For many years, the role of testosterone has been perceived to play a role in the development of prostate cancer and certain cardiovascular diseases (Jones et al., 2013); with its general therapeutic roles being much overlooked. Much of this unprecedented assumption was based upon clinical observations showing the benefit of androgen deprivation in prostate cancer patients, and the perceived reports of higher cardiovascular death amongst people abusing steroid therapies (Jones et al., 2013; Basaria et al., 2010). However, there has been compelling evidence that suggests that testosterone administration within physiological ranges does not contribute to prostate cancer or the pathogenesis of cardiovascular disease (Morgentaler et al., 2009; Jones et al., 2013; Traish et al., 2009). Recent evidence actually suggests the protective role of androgens in the management of metabolic conditions, such as: obesity, metabolic syndrome, and type-2 diabetes mellitus, all of which are known to increase the risk of cardiovascular disease (Traish et al., 2009; Morgentaler et al., 2009; Wang et al., 2000). Erectile dysfunction, which is a type of endothelial dysfunction disorder, is defined as the persistent inability to achieve or maintain an erection for satisfactory sexual performance, and it affects an estimated 30 million American men between the ages of 40 to 70 years old, and this prevalence increases with age (Nehra A, 2007; Barkin J, 2011; Guay A, 2007). The male human erection involves a multifactorial interplay between various mechanisms within the body; encompassing psychological, vascular, neural and endocrine factors (Dean et al., 2005; Castela et al, 2011). The human erection involves the increased inflow of blood into the penile arteries, and the subsequent veno-occlusion, all of which occurs at a perfectly orchestrated hormonal environment (Bivalacqua et al, 1998; Castela et al., 2011). Nitric oxide is released from the endothelium, which dilates penile arteries and relaxes the penile smooth muscles, causing the corpora cavernosa of the penis to fill with blood; the ischiocavernosus and bulbospongiosus muscles then compress the veins, which restricts the egress of blood (Bivalacqua et al, 1998; Castela et al., 2011). Nitric oxide increases cGMP, which decreases intracellular calcium uptake, and increases K+ efflux; these all cause a smooth muscle cell relaxation. The decreased venous outflow from the penis helps maintain erection. In addition to nitric oxide, several other mechanisms are involved in the erectile response. The endothelium, which regulates vascular tone and blood flow, is responsible for the cholinergic smooth muscle relaxation observed by the addition of acetylcholine (Furchgott et al., 1983). Chamness et al. (1995) have shown that androgen differentially affects nitric oxide synthase activity in the male reproductive tract endothelium. Thus, the role of androgens, namely testosterone, is of importance in maintaining erectile function. In addition to affecting nitric oxide synthase activity, testosterone is also shown to affect erectile physiology in many more ways, including its role in activating K+ channels to increase the efflux or inhibit calcium channels via hyperpolarization (Yildiz et al., 2009), and even increasing arterial blood flow to the penis (Aversa et al., 2000). Interestingly, testosterone also modulates endothelial function. Endothelial progenitor cells are responsible for the regeneration of the endothelium. The area of study of these progenitor cells is relatively new, thus, it is important to evaluate how they affect endothelial function. Since erectile dysfunction is a form of endothelial dysfunction, it has been found that patients with erectile dysfunction had significantly lower levels of circulating progenitor cells than patients with a normal erectile function (Baumhäkel et al., 2006). Endothelial cells in the penile arteries play a critical role in regulating the physiological function of the erectile response in humans. Modulation of the endothelium in the penis by androgens, thus, is a critical area of research that must be further addressed.

Submitted by Natalia Vieira (natalia.vieira@famerp.br) on 2016-05-19T21:52:28Z No. of bitstreams: 1 anacarolinadeabreu_dissert.pdf: 490120 bytes, checksum: 25e56f07305d458ef011d69e87061a78 (MD5) / Made available in DSpace on 2016-05-19T21:52:28Z (GMT). No. of bitstreams: 1 anacarolinadeabreu_dissert.pdf: 490120 bytes, checksum: 25e56f07305d458ef011d69e87061a78 (MD5) Previous issue date: 2015-12-14 / Since ancient times to nowadays, the Erectile Dysfunction has been considered a condition that has always affected men. It has been not only a reason for embarrassment, but also an issue of multifactorial cause related either to psychological or organic and drug factors. For this reason, a significant impact can be observed on the individuals quality of life and their partners while this is associated with low self-esteem, depression, difficult relationship and increased anxiety. As this issue is currently a bioethical matter, it is feasible and necessary to be solved. Its main focus is the principle of life protection; introduced into the Ethics of scientific progress and outlining the guiding and protective limits of the person. There is also the autonomy of the individual's will which has valued the man according to his own individuality as a human being with rationality and liberty. The majority of individuals are not well informed. They search also for easier or less embarrassing ways for treatment and solutions. As a result, it is up to them to choose, "searching for a skilled professional", or a searching for Websites, mysticisms and charlatan. Thus, this study by means of a search on databases such as Pubmed Index, Google and Google Scholar shows publications and data research approaching Erectile Dysfunction from 1930 to today. / Desde os tempos antigos até os dias de hoje, a Disfunção Erétil tem sido considerada uma condição que sempre afetou os homens. É não só um motivo para constrangimento, mas também uma questão de causa multifatorial e tem relação tanto a fatores, psicológicos, biológicos ou medicamentosos. Por esta razão, um impacto significativo pode ser observado na qualidade de vida dos indivíduos e suas parceiras e assim associada à diminuição da autoestima, depressão, difícil relacionamento e aumento da ansiedade. Como esta questão é atualmente de caráter bioético, torna-se oportuna e necessária para ser solucionada, esta nova ciência da vida. Seu foco principal é o princípio da proteção da vida; introduzido na ética do progresso científico e delineando os limites orientadores e protetores à pessoa. Há também a autonomia da vontade do indivíduo que tem valorizado cada um, segundo, a sua própria individualidade como um ser humano com racionalidade e a liberdade. A maioria dos indivíduos não está bem informada. Eles procuram formas mais fáceis ou menos embaraçosas para o tratamento e soluções. Como resultado, cabe-lhes escolher, “pela busca de um profissional capacitado", ou uma busca em sites, misticismos e popularismo. Assim, este estudo por meio de uma pesquisa em bases de dados indexadoras como Pubmed, Google e Google Scholar mostra publicações e dados de pesquisa sobre Disfunção Eréctil de 1930 até os dias atuais.

Σκοπός: 1) Η μελέτη της επίπτωσης της στυτικής δυσλειτουργίας σε ασθενείς με σύνδρομο επικάλυψης ( ΣΑΑΥ και ΧΑΠ ) και η συγκρισή της με την επίπτωση της στυτικής δυσλειτουργίας σε ασθενείς που παρουσίαζαν μόνο ΣΑΑΥ, και 2) η εκτίμηση της βελτίωσης της στυτικής δυσλειτουργίας (ED) σε άνδρες με σύνδρομο επικάλυψης (αποφρακτική άπνοια του ύπνου και χρόνια αποφρακτική πνευμονοπάθεια) υπό θεραπεία με cPAP (συνεχής θετική πίεση αεραγωγών) και βρογχοδιασταλτικά. Υλικό και μέθοδος : Μελετήθηκαν 48 άνδρες με μέσο όρο ηλικίας τα 52.8 + 10 χρόνια με αποφρακτική άπνοια του ύπνου (ΣΑΑΥ) και χρόνια αποφρακτική πνευμονοπάθεια (ΧΑΠ) και παράλληλα στυτική δυσλειτουργία ED. Επίσης 30 άνδρες με στυτική δυσλειτουργία και ΣΑΑΥ χωρίς αποφρακτική νόσο. Έλαβαν την κατάλληλη θεραπεία για αποφρακτική πνευμονοπάθεια (cPAP και βρογχοδιασταλτικά) για 6 μήνες και έπειτα το επίπεδο της στυτικής λειτουργίας (EF) επανεκτιμήθηκε. Η ED θεωρήθηκε ότι βελτιώθηκε εάν ο βαθμός βελτίωσης (score) αυξήθηκε για τουλάχιστον 5 μονάδες σε σύγκριση με αυτό της βασικής τιμής. Οι καθοριστικοί παράγοντες για βελτίωση της ED επίσης εκτιμήθηκαν, καθώς επίσης και ο βαθμός ικανοποίησης του κάθε ασθενή κατά τη διάρκεια της θεραπείας Αποτελέσματα : Η επίπτωση της ED σε ασθενείς με σύνδρομο επικάλυψης ήταν 81,08%. Η επίπτωση της ED σε ασθενείς πάσχοντες από ΣΑΑΥ και ED ήταν 29,17%. Η ED βελτιώθηκε σε 12 ασθενείς (25%), αλλά μόνο τα 2 /3 αυτών ήταν ικανοποιημένοι με τον βαθμό βελτίωσης μετά από θεραπεία. Η βελτίωση της ED συσχετίστηκε θετικά με την ηλικία, δείκτη άπνοιας / υπόπνοιας και αρνητικά με την διάρκεια της ED. Το score της ED, ο κορεσμός της αιμοσφαιρίνης σε Ο2 κατά τη διάρκεια της νύχτας και το BMI δεν συσχετίστηκαν σημαντικά με το βαθμό βελτίωσης της EF. Συμπεράσματα : 1) Η επίπτωση της ED σε ασθενείς με σύνδρομο επικάλυψης είναι μεγαλύτερη συγκριτικά με αυτή των ασθενών που έπασχαν μόνο από ΣΑΑΥ και συγκριτικά με το γενικό πληθυσμό. 2) Η συνήθης θεραπεία σε ασθενείς με ΣΑΑΥ και ΧΑΠ με βρογχοδιασταλτικά και cPAP έχει θετικά αποτελέσματα στην παράλληλη ED στην μειονότητα των ασθενών αυτών. Από τους άνδρες που βελτιώθηκαν, 1/3 από αυτούς δεν ήταν ικανοποιημένοι με το αποτέλεσμα αυτής της θεραπείας. Διαφορετική θεραπευτική αντιμετώπιση ή συνδυασμός αγωγής θα πρέπει πιθανά να χορηγηθεί στους ασθενείς αυτούς. / Aim: 1) To determine the prevalence of erectile dysfunction in patients with overlap syndrome (obstructive sleep apnea and chronic obstructive pulmonary disease) compared with patients suffered from sleep apnea syndrome and erectile dysfunction and 2)To assess the improvement of concurrent erectile dysfunction (ED) in these patients treated with continuous positive airway pressure (cPAP) and bronchodilators Material and Methods: We evaluated 48 men suffering from OSA, COPD and concurrent ED, and 30 men suffered from OSA and ED. They were treated with conventional therapy for pulmonary obstructive disease (cPAP and bronchodilators) for 6 months and then their erectile function status was reassessed. ED was considered as improved, if ED intensity score increased for at least five points compared to that of baseline. Results: The prevalence of ED in patients with overlap syndrome was 81,08%. The prevalence of ED in men with OSA was 29,17%. ED was improved in 12 patients (25%), but only two thirds of them were satisfied with the grade of improvement after treatment. ED improvement was related positively with age and apnea/hypopnea index and negatively with ED duration. ED intensity score, O2 saturation at night and BMI were not significantly related to the outcome of EF improvement. Conclusions: 1) The prevalence of ED in patients with overlap syndrome was higher compared with the prevalence of ED in men with OSA. 2) Conventional treatment for OSA and COPD, has a positive effect on concurrent ED on the minority of patients. The effect is possibly due to the improvement of respiration during sleep with cPAP and of oxygenation with bronchodilators continuously

Η στυτική δυσλειτουργία είναι ιδιαίτερα διαδομένη σε άνδρες προχωρημένης ηλικίας και έχει σημαντική επίπτωση στην ποιότητα ζωής και στις διαπροσωπικές σχέσεις που αναπτύσσονται μεταξύ ενός ζευγαριού. Ωστόσο, πολλοί άνδρες λόγω ντροπής αλλά και έλλειψης γνώσεων για τη φύση του προβλήματος είναι επιφυλακτικοί στην αναζήτηση ιατρικής βοήθειας. Είναι πολύ πιθανό να καταφύγουν στη λήψη φαρμάκων χωρίς σύνεση στη χρήση, κατάλληλη ενημέρωση και αξιολόγηση της κατάστασης της υγείας τους. Στη μελέτη που πραγματοποιήσαμε, οι ασθενείς σε χώρους φαρμακείων συμπλήρωσαν ένα ερωτηματολόγιο. Ένα μεγάλο ποσοστό του δείγματος ανιχνεύτηκε με στυτική δυσλειτουργίας κυρίως ήπιας μορφής. Σε όλες τις περιπτώσεις παθολογικών καταστάσεων είχαμε και πιο έντονη την εμφάνιση στυτικής δυσλειτουργίας, χωρίς όμως να προκύπτει -λόγω πληθυσμού του δείγματος- κάποια σχέση μεταξύ αυτών των μεταβλητών. Οι ασθενείς έδειξαν εμπιστοσύνη στο πρόσωπο του φαρμακοποιού καθώς τον προσεγγίζουν με άνεση ακόμα και από την πρώτη στιγμή που αποφασίζουν να μιλήσουν για το πρόβλημα στύσης τους. Συνεπώς, ο ρόλος που καλείται να παίξει ο φαρμακοποιός ως επαγγελματίας υγείας αποκτά βαρύνουσα σημασία τόσο για την πληροφόρηση που παρέχει όσο και για την αξιολόγηση της κατάστασης του ασθενούς. / -

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Estudos anteriores demonstraram que uma fraÃÃo rica (F(3-5)) em alcalÃides indÃlicos extraÃda das cascas da raiz de Aspidosperma ulei Markgr. exibe funÃÃo prÃ-eretil in vivo e relaxamento em corpos cavernosos de coelhos in vitro. Um estudo recente demonstrou que 17-nor-subincanadina E (SEC), um alcalÃide extraÃdo das cascas do caule da mesma planta, apresentou atividade prÃ-eretil in vivo. O presente trabalho teve por objetivo avaliar o efeito desse alcalÃide sobre o tÃnus de diferentes tipos de musculatura lisa de coelhos e investigar o mecanismo de aÃÃo da substancia sobre o mÃsculo liso cavernoso in vitro. Os tecidos foram montados em banhos de 5 ml contendo soluÃÃo de Krebs-Henseleit (CO2 5% - O2 95%; 37ÂC). A resposta relaxante mÃxima induzida por SEC (1 â 100 Âg/ml) em segmentos de corpos cavernosos de coelhos contraÃdos com fenilefrina (PHE-10&#956;M) foi de 100%, e apresentou um efeito relaxante preferencial para esse tecido, IC50[7, 174 (3,155 - 16,31) &#956;g/ml]. SEC promoveu tambÃm relaxamento em anÃis de aorta na presenÃa e na ausÃncia de endotÃlio, IC50[29,76 (90,32 â 115,6) &#956;g/ml] e IC50[26,13 (75,83 â 119,9) &#956;g/ml], respectivamente, anÃis de traquÃia IC50[60,25 (0,330 â 109,8) &#956;g/ml] e em segmentos de duodeno IC50[76,78 (33,09 â 178,2) &#956;g/ml]. O relaxamento induzido por SEC (1 â 100 Âg/ml) nÃo foi afetado por bloqueadores adrenÃrgicos (fentolamina e guanetidina), muscarÃnicos (atropina), ou bloqueadores dos canais de potÃssio dependentes de ATP (KATP)(glibenclamida) e ativados por cÃlcio (Kca) (apamina e iberiotoxina) e nem na presenÃa de L-NAME; a adiÃÃo de ODQ (30 ÂM) bloqueou o relaxamento induzido por SEC (79,1%  4,5%; p<0,05). Observou-se tambÃm um aumento dos nÃveis teciduais de AMPc (331,95%  26,1%; p<0,05) e GMPc (21,5%  4,2%; p<0,05). SEC (10 Âg/ml e 30 Âg/ml) potencializou o relaxamento induzido por gliceriltrinitrato (GTN) e forskolina (FK) e foi capaz de diminuir o relaxamento induzido pela estimulaÃÃo por campo elÃtrico (ECE) (65,0%  10,9%; p< 0,05). SEC 15 &#956;g/ml bloqueou a contraÃÃo induzida por CaCl2 1 - 300 mM em corpos cavernosos de coelhos prÃ-contraÃdos com K+ (40 mM), 0 Ca++. Nossos resultados indicam que SEC manifesta atividade relaxante preferencial no mÃsculo liso cavernoso a nÃvel perifÃrico e que esse efeito està aparentemente relacionado com um aumento dos nÃveis de AMPc e GMPc e um possÃvel bloqueio do fluxo de cÃlcio. Estes dados sugerem que Aspidosperma ulei Markgf. pode ser explorada como uma alternativa para o tratamento da disfunÃÃo erÃtil. / Past studies have shown that the indole alkaloidal rich fraction (F(3-5)) from Aspidosperma ulei Markgr. root bark displays pro-erectile function in vivo and a relaxant effect on isolated rabbit corpus cavernosum in vitro. Also, a recent study demonstrated the in vivo pro-erectile like activity of 17-nor-subincanadina E (SEC), an alkaloid isolated from stem bark of this plant. This study aimed to assess further the effect of SEC on the smooth muscle tone (spontaneous or induced) in vitro, utilizing the strips of tracheal, intestinal, vascular and corpus cavernosal tissues of rabbits. An attempt was also made to study the possible mechanism of SEC on rabbit corpus cavernosum (RbCC). RbCC strips, were mounted in organ baths containing Krebs solution. After equilibration, the tissues were precontracted with phenylephrine (10 ÂM) or potassium (40mM). SEC (1-100 &#956;g/ml) caused a concentration dependent relaxation in the isolated rabbit corpus cavernosum precontracted with phenylephrine and displayed comparatively greater relaxant effect on corpus cavernosum IC50 [7,174 (3,155-16,31) &#956;g/ml], SEC produced concentration-dependent relaxations of the aortic rings in endothelium intact and denuded IC50[29,76 (90,32â115,6) &#956;g/ml] and IC50[ 26,13 (75,83â119,9) &#956;g/ml], respectively, trachea rings IC50[60,25 (0,330-109,8) &#956;g/ml], and of spontaneous motility in segments of duodenum IC50[76,78 (33,09â178,2) &#956;g/ml]. The relaxant effect of SEC (1-100 Âg/ml) on phenylephrine contraction was unaffected in the presence of adrenergic blockers (phentolamine and guanethidine), muscarinic blocker (atropine), KATP channel blocker (glibenclamide), Ca2+-dependent K+ channel blockers (apamin and iberiotoxin), and in the presence of N-omega-nitro-L-arginine methyl ester (L-NAME 100 ÂM)). However, the SEC relaxation was significantly attenuated by ODQ (30 &#956; M) (79.1%Â4.5%, p <0.05). Incubations of RbCC with SEC (10 and 30 Âg/mL) caused significant increases of cGMP (21.5%Â4.2%, p <0.05) and cAMP (331.95%Â26.1%, p <0.05) levels. Preincubation with SEC (10 and 30 ÂM) also significantly enhanced the relaxation response to the exogenous NO-donor (GTN) and an activator of adenyl cyclase (forskolin). the relaxations evoked by electrical stimulation was significantly decreased by SEC (10 Âg/mL) (65.0%Â10.9%, p <0.05). The phasic component of the contraction induced by K+ 40 mM as well as the maximal contraction elicited by increasing external Ca2+ concentrations in depolarized corpora cavernosa was inhibited by SEC (15 Âg/mL). Our results indicate that SEC can induce comparatively a greater relaxant effect on rabbit cavernosal tissue in vitro via a mechanism that involves an increase of cAMP and cGMP levels and a blocking effect on calcium flux. These data suggest that Aspidiosperma ulei Markgr. can be explored as an alternative for the treatment of erectile dysfunction.

Orientadores: Gilberto de Nucci, Fabíola Taufic Monica Iglesias / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T01:00:31Z (GMT). No. of bitstreams: 1 Rodrigues_RenataLopes_M.pdf: 1896765 bytes, checksum: 79601ac40320374fce18c0c0436647a0 (MD5) Previous issue date: 2013 / Resumo: O fato da cópula em serpentes ser muito prolongada, chegando a mais de 20 horas, sem que os mecanismos farmacológicos estejam conhecidos, motivou o nosso grupo a estudar o hemipênis de Crotalus durissus terrificus (cascavel). Diferentemente do observado em corpo cavernoso de outros mamíferos, o relaxamento induzido pela estimulação elétrica foi mais duradouro, além de resistente a ação da neurotoxina tetrodotoxina (TTX) em hemipênis de Crotalus. Uma hipótese inicial aventada foi que este canal, cuja cinética de abertura e fechamento é mais lenta, seria o responsável pelo relaxamento duradouro e, portanto, pelo coito mais prolongado. Baseado nestes resultados, e considerando que a resistência à TTX e duração prolongada também foram observadas na contração induzida pela estimulação elétrica, o objetivo do presente projeto foi caracterizar através de experimentos funcionais in vitro a contração mediada por agonistas ou pela estimulação elétrica. Os experimentos funcionais foram divididos em cinco etapas: 1) contração frente a noradrenalina, adrenalina e dopamina; contração frente a estimulação elétrica ou fenilefrina na presença de 2) tetrodotoxina (TTX), fentolamina e guanetidina; 3) neurotoxinas seletivas para os canais de sódio ou cálcio dependentes de voltagem; 4) após a troca de cloreto de sódio pela N-metil-D-glucamina (NMDG) e 5) determinação na noradrenalina triciada após estimulação elétrica em corpo cavernoso de Crotalus (CCC) e de coelho (RbCC). Em CCC todas as catecolaminas produziram contração dependente da concentração, sendo este efeito reduzido na presença de fentolamina. A estimulação elétrica induziu contração que foi dependente da frequência tanto em RbCC como em CCC, sendo esta contração devido, principalmente, à liberação de catecolaminas, uma vez que tanto a fentolamina como guanetidina praticamente aboliram esta resposta. Surpreendentemente, diferente de RbCC, em CCC a substituição equimolar de NaCl por N-metil-D-glucamina (NMDG) não causou nenhuma alteração na amplitude de contração frente a estimulação elétrica. Os anestésicos locais bupivacaína e ropivacaína reduziram significantemente a contração induzida pela estimulação elétrica em CCC e RbCC, enquanto a veratridina, um ativador deste canal, causou contração que foi dependente da liberação de catecolamina. Na presença das neurotoxinas GVIIA ou MVIIA pudemos observar uma redução de, aproximadamente, 50 % na contração induzida pela estimulação elétrica em CCC e RbCC. As toxinas para os canais de sódio ou cálcio não interferiram na contração induzida pela fenilefrina. Em relação aos experimentos com noradrenalina triciada não foi detectado nenhum sinal de radioatividade no sobrenadante de CCC após a estimulação elétrica, indicando a baixa sensibilidade do método ou a liberação de outra catecolamina. Por outro lado, em RbCC na presença de TTX, NMDG e na ausência de Ca+2 houve uma redução significativa na fração de [3H]-noradrenalina liberada após o estímulo elétrico, indicando a participação do influxo de sódio e de cálcio na neurotransmissão adrenérgica no RbCC. Os experimentos funcionais sugerem que em CCC a liberação de catecolaminas independe do influxo de sódio, porém é dependente do influxo de cálcio / Abstract: The snake's coitus may last up to 20 hours, although the pharmacological mechanism remains unknown. Conversely to mammalian corpus cavernosum (CC), the relaxation induced by electrical field stimulation (EFS) in Crotalus corpus cavernosum (CCC) was long-lasting and resistant to tetrodotoxin (TTX). Since TTX-resistant sodium current has much slower activation and inactivation kinetics than TTX-sensitive sodium current, one may speculate that the prolonged coitus was due to persistent sodium channel activation, and thus nitric oxide release. Based on these results and considering that TTX-resistant was also observed in EFS-induced contraction, the aim of this study was to characterize the contraction in CCC. The functional assays were divided in five steps: 1) concentration response curve to noradrenaline, adrenaline and dopamine in the absence and presence of phentolamine; contraction induced by electrical field stimulation (EFS) or phenylephrine (PE) in the presence of 2) TTX, phentolamine or guanetidine; 3) of blockers for voltage gated sodium- or calcium channels; 4) EFS- and PE-induced contraction after NaCl replacement by N-methyl-D-glucamine (NMDG); 5) quantification of titrated [3H] noradrenaline after EFS in RbCC and CCC. Noradrenaline, adrenaline, dopamine and EFS induced contraction, which were practically abolished in the presence of phentolamine or guanethidine in RbCC and CCC. Surprisingly, low sodium levels did not affect EFS-induced contraction in CCC, but abolished in RbCC. The sodium channel activator, veratridine induced contraction in both RbCC and CCC being this response abolished in the presence of phentolamine. Local anaesthetics, ropivacaine and bupivacaine and the neuronal N-type calcium channel blocker, GVIA and MVIIA reduced by, approximately, 50 % EFS-induced contraction, without affecting the contraction by PE. In CCC no radioactivity was detected after EFS stimulation, whereas in RbCC TTX, sodium or calcium ions removal a significant reduction on [3H]-noradrenaline release was observed. Our results suggest that EFS-induced contraction was independent on sodium influx, but rather dependent on calcium influx / Mestrado / Farmacologia / Mestra em Farmacologia

Orientador: Gilberto De Nucci / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T13:06:44Z (GMT). No. of bitstreams: 1 Martins_RodrigodeOliveiraCapel_D.pdf: 3076126 bytes, checksum: 396a3a2afbc6ff0897c19649a03f2ed5 (MD5) Previous issue date: 2011 / Resumo: A ereção peniana é um fenômeno vascular sob controle psicológico modulado por andrógenos onde o estado de flacidez ou ereção peniana é determinado pela condição momentânea de contração ou relaxamento do sistema arterial cavernoso e da musculatura lisa trabecular. Já a disfunção erétil é definida como a incapacidade de alcançar ou manter uma ereção peniana satisfatória para uma relação sexual e pode acontecer por causas psicológicas ou orgânicas, podendo esta ser, vascular, neurológica, cirúrgica ou medicamentosa e atinge cerca de 50% dos homens com idade superior a 40 anos e um número crescente de adultos com 20 anos ou mais. Os inibidores de fosfodiesterase tipo 5 são, por via oral, a melhor opção terapêutica embora existam outras alternativas como a injeção intracavernosa de papaverina, fentolamina ou alprostadil e, em casos mais severos, a prótese peniana. Contudo existem casos de pessoas que não respondem de maneira satisfatória a essas drogas e, a(s) causa(s) permanece(m) pouco conhecida(s). Com o objetivo de investigar se no modelo proposto de disfunção erétil in vivo causado por orquiéctomia ocorrem também alterações da resposta do corpo cavernoso in vitro a estímulos contráteis e estímulos relaxantes, bem como, alterações morfológicas nos corpos cavernosos de camundongos utilizamos camundongos C57bl/6 adultos machos (25--30g) castrados cirurgicamente. Avaliamos a resposta contrátil à fenilefrina (agonista alfa1) na presença ou ausência de L--NAME (inibidor de NO) e fasudil (HA1077: inibidor de Rho-- cinase), estimulação elétrica (EFS: 4, 8, 16Hz, 50V, 10 segundos), bem como a resposta relaxante à acetilcolina (ACh) na presença ou ausência de L--NAME, ao Bay 41--2272 (ativador de guanilil ciclase) na ausência ou presença de ODQ (inibidor de guanilil ciclase), ao nitroprussiato de sódio (SNP: doador de NO) na ausência ou presença de ODQ e ao HA 1077. Os parâmetros morfológicos avaliados foram, comprimento, área da secção transversal e volume peniano, área da secção transversal dos corpos cavernosos, fração de musculatura lisa, colágeno e lúmen sinusoidal e a relação quantitativa musculatura lisa/tecido colágeno bem como a imunoexpressão de guanilil ciclase, fosfodiesterase tipo 5 e sintase endotelial de NO. Dois segmentos de corpos cavernosos foram obtidos de cada animal. Os tecidos foram montados em banhos para órgão isolados preenchidos com a solução Krebs--Henseleit e após o período de estabilização foram realizadas curvas concentração efeito. Nossos resultados mostraram que a castração cirúrgica aumentou a potência e a resposta máxima da fenilefrina (pEC50=5,452±0,100; Emax=0,117±0,005) em relação ao grupo controle (pEC50=6,138±0,110; Emax=0,086±0,005 e) e que, a presença de HA1077 reverte esse efeito sem causar alteração na resposta do animal controle, a resposta contraturante à estimulação elétrica foi significativamente maior nos animais castrados (p<0,001) em todas as frequências testadas. Observamos que a resposta relaxante da ACh está diminuída nos animais castrados e, as doses maiores causaram contração, já o Bay 41-- 2272 teve sua potência e resposta máxima reduzidas no grupo castrado enquanto que, ao SNP não há diferença entre os grupos. Já o relaxamento ao HA1077 foi significativamente maior tanto em potência quanto a resposta máxima no animais castrados (pEC50=5,863±0,060; Emax=0,141±0,005) em relação ao grupo controle (pEC50=6,867±0,070; Emax=0,058±0,001). A análise macroscópica mostrou que, entre a primeira e a oitava, a castração induziu no pênis dos animais uma hipoplasia passando para atrofia a partir de então. Nos parâmetros microscópicos os animais castrados perderam 7% da área dos corpos cavernosos e 30% da fração de musculatura lisa. A imunoexpressão da nNOS foi semelhante para os dois grupos já a eNOS, guanilil ciclase e PDE5 estão diminuídas nos animais castrados, os dados da guanili cilcase e da PDE5 foram, também, confirmados por western blot. Neste trabalho demonstramos que a castração cirúrgica: aumenta a sensibilidade da musculatura lisa cavernosa aos mecanismos contraturantes, quer por estimulação adrenégica quer pelo mecanismo de sensibilização ao cálcio mediado pela Rho--cinase, além de reduzir a resposta aos mecanismos relaxantes mediados pela via óxido nitrico--GMP cíclico--PDE5; provoca perda de musculatura lisa e estriada, aumento de tecido adiposo e redução na expressão de proteínas essenciais para a manutenção do funcionamento do mecanismo de ereção / Abstract: Penile erection is a vascular phenomenon under psychological control, modulated by androgens where the erection or flacid penile state is determined by the momentary condition of either contraction or relaxation of the arterial system and the cavernous trabecular smooth muscle. Since erectile dysfunction is defined as the inability to achieve or maintain a penile erection for satisfactory sexual intercourse and may be due to psychological or organic causes, which may be, vascular, neurological, surgical or drug induced and affects about 50% of men older than 40 years old and a growing number of men aged 20 years or more. The phosphodiesterase type 5 inhibitors are orally, the best treatment option although there are other alternatives such as intracavernous injection of papaverine, phentolamine, or alprostadil, and in severe cases, the penile prosthesis. However there are cases of people who do not respond satisfactorily to these drugs and, cause(s) remain unknown. In order to investigate whether the proposed model of erectile dysfunction caused by orchiectomy in vivo also changes the response of corpus cavernosum in vitro contractile and relaxing stimulation, as well as morphological changes in the corpus cavernosum of C57BL / 6 adults males mice (25-30g) surgically castrated. We evaluated the contractile response to phenylephrine (alpha1 agonist) in the presence or absence of L-NAME (NO-inhibitor) and fasudil (HA1077, Rho-kinase inhibitor), electrical stimulation (EFS: 4, 8, 16Hz, 50V, 10 seconds), as well as the relaxation response to acetylcholine (ACh) in the presence or absence of L-NAME, HA 1077, Bay 41-2272 (guanylyl cyclase activator) in the absence or presence of ODQ (guanylyl cyclase inhibitor) and sodium nitroprusside (SNP, NO donor) in the absence or presence of ODQ. The morphological parameters evaluated were length, cross-sectional area and volume of the penis, transversal sectional area of corpora cavernosa, fraction of smooth muscle, collagen xxx and sinusoidal lumen and quantitative smooth muscle / collagen tissue as well as the immunoexpression of guanylyl cyclase, phosphodiesterase 5 type and endothelial NOS. Two segments of the corpus cavernosum were obtained from each animal. Tissues were mounted in organ baths with Krebs-Henseleit and after stabilization, concentration curves were performed. Our results showed that castration increased the potency and maximal response of phenylephrine (pEC50 = 5.452 ± 0.100, Emax = 0.117 ± 0.005) compared to controls (pEC50 = 6.138 ± 0.110; Emax = ± 0.005 and 0.086) and HA1077 reverses this effect causing any alterations in the response of the animal control, electrical field stimulation was significantly higher in castrated animals (p <0.001) at all frequencies tested. We observed that the relaxation of ACh is diminished in the castrated animals, and higher doses caused contraction, Bay 41-2272 had reduced potency and maximum response in the castrated group, while SNP had no difference between groups. HA1077 was significantly higher in both potency and maximum response in castrated animals (pEC50 = 5.863 ± 0.060; Emax = 0.141 ± 0.005) compared to controls (pEC50 = 6.867 ± 0.070; Emax = 0.058 ± 0.001). Macroscopic analysis showed that, between the first and eighth weeks after castration, castrated animals showed hypoplasia and atrophy thereafter. Microscopic parameters: castrated animals lost 7% of the corpus cavernosum and 30% of the fraction of smooth muscle. The nNOS immunoreactivity was similar in both groups as eNOS, guanylyl cyclase and PDE5 are reduced in castrated animals, and data of guanyl cilcase and PDE5 were also confirmed by western blot. We demonstrated that surgical castration: increases the sensitivity of the cavernous smooth muscle contraction mechanisms, either by adrenergic stimulation or by the mechanism of calcium sensitization mediated by Rho-kinase, and reduces the relaxing response to mechanisms mediated by nitric oxide-cGMP-PDE5; causes loss of striated and smooth muscle, increased fat and decreased expression of proteins essential for maintaining the function of the erection mechanism / Doutorado / Farmacologia / Doutor em Farmacologia

Orientador: Adriano Fregonesi / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T14:29:00Z (GMT). No. of bitstreams: 1 SantosJunior_CarlosAlbertodos_M.pdf: 1616257 bytes, checksum: d70350f8e901a282f84ace52fff8b42d (MD5) Previous issue date: 2012 / Resumo: Introdução e Objetivo: A disfunção erétil (DE) é a incapacidade de ter e/ou manter uma ereção para um intercurso sexual satisfatório. Dentre os diversos fatores ligados a ela pode-se citar a queda dos níveis de testosterona na corrente sanguínea. Apesar da evolução representada pela descoberta dos inibidores da enzima PDE5 no tratamento da DE, muitos homens ainda procuram tratamentos alternativos através do uso dos fitoterápicos. Este estudo avaliou a eficácia do Tribulus terrestris no tratamento da disfunção erétil e nos níveis da testosterona sanguínea. Pacientes e Métodos: Trinta homens foram inscritos no estudo. Todos eles tinham 40 anos ou mais, não eram tabagistas, não haviam sido submetidos a nenhum tratamento para câncer de próstata, não apresentavam dislipidemia e podiam ter diabetes e/ou hipertensão controladas. Os pacientes responderam ao IIFE-5 e sua testosterona total foi medida. Os pacientes foram randomizados em dois grupos de quinze indivíduos. O grupo tratamento recebeu Tribulus na dose de 400 mg duas vezes ao dia por 30 dias. O grupo controle recebeu placebo com a mesma orientação de ingestão. Após este período, os pacientes responderam ao questionário e tiveram sua testosterona medida novamente. Resultados: Antes do tratamento os indivíduos do grupo Tribulus apresentaram IIFE-5 médio de 13,2 pontos (variação 5 -18) (dp 3,5) e testosterona total média de 417,1ng/dl (variação 270,7ng/dl - 404,7ng/dl) (dp 89,4). Após o tratamento o grupo Tribulus apresentou IIFE-5 médio de 15,3 pontos (variação 5 -21) (dp 4,3) p=0,2463 e testosterona total média de 409,3ng/dl (variação 216,9ng/dl e 760,8ng/dl) (dp 125,8) p=0,3551. Conclusões: O Tribulus terrestris na dose de 800mg dia durante 30 dias não foi superior ao placebo, estatisticamente, quando comparado o IIEF-5 e aumento da testosterona total sérica / Abstract: Introduction and Objective: Erectile dysfunction (ED) is the inability to have and/or maintain an erection sufficient for a sexual intercourse. It could be linked to many factors. Among them could be pointed low testosterone levels. Despite the huge revolution of PDE5 inhibitors in the treatment of ED, many men have been looking for alternative treatments with herbs. This study evaluated the efficacy of Tribulus terrestris in the treatment of erectile dysfunction and in the serum levels of testosterone. Patients and Methods: Thirty men were enrolled to the study. All of them had 40 years old or later, non-smoking, not have been submitted to any treatment for prostate cancer, without dyslipidemia and they could have controlled diabetes and/or hypertension. The patients answered to the IIEF-5 and the total testosterone was measured. All the patients were randomized in two groups of fifteen. The treatment group received 400mg of Tribulus twice a day during 30 days. The control group received placebo at the same way. After this period, the patients answered the questionnaire and total testosterone was measured again. Results: Both groups were statistically equivalent. Before the treatment, the patients from Tribulus group presented mean IIEF-5 of 13.2 points (variation 5 - 18) (sd 3,5) and mean total testosterone of 417.1 ng/dl (variation 270,7 - 404,7) (sd 89,4). After the treatment, the Tribulus group presented mean IIEF-5 of 15.3 points (variation 5 - 21) (sd 4,3) p=0,2463 and mean total testosterone of 409.3ng/dl (variation 216,9 - 760.8) (sd 125,8) p=0,3551. Conclusion: Daily 800 mg Tribulus terrestris during 30 days was not statistically superior to placebo when compared IIEF-5 and serum total testosterone / Mestrado / Fisiopatologia Cirúrgica / Mestre em Ciências

Abstract Altogether 406 patients were included in five studies, and all patients were examined and controlled in the Oulu University Hospital during the years 1991–1998. Twenty-nine patients with mixed-type erectile dysfunction (ED) were recruited into a randomized, controlled, double-blind crossover comparison of placebo and high-dose yohimbine hydrochloride (36 mg per day orally). Positive clinical responses were obtained in 44% of the patients during yohimbine treatment and in 48% during placebo treatment. Thirty patients with ED underwent an intracavernosal injection test (ICI) using three different active agents (prostaglandin E1(PGE1), papaverine hydrochloride (PV), moxisylyte (MS)) and physiological saline. PGE1 produced significantly better rigidity than either PV or MS. Sixty-nine patients with ED who had started ICI therapy with PGE1 at least three years previously were invited to a control examination to find out the long-term outcome of this treatment and to evaluate the patients' overall satisfaction with their sexual life. 46.4% of the patients had discontinued PGE1 therapy, the mean time of using PGE1 having been 23.3 months (range 0–48 months). 34.8% of the patients reported that their own spontaneous erections had improved during the PGE1 therapy. The sexual functions of 155 patients with benign prostatic hyperplasia (BPH) were evaluated before TURP and 6 and 12 months afterwards with questionnaires. Only 26% of the patients had completely satisfactory erections before TURP, while 22% had satisfactory erections 6 months later and 24% 12 months later. The majority of patients (about 70%) were satisfied with their sexual life both before and after the procedure. 123 men with symptoms of andropause participated in a randomized, placebo-controlled study to assess the effects of dihydrotestosterone (DHT) gel in men with andropausal symptoms. The drug was administered transdermally once a day during six months. Early morning erections improved significantly (p &lt; 0.003) in the DHT group by the three-month control, the ability to maintain erections was better, and there was also a positive effect on libido. In the patients with a elevated (&gt; 12) international index of the prostatic symptoms score (I-PSS) before DHT treatment, I-PSS decreased from 17.7 to 12.3 points. As a conclusion yohimbine hydrochloride is no better than placebo in the treatment of patients with mixed-type ED. PGE1, PV and MS are well tolerated, and PGE1 was shown to be the most effective drug of the three. ICI therapy with PGE1 in long-term use is safe and effective. Sexual functions in men did not change after TURP, and this group of aging men were fairly satisfied with their sexual life despite of the fact that they had some ED and one third of the patients had not had intercourse during the previous year. Transdermal administration of DHT in aging men improves sexual function.

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