RESUMO
The regulation of membrane potential and the contractility of vascular smooth muscle cells (VSMCs) by voltage-dependent K+ (Kv) potassium channels are well-established. In this study, native VSMCs from rabbit coronary arteries were used to investigate the inhibitory effect of sertindole, an atypical antipsychotic agent, on Kv channels. Sertindole induced dose-dependent inhibition of Kv channels, with an IC50 of 3.13 ± 0.72 µM. Although sertindole did not cause a change in the steady-state activation curve, it did lead to a negative shift in the steady-state inactivation curve. The application of 1- or 2-Hz train pulses failed to alter the sertindole-induced inhibition of Kv channels, suggesting use-independent effects of the drug. The inhibitory response to sertindole was significantly diminished by pretreatment with a Kv1.5 inhibitor but not by Kv2.1 and Kv7 subtype inhibitors. These findings demonstrate the sertindole dose-dependent and use-independent inhibition of vascular Kv channels (mainly the Kv1.5 subtype) through a mechanism that involves altering steady-state inactivation curves. Therefore, the use of sertindole as an antipsychotic drug may have adverse effects on the cardiovascular system.
Assuntos
Antipsicóticos , Imidazóis , Indóis , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Coelhos , Vasos Coronários , Antipsicóticos/toxicidade , Canais de Potássio de Abertura Dependente da Tensão da Membrana/farmacologia , Bloqueadores dos Canais de Potássio/toxicidade , Miócitos de Músculo LisoRESUMO
Voltage-dependent K+ (Kv) channels play an important role in restoring the membrane potential to its resting state, thereby maintaining vascular tone. In this study, native smooth muscle cells from rabbit coronary arteries were used to investigate the inhibitory effect of quetiapine, an atypical antipsychotic agent, on Kv channels. Quetiapine showed a concentration-dependent inhibition of Kv channels, with an IC50 of 47.98 ± 9.46 µM. Although quetiapine (50 µM) did not alter the steady-state activation curve, it caused a negative shift in the steady-state inactivation curve. The application of 1 and 2 Hz train steps in the presence of quetiapine significantly increased the inhibition of Kv current. Moreover, the recovery time constants from inactivation were prolonged in the presence of quetiapine, suggesting that its inhibitory action on Kv channels is use (state)-dependent. The inhibitory effects of quetiapine were not significantly affected by pretreatment with Kv1.5, Kv2.1, and Kv7 subtype inhibitors. Based on these findings, we conclude that quetiapine inhibits Kv channels in both a concentration- and use (state)-dependent manner. Given the physiological significance of Kv channels, caution is advised in the use of quetiapine as an antipsychotic due to its potential side effects on cardiovascular Kv channels.
Assuntos
Antipsicóticos , Vasos Coronários , Músculo Liso Vascular , Miócitos de Músculo Liso , Bloqueadores dos Canais de Potássio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Fumarato de Quetiapina , Fumarato de Quetiapina/farmacologia , Animais , Coelhos , Antipsicóticos/farmacologia , Antipsicóticos/toxicidade , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Vasos Coronários/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Masculino , Relação Dose-Resposta a Droga , Potenciais da Membrana/efeitos dos fármacos , Células CultivadasRESUMO
Paliperidone, an atypical antipsychotic, is widely used to treat schizophrenia. In this study, we explored whether paliperidone inhibited the voltage-dependent K+ (Kv) channels of rabbit coronary arterial smooth muscle cells. Paliperidone reduced Kv channel activity in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50 ) of 16.58 ± 3.03 µM and a Hill coefficient of 0.60 ± 0.04. It did not significantly shift the steady-state activation or inactivation curves, suggesting that the drug did not affect the gating properties of Kv channels. In the presence of paliperidone, the application of 20 repetitive depolarizing pulses at 1 and 2 Hz gradually increased the inhibition of the Kv current. Further, the recovery time constant after Kv channel inactivation was increased by paliperidone, indicating that it inhibited the Kv channel in a use (state)-dependent manner. Its inhibitory effects were reduced by pretreatment with a Kv1.5 subtype inhibitor. However, pretreatment with a Kv2.1 or Kv7 inhibitor did not reduce its inhibitory effect. We conclude that paliperidone inhibits Kv channels (mainly Kv1.5 subtype channels) in a concentration- and use (state)-dependent manner without changing channel gating.
Assuntos
Antipsicóticos , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Coelhos , Antipsicóticos/toxicidade , Palmitato de Paliperidona/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/farmacologia , Miócitos de Músculo LisoRESUMO
Pimozide is an antipsychotic drug used to treat chronic psychosis, such as Tourette's syndrome. Despite its widespread clinical use, pimozide can cause unexpected adverse effects, including arrhythmias. However, the adverse effects of pimozide on vascular K+ channels have not yet been determined. Therefore, we investigated the effects of pimozide on voltage-gated K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Pimozide concentration-dependently inhibited the Kv currents with an IC50 value of 1.78 ± 0.17 µM and a Hill coefficient of 0.90 ± 0.05. The inhibitory effect on the Kv current by pimozide was highly voltage-dependent in the voltage range of Kv channel activation, and additive inhibition of the Kv current by pimozide was observed in the full activation voltage range. The decay rate of inactivation was significantly accelerated by pimozide. Pimozide shifted the inactivation curve to a more negative potential. The recovery time constant from inactivation increased in the presence of pimozide. Furthermore, pimozide-induced inhibition of the Kv current was augmented by applying train pulses. Although pretreatment with the Kv2.1 subtype inhibitor guangxitoxin and the Kv7 subtype inhibitor linopirdine did not alter the degree of pimozide-induced inhibition of the Kv currents, pretreatment with the Kv1.5 channel inhibitor DPO-1 reduced the inhibitory effects of pimozide on Kv currents. Pimozide induced membrane depolarization. We conclude that pimozide inhibits Kv currents in voltage-, time-, and use (state)-dependent manners. Furthermore, the major Kv channel target of pimozide is the Kv1.5 channel.
Assuntos
Antipsicóticos , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Coelhos , Antipsicóticos/toxicidade , Pimozida/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Músculo Liso Vascular , Canais de Potássio de Abertura Dependente da Tensão da Membrana/farmacologia , Miócitos de Músculo LisoRESUMO
To investigate the adverse effects of clozapine on cardiovascular ion channels, we examined the inhibitory effect of clozapine on voltage-dependent K+ (Kv) channels in rabbit coronary arterial smooth muscle cells. Clozapine-induced inhibition of Kv channels occurred in a concentration-dependent manner with an half-inhibitory concentration value of 7.84 ± 4.86 µM and a Hill coefficient of 0.47 ± 0.06. Clozapine did not shift the steady-state activation or inactivation curves, suggesting that it inhibited Kv channels regardless of gating properties. Application of train pulses (1 and 2 Hz) progressively augmented the clozapine-induced inhibition of Kv channels in the presence of the drug. Furthermore, the recovery time constant from inactivation was increased in the presence of clozapine, suggesting that clozapine-induced inhibition of Kv channels is use (state)-dependent. Pretreatment of a Kv1.5 subtype inhibitor decreased the Kv current amplitudes, but additional application of clozapine did not further inhibit the Kv current. Pretreatment with Kv2.1 or Kv7 subtype inhibitors partially blocked the inhibitory effect of clozapine. Based on these results, we conclude that clozapine inhibits arterial Kv channels in a concentrationand use (state)-dependent manner. Kv1.5 is the major subtype involved in clozapine-induced inhibition of Kv channels, and Kv2.1 and Kv7 subtypes are partially involved.
RESUMO
Fesoterodine, an antimuscarinic drug, is widely used to treat overactive bladder syndrome. However, there is little information about its effects on vascular K+ channels. In this study, voltage-dependent K+ (Kv) channel inhibition by fesoterodine was investigated using the patch-clamp technique in rabbit coronary artery. In whole-cell patches, the addition of fesoterodine to the bath inhibited the Kv currents in a concentration-dependent manner, with an IC50 value of 3.19 ± 0.91 µM and a Hill coefficient of 0.56 ± 0.03. Although the drug did not alter the voltage-dependence of steady-state activation, it shifted the steady-state inactivation curve to a more negative potential, suggesting that fesoterodine affects the voltage-sensor of the Kv channel. Inhibition by fesoterodine was significantly enhanced by repetitive train pulses (1 or 2 Hz). Furthermore, it significantly increased the recovery time constant from inactivation, suggesting that the Kv channel inhibition by fesoterodine is use (state)-dependent. Its inhibitory effect disappeared by pretreatment with a Kv 1.5 inhibitor. However, pretreatment with Kv2.1 or Kv7 inhibitors did not affect the inhibitory effects on Kv channels. Based on these results, we conclude that fesoterodine inhibits vascular Kv channels (mainly the Kv1.5 subtype) in a concentration- and use (state)-dependent manner, independent of muscarinic receptor antagonism.
RESUMO
Tegaserod, a gastroprokinetic agent, is used to treat irritable bowel syndrome. Despite its extensive clinical use, little is known about the effects of tegaserod on vascular ion channels, especially K+ channels. Therefore, we examined the effects of tegaserod on voltage-gated K+ (Kv) channels in rabbit coronary arterial smooth muscle cells using the whole-cell patch-clamp technique. Tegaserod inhibited Kv channels in a concentration-dependent manner with an IC50 value of 1.26 ± 0.31 µmol/L and Hill coefficient of 0.81 ± 0.10. Although tegaserod had no effect on the steady-state activation curves of the Kv channels, the steady-state inactivation curve was shifted toward a more negative potential. These results suggest that tegaserod inhibits Kv channels by influencing their voltage sensors. The recovery time constant of channel inactivation was extended in the presence of tegaserod. Furthermore, application of train steps (1 and 2 Hz) in the presence of tegaserod progressively increased the inhibition of Kv currents suggesting that tegaserod-induced Kv channel inhibition is use (state)-dependent. Pretreatment with a Kv1.5 subtype inhibitor suppressed the Kv current. However, additional application of tegaserod did not induce further inhibition. Pretreatment with a Kv2.1 or Kv7 inhibitor did not affect the inhibitory effect of tegaserod on Kv channels. Based on these results, we conclude that tegaserod inhibits vascular Kv channels in a concentration- and use (state)-dependent manner independent of its own functions. Furthermore, the major Kv channel target of tegaserod is the Kv1.5 subtype.
Assuntos
Indóis , Miócitos de Músculo Liso , Animais , Músculo Liso Vascular , CoelhosRESUMO
We investigated the effect of ziprasidone, a widely used treatment for schizophrenia, on voltage-dependent K+ (Kv) channels of coronary arterial smooth muscle cells using the patch-clamp technique. Ziprasidone dose-dependently inhibited Kv channels with an IC50 value of 0.39 ± 0.06 µM and a Hill coefficient of 0.62 ± 0.03. Although ziprasidone had no effect on the steady-state inactivation kinetics of the Kv channels, the steady-state activation curve shifted towards a more positive potential. These results suggest that ziprasidone inhibits Kv channels by targeting their voltage sensors. The recovery time constant of Kv channel inactivation was increased in the presence of ziprasidone. Furthermore, application of train steps (of 1 and 2 Hz) in the presence of ziprasidone led to a progressive increase in the blockade of Kv currents, suggesting that ziprasidone-induced inhibition of Kv channels is use (state)-dependent. Pretreatment with Kv1.5, Kv2.1, and Kv7 subtype inhibitors partially suppressed the ziprasidone-induced inhibition of Kv currents. These results suggest that ziprasidone inhibits vascular Kv channels through its effect on gating properties. The Kv channel-inhibiting action of ziprasidone is concentration- and use (state)-depedent.
Assuntos
Antipsicóticos/farmacologia , Vasos Coronários/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Piperazinas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Células Cultivadas , Vasos Coronários/citologia , Vasos Coronários/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Técnicas de Patch-Clamp , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , CoelhosRESUMO
In this study, we explore the inhibitory effects of protriptyline, a tricyclic antidepressant drug, on voltage-dependent K+ (Kv) channels of rabbit coronary arterial smooth muscle cells using a whole-cell patch clamp technique. Protriptyline inhibited the vascular Kv current in a concentration-dependent manner, with an IC50 value of 5.05 ± 0.97 µM and a Hill coefficient of 0.73 ± 0.04. Protriptyline did not affect the steady-state activation kinetics. However, the drug shifted the steady-state inactivation curve to the left, suggesting that protriptyline inhibited the Kv channels by changing their voltage sensitivity. Application of 20 repetitive train pulses (1 or 2 Hz) progressively increased the protriptyline-induced inhibition of the Kv current, suggesting that protriptyline inhibited Kv channels in a use (state)-dependent manner. The extent of Kv current inhibition by protriptyline was similar during the first, second, and third step pulses. These results suggest that protriptyline-induced inhibition of the Kv current mainly occurs principally in the closed state. The increase in the inactivation recovery time constant in the presence of protriptyline also supported use (state)-dependent inhibition of Kv channels by the drug. In the presence of the Kv1.5 inhibitor, protriptyline did not induce further inhibition of the Kv channels. However, pretreatment with a Kv2.1 or Kv7 inhibitor induced further inhibition of Kv current to a similar extent to that observed with protriptyline alone. Thus, we conclude that protriptyline inhibits the vascular Kv channels in a concentration- and use-dependent manner by changing their gating properties. Furthermore, protriptyline-induced inhibition of Kv channels mainly involves the Kv1.5.
Assuntos
Miócitos de Músculo Liso/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Protriptilina/farmacologia , Animais , Antidepressivos Tricíclicos/metabolismo , Antidepressivos Tricíclicos/farmacologia , Vasos Coronários/metabolismo , Relação Dose-Resposta a Droga , Masculino , Potenciais da Membrana/efeitos dos fármacos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Técnicas de Patch-Clamp , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Protriptilina/metabolismo , CoelhosRESUMO
BACKGROUND: We evaluated the clinical performance of [-2]proPSA (p2PSA) and its derivatives in predicting the presence and aggressiveness of prostate cancer (PCa) in Korean men. METHODS: A total of 246 men with total prostate-specific antigen (tPSA) ≥ 3.5 ng/mL who underwent their first prostate biopsy were included in this prospective, multicenter, observational study. Diagnostic accuracy of tPSA, free-to-total PSA ratio (%fPSA), p2PSA, %p2PSA, and the Beckman Coulter prostate health index (PHI) was assessed by receiver operating characteristic curve analyses and logistic regression analyses. RESULTS: Overall, PCa was detected in 125 (50.8%) subjects. In men with tPSA 3.5-10 ng/mL, the detection rate of PCa was 39.4% (61/155). In this group, PHI and %p2PSA were the most accurate predictors of PCa and significantly outperformed tPSA and %fPSA; area under the curve for tPSA, %fPSA, %p2PSA, and PHI was 0.56, 0.69, 0.74, and 0.76, respectively. PHI was also the strongest predictor of PCa with Gleason score ≥ 7. CONCLUSION: This study demonstrates the superior clinical performance of %p2PSA and PHI in predicting the presence and aggressiveness of PCa in Korean men. The %p2PSA and PHI appear to improve detection of PCa and provide prognostic information.
Assuntos
Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Idoso , Área Sob a Curva , Biomarcadores/sangue , Detecção Precoce de Câncer , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/patologia , Precursores de Proteínas/sangue , Curva ROC , Kit de Reagentes para Diagnóstico , Sensibilidade e Especificidade , Índice de Gravidade de DoençaRESUMO
BACKGROUND: PTEN deletion, mutation or reduced expression occurs in 63% of metastatic prostate tumors, resulting in the activation of PI3K and its downstream targets, AKT and mTOR. Inhibition of the PI3K pathway results in upregulation of the MAPK pathway. Therefore, co-administration of inhibitors of both pathways, GSK2126458 as a dual PI3K/mTOR inhibitor, and AZD6244 as a MEK inhibitor, is able to overcome resistance and increase anti-tumor efficacy. METHODS: PC3, DU145, LNCaP, and CRPC patient-derived cells were used to assess apoptosis upon exposure to the drug combination. The human DU145 and PC3 tumor xenograft mouse model was employed to evaluate in vivo efficacy. CellTiter Glo® luminescent assay, annexin V-FITC apoptosis detection, cell cycle analysis, Western blotting and immunohistochemistry were conducted. Statistical evaluation of the results was performed by one-way ANOVA. RESULTS: The combination of GSK2126458 and AZD6244 inhibited the growth of DU145 and PC3 prostate cancer cells in vitro and in vivo. GSK2126458 decreased phospho-AKT while increasing phospho-ERK and AZD6244 decreased phospho-ERK efficiently while increasing phospho-AKT. The combination of GSK2126458 and AZD6244 decreased both phospho-AKT and phospho-ERK effectively in vitro and in vivo. The combination treatment synergistically induced annexin V-positive cells, sub-G1 cells, and cleavage of caspase-9, caspase-3 and poly-ADP ribose polymerase (PARP) in DU145 cells in vitro. Moreover, the combination decreased the level of Ki-67, and increased TUNEL-positive cells and cleaved caspase-3 in DU145 xenograft tumors implanted in mice. In addition, this combination treatment inhibited both the PI3K and MEK pathway primary in cultures from CRPC patients harboring PTEN loss, leading to synergistic anti-tumor effect. CONCLUSIONS: The combination of GSK2126458 and AZD6244 blocks both the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways simultaneously and is an effective strategy for the treatment of CRPCs.
Assuntos
Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Animais , Benzimidazóis/uso terapêutico , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridazinas , Quinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We demonstrated the inhibitory effect of NNC 55-0396, a T-type Ca(2+) channel inhibitor, on voltage-dependent K(+) (K(V)) channels in freshly isolated rabbit coronary arterial smooth muscle cells. NNC 55-0396 decreased the amplitude of K(V) currents in a concentration-dependent manner, with an IC(50) of 0.080 µM and a Hill coefficient of 0.76.NNC 55-0396 did not affect steady-state activation and inactivation curves, indicating that the compound does not affect the voltage sensitivity of K(V) channel gating. Both the K(V) currents and the inhibitory effect of NNC 55-0396 on K(V) channels were not altered by depletion of extracellular Ca(2+) or intracellular ATP, suggesting that the inhibitory effect of NNC 55-0396 is independent of Ca(2+)-channel activity and phosphorylation-dependent signaling cascades. From these results, we concluded that NNC 55-0396 dosedependently inhibits K(V) currents, independently of Ca(2+)-channel activity and intracellular signaling cascades.
Assuntos
Benzimidazóis/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Vasos Coronários/citologia , Ciclopropanos/farmacologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Naftalenos/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Animais , Canais de Cálcio Tipo T/fisiologia , Sinalização do Cálcio , Células Cultivadas , Relação Dose-Resposta a Droga , Fosforilação , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , CoelhosRESUMO
Aripiprazole, a third-generation antipsychotic, has been widely used to treat schizophrenia. In this study, we evaluated the effect of aripiprazole on voltage-gated potassium (Kv) channels in rabbit coronary arterial smooth muscle cells using the patch clamp technique. Aripiprazole reduced the Kv current in a concentration-dependent manner with a half-maximal inhibitory concentration of 0.89 ± 0.20 µM and a Hill coefficient of 1.30 ± 0.25. The inhibitory effect of aripiprazole on Kv channels was voltage-dependent, and an additional aripiprazole-induced decrease in the Kv current was observed in the voltage range of full channel activation. The decay rate of Kv channel inactivation was accelerated by aripiprazole. Aripiprazole shifted the steady-state activation curve to the right and the inactivation curve to the left. Application of a repetitive train of pulses (1 and 2 Hz) promoted inhibition of the Kv current by aripiprazole. Furthermore, the recovery time constant from inactivation increased in the presence of aripiprazole. Pretreatment of Kv1.5 subtype inhibitor reduced the inhibitory effect of aripiprazole. However, pretreatment with Kv 7 and Kv2.1 subtype inhibitors did not change the degree of aripiprazole-induced inhibition of the Kv current. We conclude that aripiprazole inhibits Kv channels in a concentration-, voltage-, time-, and use (state)-dependent manner by affecting the gating properties of the channels.
Assuntos
Aripiprazol , Vasos Coronários , Miócitos de Músculo Liso , Bloqueadores dos Canais de Potássio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Aripiprazol/farmacologia , Coelhos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/citologia , Bloqueadores dos Canais de Potássio/farmacologia , Masculino , Antipsicóticos/farmacologia , Relação Dose-Resposta a DrogaRESUMO
PURPOSE: To create a nomogram that can predict the probability of prostate cancer using prostate health index (PHI) and clinical parameters of patients. And the optimal cut-off value of PHI for prostate cancer was also assessed. MATERIALS AND METHODS: A prospective, multi-center study was conducted. PHI was evaluated prior to biopsy in patients requiring prostate biopsy due to high prostate-specific antigen (PSA). Among screened 1,010 patients, 626 patients with clinically suspected prostate cancer with aged 40 to 85 years, and with PSA levels ranging from 2.5 to 10 ng/mL were analyzed. RESULTS: Among 626 patients, 38.82% (243/626) and 22.52% (141/626) were diagnosed with prostate cancer and clinically significant prostate cancer, respectively. In the PSA 2.5 to 4 ng/mL group, the areas under the curve (AUCs) of the nomograms for overall prostate cancer and clinically significant prostate cancer were 0.796 (0.727-0.866; p<0.001), and 0.697 (0.598-0.795; p=0.001), respectively. In the PSA 4 to 10 ng/mL group, the AUCs of nomograms for overall prostate cancer and clinically significant prostate cancer were 0.812 (0.783-0.842; p<0.001), and 0.839 (0.810-0.869; p<0.001), respectively. CONCLUSIONS: Even though external validations are necessary, a nomogram using PHI might improve the prediction of prostate cancer, reducing the need for prostate biopsies.
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AIMS: The present study investigated the vasorelaxant mechanisms of an oral antidiabetic drug, anagliptin, using phenylephrine (Phe)-induced pre-contracted rabbit aortic rings. METHODS: Arterial tone measurement was performed in rabbit thoracic aortic rings. RESULTS: Anagliptin induced vasorelaxation in a dose-dependent manner. Pre-treatment with the classical voltagedependent K+ (Kv) channel inhibitors 4-aminopyridine and tetraethylammonium significantly decreased the vasorelaxant effect of anagliptin, whereas pre-treatment with the inwardly rectifying K+ (Kir) channel inhibitor Ba2+, the ATP-sensitive K+ (KATP) channel inhibitor glibenclamide, and the large-conductance Ca2+-activated K+ (BKCa) channel inhibitor paxilline did not attenuate the vasorelaxant effect. Furthermore, the vasorelaxant response of anagliptin was effectively inhibited by pre-treatment with the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid. Neither cAMP/protein kinase A (PKA)-related signaling pathway inhibitors (adenylyl cyclase inhibitor SQ 22536 and PKA inhibitor KT 5720) nor cGMP/protein kinase G (PKG)-related signaling pathway inhibitors (guanylyl cyclase inhibitor ODQ and PKG inhibitor KT 5823) reduced the vasorelaxant effect of anagliptin. Similarly, the anagliptin-induced vasorelaxation was independent of the endothelium. CONCLUSIONS: Based on these results, we suggest that anagliptin-induced vasorelaxation in rabbit aortic smooth muscle occurs by activating Kv channels and the SERCA pump, independent of other vascular K+ channels, cAMP/PKA- or cGMP/PKG-related signaling pathways, and the endothelium.
RESUMO
We explored the vasorelaxant effects of ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, on rabbit femoral arterial rings. Ipragliflozin relaxed phenylephrine-induced pre-contracted rings in a dose-dependent manner. Pre-treatment with the ATP-sensitive K+ channel inhibitor glibenclamide (10 µM), the inwardly rectifying K+ channel inhibitor Ba2+ (50 µM), or the Ca2+-sensitive K+ channel inhibitor paxilline (10 µM) did not influence the vasorelaxant effect. However, the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine (3 mM) reduced the vasorelaxant effect. Specifically, the vasorelaxant response to ipragliflozin was significantly attenuated by pretreatment with the Kv7.X channel inhibitors linopirdine (10 µM) and XE991 (10 µM), the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin (1 µM) and cyclopiazonic acid (10 µM), and the cAMP/protein kinase A (PKA)-associated signaling pathway inhibitors SQ22536 (50 µM) and KT5720 (1 µM). Neither the cGMP/protein kinase G (PKG)-associated signaling pathway nor the endothelium was involved in ipragliflozin-induced vasorelaxation. We conclude that ipragliflozin induced vasorelaxation of rabbit femoral arteries by activating Kv channels (principally the Kv7.X channel), the SERCA pump, and the cAMP/PKA-associated signaling pathway independent of other K+ (ATP-sensitive K+, inwardly rectifying K+, and Ca2+-sensitive K+) channels, cGMP/PKG-associated signaling, and the endothelium.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico , Artéria Femoral , Glucosídeos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Transdução de Sinais , Tiofenos , Vasodilatação , Animais , Coelhos , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/fisiologia , Vasodilatação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Tiofenos/farmacologia , Masculino , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Vasodilatadores/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidoresRESUMO
We investigated the vasodilatory effect of omarigliptin, an oral antidiabetic drug in the dipeptidyl peptidase-4 inhibitor class, and its related mechanisms using phenylephrine (Phe)-induced pre-contracted aortic rings. Omarigliptin dilated aortic rings pre-constricted with Phe in a dose-dependent manner. Pretreatment with the voltage-dependent K+ channel inhibitor 4-aminopyridine significantly attenuated the vasodilatory effect of omarigliptin, whereas pretreatment with the inwardly rectifying K+ channel inhibitor Ba2+ , ATP-sensitive K+ channel inhibitor glibenclamide, and large-conductance Ca2+ -activated K+ channel inhibitor paxilline did not alter its vasodilation. Pretreatment with the sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid significantly reduced the vasodilatory effect of omarigliptin. Neither cAMP/PKA-related signaling pathway inhibitors nor cGMP/PKG-related signaling pathway inhibitors modulated the vasodilatory effect of omarigliptin. Removal of endothelium did not diminish the vasodilatory effect of omarigliptin. Furthermore, pretreatment with the nitric oxide synthase inhibitor L-NAME or small-conductance Ca2+ -activated K+ channel inhibitor apamin, together with the intermediate-conductance Ca2+ -activated K+ channel inhibitor TRAM-34, did not influence the vasodilatory effect of omarigliptin. In conclusion, omarigliptin induced vasodilation in rabbit aortic smooth muscle by activating voltage-dependent K+ channels and the SERCA pump independently of other K+ channels, cAMP/PKA- and cGMP/PKG-related signaling pathways, and the endothelium.
Assuntos
Adenosina Trifosfatases , Hipoglicemiantes , Animais , Coelhos , Hipoglicemiantes/farmacologia , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/farmacologia , Músculo Liso Vascular/metabolismo , Aorta , Vasodilatação , Endotélio Vascular , Vasodilatadores/farmacologia , Aorta TorácicaRESUMO
Lurasidone is a second-generation antipsychotic drug used to treat schizophrenia, mania, and bipolar disorder. The drug is an antagonist of the 5-HT2A and D2 receptors. No effect of lurasidone on the voltage-gated K+ (Kv) channels has yet been identified. Here, we show that lurasidone inhibits the vascular Kv channels of rabbit coronary arterial smooth muscle cells in a dose-dependent manner with an IC50 of 1.88 ± 0.21 µM and a Hill coefficient of 0.98 ± 0.09. Although lurasidone (3 µM) did not affect the activation kinetics, the drug negatively shifted the inactivation curve, suggesting that the drug interacted with the voltage sensors of Kv channels. Application of 1 or 2 Hz train steps in the presence of lurasidone significantly increased Kv current inhibition. The recovery time after channel inactivation increased in the presence of lurasidone. These results suggest that the inhibitory action of lurasidone is use (state)-dependent. Pretreatment with a Kv 1.5 subtype inhibitor effectively reduced the inhibitory effect of lurasidone. However, the inhibitory effect on Kv channels did not markedly change after pretreatment with a Kv 2.1 or a Kv7 subtype inhibitor. In summary, lurasidone inhibits vascular Kv channels (primarily the Kv1.5 subtype) in a concentration- and use (state)-dependent manner by shifting the steady-state inactivation curve.
Assuntos
Antipsicóticos , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Coelhos , Cloridrato de Lurasidona/farmacologia , Antipsicóticos/farmacologia , Vasos Coronários , Miócitos de Músculo LisoRESUMO
PURPOSE: Cisplatin is the mainstay of treatment for advanced bladder cancer. However, intrinsic or acquired resistance to cisplatin is common, which severely limits its therapeutic potential. We determined the synergistic antitumor effect of cisplatin and the histone deacetylase inhibitor trichostatin A in cisplatin resistant human bladder cancer cells. MATERIALS AND METHODS: The cisplatin resistant human bladder cancer cell line T24R2 was exposed to cisplatin and/or trichostatin A. Tumor cell proliferation was examined by cell counting kit assay. Synergism between 2 drugs was examined by the combination index. Changes in cell cycle and apoptosis were determined by flow cytometry. We analyzed the expression of caspase-3, 8 and 9, poly(adenosine diphosphate-ribose) polymerase, p21WAF1/CIP1, cyclin A, B1 and D1, Cdc2c, p-Cdc2c, Cdc25c, p-Cdc25c, cytochrome c, p-Akt, t-Akt, Bcl-2, Bax, Bad, vascular endothelial growth factor and fetal liver kinase-1 by Western blot and colorimetric assay. RESULTS: Based on the combination index and isobole analysis of the Cell Counting Kit-8 assay we observed a strong synergistic antitumor effect between cisplatin and trichostatin A, allowing a 3.5 and 4.9-fold dose reduction in cisplatin and trichostatin A, respectively, while achieving an estimated 90% kill of T24R2 cells. The underlying mechanism could be synergistic cell cycle arrest, induction of caspase mediated apoptosis or up-regulated expression of pro-apoptotic Bad and Bax. CONCLUSIONS: Results indicate that trichostatin A may synergistically enhance the antitumor effect of cisplatin and resensitize cisplatin resistant bladder cancer cells. These findings suggest the potential use of histone deacetylase inhibitor as a combination agent to enhance the antitumor effect of cisplatin in patients with advanced bladder cancer.
Assuntos
Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Neoplasias da Bexiga Urinária/patologiaRESUMO
OBJECTIVES: To determine the association of vesico-urethral anastomosis location (VUAL) with early recovery of urinary continence (UC) after radical prostatectomy (RP). METHODS: A retrospective analysis of 678 patients who underwent RP was carried out. Patients were divided into three groups based on the VUAL as determined by postoperative cystography: group I - VUAL above the upper margin of the symphysis pubis (SP), group II - between the upper margin and the middle of the SP, and group III - below the middle of the SP. Early recovery of UC was defined as using no pads or an occasional security pad within 3 months. Recovery rates were compared between the groups and factors predicting an early recovery of UC were investigated. RESULTS: Among all patients, 62.2% achieved an early recovery of UC. Patients in group I were younger, with a longer membranous urethra, greater percent of nerve sparing and shorter time to continence than those in groups II or III. Early recovery rates were 89.5%, 69.8% and 40.7% in group I, II and III, respectively (P < 0.001). VUAL remained an independent predictor of early recovery of UC (OR 3.2 for group I vs II and 10.8 for group I vs III [P < 0.001]) when adjusted for age, operative time, membranous urethral length and operation by surgeon with high surgical volume. CONCLUSION: VUAL represents an independent predictor of recovery of UC after RP. A higher VUAL is associated with a higher rate of early recovery of UC.