disruption, increased apoptosis) were lower with BUPS. BUPS can be a cost-effective perfusion solution in transplantation.
Assuntos
Isquemia Fria , Transplante de Rim , Soluções para Preservação de Órgãos , Adenosina , Alopurinol , Animais , Glucose , Glutationa , Insulina , Masculino , Manitol , Cloreto de Potássio , Procaína , Rafinose , Ratos , Ratos Sprague-DawleyRESUMO
Expression of catecholamine biosynthesizing enzymes, tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DbetaH) increase with age in the adrenal medulla, however, the underlying mechanisms are unclear. In the present study, we examined the effect of peripheral angiotensin II (AngII) on the expression of TH and DbetaH, in the adrenal medulla of young (6 mo) and old (23 mo) Fischer-344 rats. Saline or AngII (230 ng/kg/min sc) was infused for 3 days using osmotic minipumps. Adrenomedullary TH and DbetaH mRNA levels increased significantly with age, and while AngII reduced the expression of these enzymes in young animals, it had no such effect in the old animals. Neuropeptide Y (NPY), which is co-released with catecholamines in the adrenal medulla and stimulates the synthesis of TH and DbetaH, was also upregulated with age and downregulated in response to AngII in young rats. However, in the old animals, the already elevated NPY expression remained unchanged following AngII treatment. This data indicate that the hypertensive effect of peripheral AngII is compensated by an inhibition of adrenomedullary catecholamine biosynthesis in young animals, but this mechanism is impaired in senescence, potentially contributing to the age-related increase in catecholamine biosynthesis.
Assuntos
Medula Suprarrenal/enzimologia , Envelhecimento/fisiologia , Angiotensina II/farmacologia , Dopamina beta-Hidroxilase/biossíntese , Tirosina 3-Mono-Oxigenase/biossíntese , Medula Suprarrenal/efeitos dos fármacos , Animais , Dopamina beta-Hidroxilase/genética , Regulação para Baixo/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Neuropeptídeo Y/biossíntese , Neuropeptídeo Y/genética , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos F344 , Tirosina 3-Mono-Oxigenase/genéticaRESUMO
The incorporation of pharmacogenomics information into the drug dosing estimation formulations has been shown to increase the accuracy in drug dosing and decrease the frequency of adverse drug effects in many studies in the literature. In this paper, an estimation framework based on the Bayesian structural equation modeling, which is driven by pharmacogenomics, is proposed. The results show that the model compares favorably with the linear models in terms of prediction and explaining the variations in warfarin dosing.
Assuntos
Farmacogenética/métodos , Medicina de Precisão/métodos , Varfarina/administração & dosagem , Varfarina/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Criança , Estudos de Coortes , Citocromo P-450 CYP2C9/genética , Mineração de Dados , Bases de Dados Factuais , Humanos , Pessoa de Meia-Idade , Turquia , Vitamina K Epóxido Redutases/genética , População Branca/genética , Adulto JovemRESUMO
The elevated levels of circulating catecholamines (CAs) with age may be related to the increased expression of CA biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DbetaH) in the adrenal medulla of senescent compared with younger animals. Neuropeptide Y (NPY) is co-synthesized and co-released with CAs in the adrenal medulla. NPY inhibits the stimulated secretion of CAs, however, its role in regulation of the genes encoding CA biosynthetic enzymes is not clear. We hypothesized that NPY up-regulates TH, DbetaH and NPY expression in the adrenal medullae of young and old Fischer-344 rats. NPY increased mRNA expression of TH, DbetaH, NPY and also enhanced TH protein level in the adrenal medullae of young rats by 50%, 35%, 45% and by 20%, respectively. We also examined the effect of NPY on TH and NPY mRNA in the hypothalamus. Basal expression of TH mRNA was decreased in the hypothalamus with age. DNA binding activities of activator protein-1 and cAMP response element binding protein were also augmented only in the young by 140% and 125%, respectively. We conclude that NPY stimulates the CA biosynthetic pathway in the adrenal medulla and positive auto-regulation of NPY might be involved in this process. The stimulatory effect of NPY on adrenomedullary CA biosynthetic pathway is blunted with age.
Assuntos
Medula Suprarrenal/efeitos dos fármacos , Dopamina beta-Hidroxilase/biossíntese , Hipotálamo/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Tirosina 3-Mono-Oxigenase/biossíntese , Medula Suprarrenal/enzimologia , Fatores Etários , Animais , Catecolaminas/biossíntese , Enzimas/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Hipotálamo/enzimologia , Masculino , RNA Mensageiro/biossíntese , Ratos , Ratos Endogâmicos F344RESUMO
The effect of submaximal endurance training (SET) on sympathoadrenal activity is not clear. We tested the hypothesis that SET (90 min/day, 5 days/wk, for 12 wk) elevates mRNA expression of catecholamine (CA) biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DbetaH) in the adrenal medullae of adult, female Sprague-Dawley rats. SET increased TH protein level by 35%, TH activity by 62%, TH mRNA expression by 40%, and DbetaH mRNA expression by 67%. In addition, we examined the effect of SET on Fos-related antigens (FRAs), FRA-2 immunoreactivity, and activator protein (AP)-1 binding activity. SET increased AP-1 binding activity by 78%; however, it did not affect late FRAs and FRA-2 immunoreactivity. Because the regulation of neuropeptide Y (NPY) often parallels that of CAs, we also examined the effect of SET on NPY mRNA expression. Indeed, SET elevated NPY mRNA expression as well. We conclude that 1) SET elicits a pretranslational stimulatory effect on adrenomedullary CA biosynthetic enzymes, 2) another immediate early mRNA product, rather than FRA-2, may contribute to the increase in AP-1 binding activity in response to SET, and 3) SET increases NPY mRNA expression.
Assuntos
Medula Suprarrenal/enzimologia , Dopamina beta-Hidroxilase/genética , Condicionamento Físico Animal/fisiologia , Esforço Físico/fisiologia , Tirosina 3-Mono-Oxigenase/genética , Medula Suprarrenal/anatomia & histologia , Animais , Anticorpos , Peso Corporal , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Feminino , Antígeno 2 Relacionado a Fos , Regulação Enzimológica da Expressão Gênica/fisiologia , Neuropeptídeo Y/genética , Tamanho do Órgão , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição/análise , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
OBJECTIVE: To investigate the effect of spironolactone, as an angiogenesis inhibitor, on the isometric contractile responses in isolated vas deferens strips from left varicocele-induced rats. METHODS: Twenty-four adult (12-14 months) male Wistar albino rats were randomly assigned to 4 groups (n = 6 in each): (1) Control group, (2) sham-operated group, (3) experimental left varicocele group, and (4) Spironolactone (20 mg/kg/d)-treated experimental left varicocele group. Histopathologic and immunohistochemical (CD31 staining) findings in the rat testis and functional findings in the rat isolated vas deferens were investigated. RESULTS: Angiogenesis increased in the varicocele group and the spironolactone inhibited angiogenesis in the spironolactone-treated group. Spironolactone seemed to change phenylephrine and serotonin responses in the left vas deferens. CONCLUSION: It is possible that by inhibiting angiogenesis, spironolactone treatment negatively impairs testicular morphology and functional (vas deferens) pathways. Varicocele formation seems to elicit an increase to 5-HT sensitivity in rat vas deferens, and this process is prevented by spironolactone pretreatment.
Assuntos
Inibidores da Angiogênese/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Espironolactona/farmacologia , Varicocele/fisiopatologia , Ducto Deferente/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Ketanserina/farmacologia , Masculino , Microvasos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Fenilefrina/farmacologia , Prazosina/farmacologia , Ratos , Ratos Wistar , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Espermatogênese/efeitos dos fármacos , Estatísticas não Paramétricas , Testículo/irrigação sanguínea , Testículo/fisiopatologia , Ducto Deferente/irrigação sanguínea , Ducto Deferente/fisiologiaRESUMO
AIMS: To bring further insight into the mechanism of cyclosporine A (CsA)-induced hepatotoxicity, the acute effect of CsA on local hepatic blood flow (LHBF) and its association with systemic hemodynamics, histopathological and biochemical indicators of liver toxicity were studied in guinea pigs in vivo. The association of endothelin (ET) and/or Cremophor-EL (C-EL, vehicle in parenteral CsA preparation) with CsA effects was also investigated. MAIN METHODS: Animals were assigned into five groups; control, CsA, C-EL, Bosentan (non-selective ET receptor antagonist)+CsA, and BQ-123 (ET(A) receptor antagonist)+CsA. CsA was infused intravenously (i.v.) at 20 and 10mg/kg doses by 15 min interval. Antagonists were administered 15 min before CsA infusion. LHBF and mean arterial blood pressure (MAP) changes were simultaneously recorded. Blood and liver samples were collected for biochemical and histopathological examinations. KEY FINDINGS: CsA, but not C-EL, decreased LHBF by 53.3% at the end of 30 min. Although being non-significant, CsA slightly increased MAP suggesting that, CsA-induced acute decrease in LHBF was likely independent of MAP changes. Bosentan (5mg/kg, i.v.) and BQ-123 (1mg/kg, i.v.) pre-treatments prevented the CsA-induced decrease in LHBF suggesting that CsA decreases LHBF through an ET-related mechanism. Additionally, CsA, but not its vehicle C-EL, caused marked acute pathological changes in the liver morphology. SIGNIFICANCE: CsA-induced findings of acute hepatotoxicity were prevented by bosentan and BQ-123 pre-treatments. Thus, CsA seems to exert acute hepatotoxic effect through ET-related mechanisms.
Assuntos
Ciclosporina/toxicidade , Endotelinas/fisiologia , Circulação Hepática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Animais , Bosentana , Ciclosporina/antagonistas & inibidores , Ciclosporina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Glicerol/análogos & derivados , Glicerol/farmacologia , Cobaias , Fígado/irrigação sanguínea , Fígado/enzimologia , Fígado/patologia , Circulação Hepática/fisiologia , Masculino , Peptídeos Cíclicos/farmacologia , Sulfonamidas/farmacologiaRESUMO
The effect of captopril, angiotensin-converting enzyme inhibitor, on angiogenesis in several reports remained unclear. Its effect on neovascularization in rat abdominal skin flaps was investigated. Flap elevation, based on the right superficial inferior epigastric artery was performed with or without the administration of captopril (10 mg/kg/d), Ang II (100 microg/kg/d), or captopril and Ang II cotreatment. Mean arterial pressure (MAP), microangiography, capillary density measurement, necrosis area determination, laser Doppler flowmetry (LDF), AT1 and vascular endothelial growth factor (VEGF) immunostaining were used to evaluate the effects of captopril and the interaction between captopril and Ang II on the angiogenesis. Ang II and captopril cotreatment improved angiogenesis more than Ang II or captopril alone. The reduction of necrosis, enhancement of vascular network formation, capillary density, VEGF immunostaining, and local blood flow were evident in the cotreated group. We suggest that Ang II and captopril cotreatment improves ischemia-induced angiogenesis and increased viability and vascularity of skin flap in rats.
Assuntos
Angiotensina II/farmacologia , Captopril/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Retalhos Cirúrgicos/irrigação sanguínea , Análise de Variância , Angiografia , Animais , Técnicas Imunoenzimáticas , Fluxometria por Laser-Doppler , Necrose , Ratos , Ratos Sprague-DawleyRESUMO
The aim of this study was to investigate the modulatory role of nitric oxide (NO) in the electrical field stimulation (EFS)-induced contractions of isolated sphincter of Oddi (SO) and gallbladder strips from guinea pigs. EFS was used to activate the intrinsic nerves in SO and gallbladder strips. EFS produced frequency-dependent biphasic contractile responses in the SO strips. A smaller contraction, "on response", occurred during EFS, which was followed by a bigger contraction, "off response". Both responses were completely and irreversibly abolished by tetrodotoxin (TTX) (10(-6) M). Atropine (10(-6) M) inhibited the "on response", but not the "off response". EFS produced frequency-dependent monophasic contractile responses in gallbladder strips, which were completely and irreversibly abolished by TTX (10(-6) M) and atropine (10(-6) M). A nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine (10(-4) M and 3 x 10(-4) M, in SO and gallbladder strips, respectively), significantly increased all EFS-induced contractions of SO and gallbladder strips. L-Arginine, but not D-arginine reversed the effect induced by the NOS inhibitor, at all frequencies, in both strips. These results suggested that NO released from nitrergic nerve endings might play a regulatory role in the cholinergic neurotransmission of guinea pig SO and gallbladder strips. The "off response" in he SO preparations might be a rebound increase that was modulated by the nonadrenergic, noncholinergic inhibitory mediator NO.
Assuntos
Vesícula Biliar/metabolismo , Contração Muscular , Músculo Liso/metabolismo , Neurônios Nitrérgicos/metabolismo , Óxido Nítrico/metabolismo , Esfíncter da Ampola Hepatopancreática/metabolismo , Animais , Arginina/farmacologia , Atropina/farmacologia , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Vesícula Biliar/efeitos dos fármacos , Vesícula Biliar/inervação , Cobaias , Técnicas In Vitro , Músculo Liso/efeitos dos fármacos , Músculo Liso/inervação , Neurônios Nitrérgicos/efeitos dos fármacos , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Nitroarginina/farmacologia , Esfíncter da Ampola Hepatopancreática/efeitos dos fármacos , Esfíncter da Ampola Hepatopancreática/inervação , Tetrodotoxina/farmacologiaRESUMO
The involvement of endothelin (ET), ET(A) receptors and nitric oxide (NO) in the contractions induced by cyclosporine A (CyA) were investigated in guinea pig isolated gallbladder strips. Both BQ-123, a selective ET(A) receptor antagonist, and phosphoramidon, an ET converting enzyme inhibitor, inhibited the contractile responses to the parenteral and oral CyA preparations, whereas l-NOARG, a NO synthase inhibitor, potentiated these contractions. Additionally, the pattern of the concentration-dependent contractions in response to ET-1 was similar to that of CyA preparations in gallbladder strips. Both bosentan, a non-selective ET receptor antagonist, and BQ-123 inhibited the ET-1-induced contractions. These findings suggest that an ET-1-mediated mechanism contributes to the contractile response to CyA preparations in guinea pig isolated gallbladder strips. ET(A) receptor activation is likely to be involved in this process. We also speculate that CyA-induced stimulation of NO production might act as a counter-regulatory mechanism in the effect of CyA preparations in this tissue.