RESUMO
The kallikrein-kinin system is expressed in the corpus cavernosa, and bradykinin (BK) relaxes isolated corpora cavernosal strips. However, erectile responses to BK in the rat have not been investigated in vivo. In the present study, responses to intracorporal (ic) injections of BK were investigated in the anesthetized rat. BK, in doses of 1-100 µg/kg ic, produced dose-related increases in intracavernosal pressure (ICP) and dose-related deceases in mean arterial pressure (MAP). When decreases in MAP were prevented by intravenous injections of angiotensin II (Ang II), increases in ICP, in response to BK, were enhanced. Increases in ICP, ICP/MAP ratio, and area under the curve and decreases in MAP in response to BK were inhibited by the kinin B2 receptor antagonist HOE-140 and enhanced by the angiotensin-converting enzyme (ACE) inhibitor captopril and by Ang-(1-7). Increases in ICP, in response to BK, were not attenuated by the nitric oxide (NO) synthase inhibitor (N(ω)-nitro-L-arginine methyl ester) or the soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) but were attenuated by the cyclooxygenase inhibitor, sodium meclofenamate. Decreases in MAP were not attenuated by either inhibitor. These data suggest that erectile responses are mediated by kinin B2 receptors and modulated by decreases in MAP. These data indicate that ACE is important in the inactivation of BK and that erectile and hypotensive responses are independent of NO in the penis or the systemic vascular bed. Erectile responses to cavernosal nerve stimulation are not altered by BK or HOE-140, suggesting that BK and B2 receptors do not modulate nerve-mediated erectile responses under physiologic conditions. These data suggest that erectile responses to BK are mediated, in part, by the release of cyclooxygenase products.
Assuntos
Bradicinina/farmacologia , Ereção Peniana/efeitos dos fármacos , Pênis/irrigação sanguínea , Vasodilatadores/farmacologia , Anestesia , Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Pressão Sanguínea , Bradicinina/análogos & derivados , Antagonistas de Receptor B2 da Bradicinina/farmacologia , Captopril/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Masculino , Óxido Nítrico Sintase/antagonistas & inibidores , Pênis/efeitos dos fármacos , Pênis/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Guanilil Ciclase SolúvelRESUMO
PURPOSE: We sought to develop a reproducible TGF-ß1 injection technique to induce urethral fibrosis in the rat urethra. MATERIALS AND METHODS: A total of 32 male Sprague Dawley® rats weighing 300 to 350 gm were anesthetized with ketamine/xylazine intraperitoneally. Using a 5 mm penoscrotal incision the rat urethra was exposed. In the experimental group varying doses of TGF-ß1 (5, 10 and 25 µg) were injected in each side of the urethral wall. Normal saline infiltration was used in the sham treated group. Rats were sacrificed 2 and 4 weeks following TGF-ß1 injection. Urethral specimens were stained with hematoxylin and eosin, and Masson trichrome, and Western blot evaluations were performed. Normal and strictured urethral tissues from patients were collected and evaluated in the same fashion. RESULTS: There was no evidence of urethral wall thickening or fibrosis in the sham treated group. Varied histological evidence of fibrosis was noted in all experimental groups. There was a significant increase in collagen type I expression 2 weeks after injection of 5, 10 and 25 µg TGF-ß1. Collagen type III expression was significantly increased 2 weeks after injecting 10 and 25 µg of TGF-ß1, which persisted to 28 days after injection. CONCLUSIONS: TGF-ß1 injection can successfully generate a reproducible rat model of urethral spongiofibrosis. This technique is simple, inexpensive and reproducible. Our series is a proof of concept study. Additional studies in larger animals are needed to further confirm our findings.
Assuntos
Modelos Animais de Doenças , Fator de Crescimento Transformador beta1/administração & dosagem , Uretra/patologia , Estreitamento Uretral/induzido quimicamente , Animais , Fibrose/induzido quimicamente , Injeções , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Peyronie's disease (PD) has frequently been associated with erectile dysfunction (ED) and may further compromise coitus. AIM: To investigate the efficacy of intratunical injection of genetically modified rat adipose tissue-derived stem cells (ADSCs) expressing human interferon α-2b (ADSCs-IFN) in decreasing fibrosis and restoring erectile function in a rat model of tunica albugineal fibrosis (TAF). METHODS: A total of 36 Sprague-Dawley rats (12 weeks old; 300-350 g) were randomly divided in six equal groups: (i) sham group (50 µL saline-injected into the tunica albuginea [TA]); (ii) TAF group (transforming growth factor [TGF]-ß1 [0.5 µg/50 µL] injected into the TA); (iii) TGF-ß1 plus 5 × 10(5) control ADSCs injected same day; (iv) TGF-ß1 plus 5 × 10(5) ADSCs-IFN injected same day; (v) TGF-ß1 plus 5 × 10(5) control ADSCs injected after 30 days; and (vi) TGF-ß1 plus 5 × 10(5) ADSCs-IFN injected after 30 days. Rat allogeneic ADSCs were harvested from inguinal fat tissue. MAIN OUTCOME MEASURES: Forty-five days following the TGF-ß1 injection, erectile function was assessed, and penile tissues were harvested for further evaluations. RESULTS: In the same-day injection groups, intratunical injection of ADSCs and ADSC-IFN improved erectile response observed upon stimulation of cavernous nerve compared with TAF group. Intratunical ADSC-IFN injection at day 30 improved erectile responses 3.1, 1.8, and 1.3 fold at voltages of 2.5, 5.0, and 7.0, respectively, when compared with TAF group. Furthermore, at voltages of 2.5 and 5.0, treatment on day 30 with ADSCs-IFN improved erectile responses 1.6- and 1.3-fold over treatment with ADSCs alone. Local injection of ADSCs or ADSCs-IFN reduced Peyronie's-like manifestations, and these effects might be associated with a decrease in the expression of tissue inhibitors of metalloproteinases. CONCLUSION: This study documents that transplantation of genetically modified ADSCs, with or without human IFN α-2b, attenuated Peyronie's-like changes and enhanced erectile function in a rat model of TAF.
Assuntos
Tecido Adiposo/transplante , Disfunção Erétil/terapia , Interferon-alfa/farmacologia , Induração Peniana/terapia , Pênis/patologia , Transplante de Células-Tronco , Animais , Modelos Animais de Doenças , Fibrose/terapia , Humanos , Injeções Intralesionais , Interferon alfa-2 , Masculino , Pênis/inervação , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologiaRESUMO
Nitric oxide (NO) is the principal mediator of penile erection, and PDE-5 inhibitors are the first-line agents used to treat erectile dysfunction (ED). When NO formation or bioavailability is decreased by oxidative stress and PDE-5 inhibitors are no longer effective, a new class of agents called soluble guanylate cyclase (sGC) stimulators like BAY 41-8543 will induce erection. sGC stimulators bind to the normally reduced, NO-sensitive form of sGC to increase cGMP formation and promote erection. The sGC stimulators produce normal erectile responses when NO formation is inhibited and the nerves innervating the corpora cavernosa are damaged. However, with severe oxidative stress, the heme iron on sGC can be oxidized, rendering the enzyme unresponsive to NO or sGC stimulators. In this pathophysiological situation, another newly developed class of agents called sGC activators can increase the catalytic activity of the oxidized enzyme, increase cGMP formation, and promote erection. The use of newer agents that stimulate or activate sGC to promote erection and treat ED is discussed in this brief review article.
Assuntos
Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/fisiopatologia , Guanilato Ciclase/uso terapêutico , Ereção Peniana/fisiologia , GMP Cíclico/fisiologia , Guanilato Ciclase/fisiologia , Humanos , Masculino , Morfolinas/uso terapêutico , Óxido Nítrico/fisiologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do TratamentoRESUMO
The transient receptor potential vanilloid 4 (TRPV4) channel is a nonselective cation channel expressed on many cell types, including the vascular endothelium and smooth muscle cells. TRPV4 channels play a role in regulating vasomotor tone and capillary permeability. The present study was undertaken to investigate responses to the TRPV4 agonist GSK101790A on the pulmonary and systemic vascular beds in the rat. Intravenous injection of GSK1016790A at doses of 2-10 µg/kg produced dose-dependent decreases in systemic arterial pressure, small decreases in pulmonary arterial pressure, and small increases in cardiac output, and responses were not altered by the cyclooxygenase inhibitor meclofenamate or the cytochrome P-450 inhibitor miconazole. Injection of GSK1016790A at a dose of 12 µg/kg iv produced cardiovascular collapse that was reversible in some animals. GSK1016790A produced dose-related decreases in pulmonary and systemic arterial pressure when baseline tone in the pulmonary vascular bed was increased with U-46619. After treatment with the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester, GSK1016790A produced larger decreases in systemic arterial pressure and dose-dependent increases in pulmonary arterial pressure followed by a small decrease. These results demonstrate that GSK1016790A has vasodilator activity in pulmonary and systemic vascular beds and that when NOS is inhibited, GSK1016790A produced pulmonary vasoconstrictor responses that were attenuated by the L-type Ca(2+) channel antagonist isradipine. The presence of TRPV4 immunoreactivity was observed in small pulmonary arteries and airways. The present data indicate that responses to TRPV4 are modulated differently by NOS in pulmonary and systemic vascular beds and are attenuated by the TRPV4 antagonist GSK2193874.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Leucina/análogos & derivados , Artéria Pulmonar/efeitos dos fármacos , Sulfonamidas/farmacologia , Canais de Cátion TRPV/agonistas , Animais , Débito Cardíaco/efeitos dos fármacos , Isradipino/farmacologia , Leucina/farmacologia , Masculino , Ácido Meclofenâmico/farmacologia , Miconazol/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiologia , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismoRESUMO
INTRODUCTION: Premature ejaculation (PE) is the most common male sexual dysfunction. A variety of pharmacotherapeutic strategies have been employed to treat men suffering with lifelong PE. However, there are currently no pharmaceuticals approved by the U.S. Food and Drug Administration specifically designed for PE treatment. AIM: Given that the bulbospongiosus muscle is involved in the ejaculatory reflex in both humans and rodents and that local administration of botulinum-A can abolish muscle contractions, the current study examined the effect of injection of botulinum-A toxin into the bulbospongiosus muscle on the ejaculatory latency of male rats. METHODS: After screening for normal sexual activity with sexually receptive female rats, 33 sexually experienced male Long-Evans rats (Harlan Laboratories, Indianapolis, IN, USA) underwent an additional four pretreatment sexual exposures over the course of the following week, during which all components of sexual behavior were video recorded by trained observers. On the day after their fourth experience, rats were anesthetized and received a single injection of either 0.5 unit (n = 11) or 1 unit (n = 11) of botulinum-A toxin or saline vehicle (n = 11). Botulinum-A toxin was dissolved in 0.1 mL of saline vehicle and injected bilaterally into the bulbospongiosus muscle by the percutaneous route. Beginning 2 days after treatment, sexual behaviors were reexamined over the course of the following week on four separate occasions. MAIN OUTCOME MEASURES: The latency to achieve ejaculation, and the frequencies and latencies of mounts and intromissions were video recorded by trained observers in a blinded fashion. RESULTS: Relative to pretreatment measurements, bilateral injection of saline vehicle into the bulbospongiosus muscle did not affect ejaculation latencies. However, rats treated with either 0.5 or 1 unit of botulinum-A toxin exhibited significantly longer latencies to achieve ejaculation relative to pretreatment performance. Of note, botulinum-A toxin did not affect the ability to achieve mounts, intromissions, or ejaculation. CONCLUSIONS: These results demonstrate that botulinum-A toxin injection into the bulbospongiosus muscle is a safe and effective treatment that extends ejaculatory latency in rats without affecting the ability to engage in sexual activity or achieve ejaculation. Further studies are required to evaluate this therapeutic concept in PE patients.
Assuntos
Toxinas Botulínicas Tipo A/farmacologia , Ejaculação/efeitos dos fármacos , Fármacos Neuromusculares/farmacologia , Animais , Ejaculação/fisiologia , Injeções Intramusculares , Masculino , Contração Muscular/efeitos dos fármacos , Ejaculação Precoce/tratamento farmacológico , Ratos Long-Evans , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologiaRESUMO
Cardiovascular responses to the tyrosine kinase inhibitor imatinib were investigated in the rat. Intravenous injections of 0.3-30 mg/kg imatinib produced small decreases in pulmonary arterial pressure, larger dose-dependent decreases in systemic arterial pressure, and no change or small increases in cardiac output, suggesting that the systemic vasodilator response is more pronounced under baseline conditions. When pulmonary arterial pressure was increased with U-46619 or N(ω)-nitro-L-arginine methyl ester (L-NAME), intravenous injections of imatinib produced larger dose-dependent decreases in pulmonary arterial pressure. Imatinib attenuated the acute hypoxic pulmonary vasoconstrictor response. Vasodilator responses to imatinib were not inhibited by meclofenamate, glybenclamide, or rolipram, suggesting that cyclooxygenase, ATP-sensitive K(+) (KATP) channels, and cAMP were not involved in mediating the response. In a 21-day prevention study, imatinib treatment (50 mg/kg ip) attenuated the increase in pulmonary arterial pressure, right ventricular hypertrophy, and small vessel remodeling induced by monocrotaline. Imatinib reduced PDGF receptor phosphorylation and PDGF-stimulated thymidine incorporation in rat pulmonary artery smooth muscle cells. These data suggest that the beneficial effect of imatinib in pulmonary hypertension may involve inhibition of PDGF tyrosine kinase receptor-mediated effects on smooth muscle cell proliferation and on vasoconstrictor tone. These results indicate that imatinib has nonselective vasodilator activity in the pulmonary and systemic vascular beds similar to the Rho kinase inhibitor fasudil and the calcium entry antagonist isradipine. The present results are consistent with the hypothesis that imatinib may inhibit a constitutively active tyrosine kinase vasoconstrictor pathway in the pulmonary and systemic vascular beds in the rat.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Benzamidas/farmacologia , Hipertensão Pulmonar/prevenção & controle , Monocrotalina , Piperazinas/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Pirimidinas/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/prevenção & controle , Mesilato de Imatinib , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiopatologia , Inibidores da Fosfodiesterase 4/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Vasoconstrição/efeitos dos fármacosRESUMO
Nitric oxide (NO) is the principal mediator of penile erection, and soluble guanylate cyclase (sGC) is the receptor for NO. In pathophysiological conditions when sGC is inactivated and not responsive to NO or sGC stimulators a new class of agents called sGC activators increase the activity of NO-insensitive sGC and produce erection. The aim of this study was to investigate erectile responses to BAY 60-2770, a sGC activator, under physiological and pathophysiological conditions. In the present study increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 60-2770 were investigated under baseline conditions, when sGC was inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), when nitric oxide synthase (NOS) was inhibited by N-nitro-L-arginine methyl ester (L-NAME), and after cavernosal nerve crush injury. Under baseline conditions ic injections of BAY 60-2770 increase ICP, ICP/mean arterial pressure (MAP), and area under the ICP curve (AUC) and produce small decreases in MAP at the highest doses studied. BAY 60-2770 was very potent in its ability to induce erection and responses to BAY 60-2770 were enhanced by ODQ which attenuates erectile responses to sodium nitroprusside (SNP), diethylamine NONOate (DEA/NO), and cavernosal nerve stimulation. Responses to BAY 60-2770 were not altered by L-NAME or cavernosal nerve crush injury. These data indicate that BAY 60-2770 has potent erectile activity that is enhanced by ODQ and show that responses to BAY 60-2770 are not attenuated by NOS inhibition or cavernosal nerve injury. These results suggest that BAY 60-2770 would be effective in the treatment of erectile dysfunction when NO bioavailability is reduced, after pelvic nerve injury, and when sGC is oxidized.
Assuntos
Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Ereção Peniana/efeitos dos fármacos , Animais , Benzoatos/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Guanilato Ciclase , Hidrazinas/farmacologia , Hidrocarbonetos Fluorados/administração & dosagem , Injeções , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Compressão Nervosa , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroprussiato/farmacologia , Oxidiazóis/farmacologia , Pênis/inervação , Nervos Periféricos/fisiologia , Nervos Periféricos/cirurgia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/agonistas , Guanilil Ciclase SolúvelRESUMO
INTRODUCTION: Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) and in pathophysiologic conditions where NO formation or bioavailability is impaired, erectile dysfunction (ED) occurs. AIM: The aim of this study was to investigate erectile responses to the sGC stimulator BAY 41-8543 in physiologic and pathophysiologic conditions. METHODS: Increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 41-8543 were investigated in the anesthetized rat. MAIN OUTCOME MEASURES: Increases in ICP/MAP in response to ic injections of BAY 41-8543 and the interaction of BAY 41-8543 with exogenous and endogenously released NO were investigated and the effect of the sGC stimulator on cavernosal nerve injury was assessed. The mechanism of the increase in ICP/MAP in response to ic injection of acetylcholine was investigated. RESULTS: The ic injections of BAY 41-8543 increased ICP/MAP and the duration of the response. BAY 41-8543 was less potent than sodium nitroprusside (SNP) and ic injections of BAY 41-8543 and SNP produced a larger response than the algebraic sum of responses to either agent alone. Simultaneous ic injection of BAY 41-8543 and cavernosal nerve stimulation produced a greater response than either intervention alone. Atropine and cavernosal nerve crush injury decreased the response to nerve stimulation and ic injection of BAY 41-8543 restored the response. CONCLUSION: These data show that BAY 41-8543 has significant erectile activity and can synergize with exogenous and endogenously released NO. This study shows that atropine and nerve crush attenuate the response to cavernosal nerve stimulation and that BAY 41-8543 can restore the response. The results with atropine, L-NAME and hexamethonium indicate that the response to ic injection of acetylcholine is mediated by muscarinic receptors and the release of NO with no significant role for nicotinic receptors. These results suggest that BAY 41-8543 would be useful in the treatment of ED.
Assuntos
Estimulação Elétrica , Morfolinas/farmacologia , Ereção Peniana/efeitos dos fármacos , Pênis/inervação , Pirimidinas/farmacologia , Acetilcolina/farmacologia , Animais , Atropina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Agonistas Colinérgicos/farmacologia , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hexametônio/farmacologia , Injeções , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Antagonistas Nicotínicos/farmacologia , Doadores de Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Parassimpatolíticos/farmacologia , Traumatismos dos Nervos Periféricos , Ratos , Ratos Sprague-DawleyRESUMO
Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60 mg; daily ip injections of sodium nitrite (3mg/kg) starting on day 14 and continuing for 21 days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21 days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is effective in the treatment of monocrotaline-induced PH in the rodent.
Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Nitrito de Sódio/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/patologia , Hipertrofia Ventricular Direita/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pulmão/patologia , Monocrotalina , Morfolinas , Óxido Nítrico/metabolismo , Nitroprussiato , Pirimidinas , Ratos , Ratos Sprague-Dawley , Túnica Média/efeitos dos fármacos , Túnica Média/patologiaRESUMO
It has been reported that sodium nitrite (NaNO2) can act as a storage form of nitric oxide (NO) that can have beneficial pharmacologic actions. The present study was undertaken to investigate the effects of NaNO2 on erectile function in the rat. The intracavernosal (i.c.) injection of NaNO2 produced dose-related increases in i.c. pressure and decreases in systemic arterial pressure. NaNO2 was 1000-fold less potent than sodium nitroprusside in increasing i.c. pressure. Increases in i.c. pressure in response to NaNO2 were attenuated by the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME). The increases in i.c. pressure in response to NaNO2 were not altered by the xanthine oxidoreductase inhibitor allopurinol. The decreases in systemic arterial pressure in response to i.c. injections of NaNO2 were attenuated by allopurinol and were either unchanged or increased by L-NAME. These data suggest that NaNO2 is converted to vasoactive NO in the corpora cavernosum and systemic vascular bed of the rat by different mechanisms. The present data suggest that the conversion of NaNO2 to vasoactive NO is mediated by NOS in the corpora cavernosum and by xanthine oxidoreductase in the systemic vascular bed of the rat. These data show NaNO2 can serve as a NO donor that increases erectile activity in the rat.
Assuntos
Disfunção Erétil/tratamento farmacológico , Ereção Peniana/efeitos dos fármacos , Nitrito de Sódio/administração & dosagem , Alopurinol/administração & dosagem , Animais , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Disfunção Erétil/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/administração & dosagem , Doadores de Óxido Nítrico/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroprussiato/administração & dosagem , Ereção Peniana/fisiologia , Pênis/irrigação sanguínea , Pênis/efeitos dos fármacos , Pênis/fisiologia , Ratos , Ratos Sprague-Dawley , Vasodilatadores/administração & dosagemRESUMO
TARGET POPULATION: Adult patients (older than 18 yr of age) with newly diagnosed brain metastases. QUESTION: If whole brain radiation therapy (WBRT) is used, is there an optimal dose/fractionation schedule? RECOMMENDATIONS: Level 1: A standard WBRT dose/fractionation schedule (ie, 30 Gy in 10 fractions or a biological equivalent dose [BED] of 39 Gy10) is recommended as altered dose/fractionation schedules do not result in significant differences in median survival or local control. Level 3: Due to concerns regarding neurocognitive effects, higher dose per fraction schedules (such as 20 Gy in 5 fractions) are recommended only for patients with poor performance status or short predicted survival. Level 3: WBRT can be recommended to improve progression-free survival for patients with more than 4 brain metastases. QUESTION: What impact does tumor histopathology or molecular status have on the decision to use WBRT, the dose fractionation scheme to be utilized, and its outcomes? RECOMMENDATIONS: There is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology. Molecular status may have an impact on the decision to delay WBRT in subgroups of patients, but there is not sufficient data to make a more definitive recommendation. QUESTION: Separate from survival outcomes, what are the neurocognitive consequences of WBRT, and what steps can be taken to minimize them? RECOMMENDATIONS: Level 2: Due to neurocognitive toxicity, local therapy (surgery or SRS) without WBRT is recommended for patients with ≤4 brain metastases amenable to local therapy in terms of size and location. Level 2: Given the association of neurocognitive toxicity with increasing total dose and dose per fraction of WBRT, WBRT doses exceeding 30 Gy given in 10 fractions, or similar biologically equivalent doses, are not recommended, except in patients with poor performance status or short predicted survival. Level 2: If prophylactic cranial irradiation (PCI) is given to prevent brain metastases for small cell lung cancer, the recommended WBRT dose/fractionation regimen is 25 Gy in 10 fractions, and because this can be associated with neurocognitive decline, patients should be told of this risk at the same time they are counseled about the possible survival benefits. Level 3: Patients having WBRT (given for either existing brain metastases or as PCI) should be offered 6 mo of memantine to potentially delay, lessen, or prevent the associated neurocognitive toxicity. QUESTION: Does the addition of WBRT after surgical resection or radiosurgery improve progression-free or overall survival outcomes when compared to surgical resection or radiosurgery alone? RECOMMENDATIONS: Level 2: WBRT is not recommended in WHO performance status 0 to 2 patients with up to 4 brain metastases because, compared to surgical resection or radiosurgery alone, the addition of WBRT improves intracranial progression-free survival but not overall survival. Level 2: In WHO performance status 0 to 2 patients with up to 4 brain metastases where the goal is minimizing neurocognitive toxicity, as opposed to maximizing progression-free survival and overall survival, local therapy (surgery or radiosurgery) without WBRT is recommended. Level 3: Compared to surgical resection or radiosurgery alone, the addition of WBRT is not recommended for patients with more than 4 brain metastases unless the metastases' volume exceeds 7 cc, or there are more than 15 metastases, or the size or location of the metastases are not amenable to surgical resection or radiosurgery.The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_3.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/radioterapia , Irradiação Craniana/normas , Fracionamento da Dose de Radiação , Neurocirurgiões/normas , Guias de Prática Clínica como Assunto/normas , Adulto , Encéfalo/efeitos da radiação , Neoplasias Encefálicas/cirurgia , Congressos como Assunto/normas , Irradiação Craniana/métodos , Feminino , Humanos , Masculino , Radiocirurgia/efeitos adversos , Radiocirurgia/normasRESUMO
OBJECTIVE Compressive cranial nerve syndromes can be useful bedside clues to the diagnosis of an enlarging intracranial aneurysm and can also guide subsequent evaluation, as with an acute oculomotor nerve (cranial nerve [CN] III) palsy that is presumed to be a posterior communicating artery aneurysm and a surgical emergency until proven otherwise. The CN VI has a short cisternal segment from the pontomedullary sulcus to Dorello's canal, remote from most PICA aneurysms but in the hemodynamic pathway of a rupturing PICA aneurysm that projects toward Dorello's canal. The authors describe a cranial nerve syndrome for posterior inferior cerebellar artery (PICA) aneurysms that associates subarachnoid hemorrhage (SAH) and an isolated abducens nerve (CN VI) palsy. METHODS Clinical and radiological data from 106 surgical patients with PICA aneurysms (66 ruptured and 40 unruptured) were retrospectively reviewed. Data from a group of 174 patients with other aneurysmal SAH (aSAH) were analyzed in a similar manner to control for nonspecific effects of SAH. Univariate statistical analysis compared incidence and risk factors associated with CN VI palsy in subarachnoid hemorrhage. RESULTS Overall, 13 (4.6%) of 280 patients had CN VI palsy at presentation, and all of them had ruptured aneurysms (representing 13 [5.4%] of the 240 cases of ruptured aneurysms). CN VI palsies were observed in 12 patients with ruptured PICA aneurysms (12/66 [18.1%]) and 1 patient with other aSAH (1/174 [0.1%], p < 0.0001). PICA aneurysm location in ruptured aneurysms was an independent predictor for CN VI palsy on multivariate analysis (p = 0.001). PICA aneurysm size was not significantly different in patients with or without CN VI palsy (average size 4.4 mm and 5.2 mm, respectively). Within the PICA aneurysm cohort, modified Fisher grade (p = 0.011) and presence of a thick cisternal SAH (modified Fisher Grades 3 and 4) (p = 0.003) were predictors of CN VI palsy. In all patients with ruptured PICA aneurysms and CN VI palsy, dome projection and presumed direction of rupture were directed toward the ipsilateral and/or contralateral Dorello's canal, in agreement with laterality of the CN palsy. In patients with bilateral CN VI palsies, a medial projection with extensive subarachnoid blood was observed near bilateral canals. CONCLUSIONS This study establishes a localizing connection between an isolated CN VI palsy, SAH, and an underlying ruptured PICA aneurysm. CN VI palsy is an important clinical sign in aSAH and when present on initial clinical presentation may be assumed to be due to ruptured PICA aneurysms until proven otherwise. The deficit may be ipsilateral, contralateral, or bilateral and is determined by the direction of the aneurysm dome projection and extent of subarachnoid bleeding toward Dorello's canal, rather than by direct compression.
Assuntos
Doenças do Nervo Abducente/etiologia , Aneurisma Roto/complicações , Doenças Cerebelares/complicações , Aneurisma Intracraniano/complicações , Hemorragia Subaracnóidea/complicações , Doenças do Nervo Abducente/diagnóstico por imagem , Doenças do Nervo Abducente/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneurisma Roto/diagnóstico por imagem , Aneurisma Roto/cirurgia , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/cirurgia , Revascularização Cerebral/métodos , Estudos de Coortes , Embolização Terapêutica , Feminino , Humanos , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/cirurgia , Masculino , Pessoa de Meia-Idade , Paralisia/diagnóstico por imagem , Paralisia/etiologia , Paralisia/cirurgia , Estudos Retrospectivos , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/cirurgia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto JovemRESUMO
As the population ages, the question of how to manage brain arteriovenous malformations in the elderly becomes increasingly relevant. Is resection a reasonable option for these patients? In this study, the authors examined the outcomes of surgical patients 60 years or older and found that favorable outcomes were achieved with careful patient selection. Preoperative grading scales were more predictive of outcomes in patients older than 65 years than in those 60-65 years of age.
Assuntos
Encéfalo/cirurgia , Malformações Arteriovenosas Intracranianas/cirurgia , Microcirurgia/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Estudos Retrospectivos , Medição de Risco , Resultado do TratamentoRESUMO
OBJECTIVEBrain arteriovenous malformations (bAVMs) are rupture-prone tangles of blood vessels with direct shunting of blood flow between arterial and venous circulations. The molecular and/or cellular mechanisms contributing to bAVM pathogenesis and/or destabilization in sporadic lesions have remained elusive. Initial insights into AVM formation have been gained through models of genetic AVM syndromes. And while many studies have focused on endothelial cells, the contributions of other vascular cell types have yet to be systematically studied. Pericytes are multifunctional mural cells that regulate brain angiogenesis, blood-brain barrier integrity, and vascular stability. Here, the authors analyze the abundance of brain pericytes and their association with vascular changes in sporadic human AVMs.METHODSTissues from bAVMs and from temporal lobe specimens from patients with medically intractable epilepsy (nonvascular lesion controls [NVLCs]) were resected. Immunofluorescent staining with confocal microscopy was performed to quantify pericytes (platelet-derived growth factor receptor-beta [PDGFRß] and aminopeptidase N [CD13]) and extravascular hemoglobin. Iron-positive hemosiderin deposits were quantified with Prussian blue staining. Syngo iFlow post-image processing was used to measure nidal blood flow on preintervention angiograms.RESULTSQuantitative immunofluorescent analysis demonstrated a 68% reduction in the vascular pericyte number in bAVMs compared with the number in NVLCs (p < 0.01). Additional analysis demonstrated 52% and 50% reductions in the vascular surface area covered by CD13- and PDGFRß-positive pericyte cell processes, respectively, in bAVMs (p < 0.01). Reductions in pericyte coverage were statistically significantly greater in bAVMs with prior rupture (p < 0.05). Unruptured bAVMs had increased microhemorrhage, as evidenced by a 15.5-fold increase in extravascular hemoglobin compared with levels in NVLCs (p < 0.01). Within unruptured bAVM specimens, extravascular hemoglobin correlated negatively with pericyte coverage (CD13: r = -0.93, p < 0.01; PDGFRß: r = -0.87, p < 0.01). A similar negative correlation was observed with pericyte coverage and Prussian blue-positive hemosiderin deposits (CD13: r = -0.90, p < 0.01; PDGFRß: r = -0.86, p < 0.01). Pericyte coverage positively correlated with the mean transit time of blood flow or the time that circulating blood spends within the bAVM nidus (CD13: r = 0.60, p < 0.05; PDGFRß: r = 0.63, p < 0.05). A greater reduction in pericyte coverage is therefore associated with a reduced mean transit time or faster rate of blood flow through the bAVM nidus. No correlations were observed with time to peak flow within feeding arteries or draining veins.CONCLUSIONSBrain pericyte number and coverage are reduced in sporadic bAVMs and are lowest in cases with prior rupture. In unruptured bAVMs, pericyte reductions correlate with the severity of microhemorrhage. A loss of pericytes also correlates with a faster rate of blood flow through the bAVM nidus. This suggests that pericytes are associated with and may contribute to vascular fragility and hemodynamic changes in bAVMs. Future studies in animal models are needed to better characterize the role of pericytes in AVM pathogenesis.
Assuntos
Barreira Hematoencefálica/patologia , Encéfalo/patologia , Malformações Arteriovenosas Intracranianas/patologia , Pericitos/patologia , Doenças Vasculares/patologia , Adolescente , Adulto , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Criança , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Malformações Arteriovenosas Intracranianas/metabolismo , Masculino , Pessoa de Meia-Idade , Pericitos/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Doenças Vasculares/metabolismo , Adulto JovemRESUMO
OBJECTIVE: To investigate the effects of pioglitazone on pelvic ganglion neurons in a rat model of bilateral cavernosal nerve crush injury (BCNI), thereby elucidating the actions of pioglitazone in preventing post-prostatectomy neurogenic erectile dysfunction. METHODS: Sprague-Dawley rats aged 12 weeks were divided into four groups: (a) sham procedure, (b) BCNI, (c) BCNI + postsurgical pioglitazone, and (d) BCNI + pre and postsurgical pioglitazone (preventive therapy). Preoperative injection of Fluoro-Gold (FG) fluorescent tracer into the cavernosal tissue was performed for retrograde labeling of pelvic ganglion cells. Pelvic ganglia were resected at 2 weeks in all rats and processed for real-time polymerase chain reaction, immunohistochemistry, and Western blot to examine the expression of FG, neuronal nitric oxide synthase, ß-III tubulin, neurturin, and glial cell line-derived neurotrophic factor family receptor alpha-2 (GFRα2). RESULTS: Animals treated with pre- and postsurgical pioglitazone demonstrated increased staining for FG similar to sham levels. Gene expression of neuronal nitric oxide synthase, neurturin, GFRα2, and ß-III tubulin was also upregulated in the group receiving preventive therapy. CONCLUSION: Pioglitazone provides a protective effect on pelvic ganglion neurons after BCNI.
Assuntos
Regeneração Nervosa/efeitos dos fármacos , Pelve/inervação , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Animais , Sobrevivência Celular , Masculino , Neurônios/efeitos dos fármacos , Pelve/lesões , Pioglitazona , Ratos , Ratos Sprague-DawleyRESUMO
Premature ejaculation is one of the most prevalent sexual disorders affecting men today. The lack of approved therapies has resulted in the prescription of many 'off-label' treatments to manage the condition. Selective serotonin reuptake inhibitors have an interesting side effect of prolonging ejaculatory latency. Consequently, these agents are often considered a first line treatment for patients suffering from premature ejaculation. Erectile dysfunction is another common side effect reported by men treated with selective serotonin reuptake inhibitors. Nitric oxide is the primary mediator of erectile function. Preclinical studies have provided evidence that selective serotonin reuptake inhibitors decrease nitric oxide bioavailability. This invited mini-review aims to examine the physiology of the erectile and ejaculatory responses, discuss the indicated and 'off-label' clinical utility of selective serotonin reuptake inhibitors, and to summarize evidence from basic science and clinical studies pertaining to mechanisms of how selective serotonin reuptake inhibitor therapy modifies ejaculatory and erectile function.
Assuntos
Ejaculação Precoce/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Ejaculação/fisiologia , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Ereção Peniana/fisiologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversosRESUMO
OBJECTIVE: To examine the effect of pioglitazone on erectile function in a rat model of postprostatectomy erectile dysfunction. METHODS: Twenty adult rats were divided into 4 groups: (a) sham, (b) control--bilateral cavernosal nerve crush injury (BCNI), (c) BCNI + low-dose pioglitazone (PioL), and (d) BCNI + high-dose pioglitazone (PioH). Sham and control rats were administered phosphate-buffered saline, whereas PioL and PioH rats received 0.65 and 6.5 mg/kg of pioglitazone, respectively. All treatments were administered by oral gavage for 14 days. After treatment, animals underwent surgery for endpoint cavernosal response to define hemodynamic parameters of erectile function, reported as the ratio of intracavernosal pressure to mean arterial pressure. Corporal tissue was retrieved for histologic and molecular analysis. RESULTS: Animals treated with pioglitazone experienced dose-dependent improvements in the ratio of intracavernosal pressure to mean arterial pressure, with the PioH group achieving results similar to the sham group: sham, 0.774; BCNI, 0.421; PioL, 0.616; PioH, 0.758 (P = .0006). PioH animals demonstrated increased expression of endothelial nitric oxide (eNOS) and neuronal nitric oxide (nNOS), whereas both PioL and PioH animals had increased staining for anti--smooth muscle actin antibody and nonsignificant increases in cyclic guanosine monophosphate (cGMP). CONCLUSION: Pioglitazone improves erectile function in rats undergoing BCNI via a nitric oxide--mediated pathway.
Assuntos
Disfunção Erétil/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Animais , Pressão Arterial , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hemodinâmica , Masculino , Microscopia de Fluorescência , Músculo Liso/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ereção Peniana/efeitos dos fármacos , Pênis/efeitos dos fármacos , Pênis/fisiologia , Pioglitazona , Ratos , Resultado do TratamentoRESUMO
Nitric oxide is a potent vasodilator that plays a critical role in disorders of erythrocyte function. Sickle cell disease, paroxysmal nocturnal hemoglobinuria and banked blood preservation are three conditions where nitric oxide is intimately related to dysfunctional erythrocytes. These conditions are accompanied by hemolysis, thrombosis and vasoocclusion. Our understanding of the interaction between nitric oxide, hemoglobin, and the vasculature is constantly evolving, and by defining this role we can better direct trials aimed at improving the treatments of disorders of erythrocyte function. Here we briefly discuss nitric oxide's interaction with hemoglobin through the hypothesis regarding Snitrosohemoglobin, deoxyhemoglobin, and myoglobin as nitrite reductases. We then review the current understanding of the role of nitric oxide in sickle cell disease, paroxysmal nocturnal hemoglobinuria, and banked blood, and discuss therapeutics in development to target nitric oxide in the treatment of some of these disorders.
Assuntos
Eritrócitos/metabolismo , Eritrócitos/patologia , Doenças Hematológicas/sangue , Doenças Hematológicas/patologia , Óxido Nítrico/sangue , Animais , Ensaios Clínicos Fase II como Assunto , Hemoglobinas/metabolismo , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVE: To investigate the erectile and cardiovascular responses to the tyrosine kinase inhibitor imatinib in the rat. MATERIALS AND METHODS: The effect of intracavernosal injection of imatinib on the intracavernosal pressure (ICP), ICP/mean arterial pressure (MAP) ratio, area under the curve, and duration of the increase in ICP and the effect of intravenous injection of imatinib on the MAP, cardiac output, and total peripheral resistance were investigated. The effect of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on the responses to imatinib was investigated. RESULTS: Intracavernosal injection of imatinib produced significant dose-related increases in the ICP, ICP/MAP ratio, area under the curve, and duration of the increase in ICP and decreases in the MAP. The erectile responses to imatinib were rapid in onset and short in duration. The erectile responses to imatinib were not significantly altered by NG-nitro-L-arginine methyl ester or cavernosal nerve crush injury, and imatinib was significantly less potent than the nitric oxide donor sodium nitroprusside in inducing erection. Intravenous injection of imatinib produced significant dose-related decreases in the MAP without significantly changing the cardiac output, and imatinib was significantly less potent than sodium nitroprusside in decreasing the MAP. Systemic vascular resistance was decreased in a significant dose-related manner, and the vasodilator responses to imatinib were not altered by NG-nitro-L-arginine methyl ester. CONCLUSION: The present results have indicated that imatinib has significant erectile and systemic vasodilator activity in the rat that is not dependent on nitric oxide release. Another tyrosine kinase inhibitor, nilotinib, also increased the ICP and decreased the MAP in the rat. These data suggest that tyrosine kinases might play a constitutive role in maintaining penile tumescence and the baseline vasoconstrictor tone in the peripheral vascular bed.