Ca2+ -activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction.

BACKGROUND AND PURPOSE: We have evaluated the influence of calcium-activated potassium channels (KCa ) activation on cGMP-mediated relaxation in human penile tissues from non-diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats. EXPERIMENTAL APPROACH: Cavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non-diabetic rats. KEY RESULTS: Concentration-dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS-8 (10 µM) significantly potentiated sildenafil-induced relaxations in HPRA (EC50 0.49 ± 0.22 vs. 5.21 ± 0.63 µM). In HCC, sildenafil-induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large-conductance KCa (BK) and intermediate-conductance KCa (IK) contribute to NS-8-induced effects and were immunodetected in human and rat penile arteries. NS-8 potentiated sildenafil-induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes-induced ED in rats only when combined with KCa activation. CONCLUSIONS AND IMPLICATIONS: Activation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non-diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED.

Integrating partners into erectile dysfunction treatment: improving the sexual experience for the couple.

INTRODUCTION: Erectile dysfunction (ED) is a common condition estimated to affect more than 150 million men worldwide. ED should be regarded as a shared sexual problem which has significant detrimental effects both on the men who experience this condition and on their partners. EVIDENCE TO SUPPORT PARTNER INVOLVEMENT IN ED THERAPY: Evidence shows that the partner plays a key supportive role in the man's ED treatment and in successful long-term ED therapy. Including the partner in consultations may highlight discordant attitudes and communication problems between couple members which may indicate treatment acceptance or rejection, or realistic or unrealistic treatment expectations. OPTIONS FOR PARTNER INVOLVEMENT IN ED THERAPY: Most patients with ED consult their physician in the absence of their partner. Therefore, involving the partner in therapy can be challenging. Two options which physicians should consider are: encouraging the patient to bring the partner into the office and, often more realistically, seeking information about, and providing information to, the partner, via the patient. OBJECTIVES: The objective of these recommendations is to provide practical guidance on treating couples affected by ED, and suggest techniques that may be helpful in integrating the partner into the process of ED treatment.

Peritoneal carcinomatosis of colorectal origin. Current treatment. Review and update.

Colorectal cancer is the most frequent tumor of the digestive tract. The high incidence of abdominal dissemination; the poor prognosis of these patients, with median survival consistently ranging from 5 to 9 months in all studies of peritoneal carcinomatosis from colorectal cancer; the failure of adjuvant systemic chemotherapy treatment with a maximal survival of 18 months despite the development of new cytostatic drugs, and new combinations of use, make it crucial to search for and develop new treatment strategies. We review the principles of Sugarbaker s treatment protocol, which involves the combination of maximum cytoreductive radical oncological surgery for the treatment of all macroscopically disseminated disease with maximum perioperative intraperitoneal intensification chemotherapy to treat residual microscopic disease. We present the results of several scientific papers, all of them phase II studies with more than 10 patients treated, published in the medical literature by the main groups working in this line of treatment, together with the only phase III study reported and published so far, and finally the results of a recently reported retrospective international multicenter study. With this new alternative therapeutic approach, overall mean survival is 40% at 36 months, and 20% at 5 years. Based on these results, this new therapeutic approach is proposed as the treatment of choice for these unfortunate patients.

Carcinomatosis peritoneal de origen colorrectal. Estado actual del tratamiento. Revisión y puesta al día / Peritoneal carcinomatosis of colorectal origin. Current treatment. Review and update

El cáncer colorrectal es el tumor más frecuente del tracto digestivo.La alta incidencia de diseminación abdominal, el pobre pronósticode estos pacientes con una mediana de supervivencia entre5 y 9 meses demostrada repetidamente en todos los estudiosde carcinomatosis peritoneal por cáncer colorrectal, el fracaso delos tratamientos sistémicos adyuvantes con quimioterapia con supervivenciasmáximas de 18 meses independientemente del desarrollode nuevas drogas citostáticas y las nuevas combinaciones oformas de uso, hacen crucial la investigación y el desarrollo denuevas estrategias de tratamiento.Revisamos los principios del protocolo del tratamiento de Sugarbaker,que contempla la combinación de la máxima cirugía radicaloncológica citorreductora para el tratamiento de la enfermedadmacroscópica diseminada con la máxima quimioterapia deintensificación intraperitoneal perioperatoria para el tratamientode la enfermedad microscópica residual.Se presentan los resultados de las publicaciones científicas, detodos los estudios fase II con más de 10 pacientes tratados publicadosen la literatura médica por los principales grupos de trabajoen esta línea de tratamiento, junto con el único estudio fase III publicadohasta el momento, y finalmente los resultados de un recienteestudio multicéntrico internacional retrospectivo.Con esta nueva alternativa terapéutica, la supervivencia mediaa los 36 meses es del 40, y del 20% a los 5 años. Basados en estosresultados, proponemos esta alternativa de tratamiento comoel tratamiento de elección de estos desafortunados pacientes

Colorectal cancer is the most frequent tumor of the digestivetract. The high incidence of abdominal dissemination; the poorprognosis of these patients, with median survival consistentlyranging from 5 to 9 months in all studies of peritoneal carcinomatosisfrom colorectal cancer; the failure of adjuvant systemicchemotherapy treatment with a maximal survival of 18 monthsdespite the development of new cytostatic drugs, and new combinationsof use, make it crucial to search for and develop newtreatment strategies.We review the principles of Sugarbaker´s treatment protocol,which involves the combination of maximum cytoreductive radicaloncological surgery for the treatment of all macroscopically disseminateddisease with maximum perioperative intraperitoneal intensificationchemotherapy to treat residual microscopic disease.We present the results of several scientific papers, all of themphase II studies with more than 10 patients treated, published inthe medical literature by the main groups working in this line oftreatment, together with the only phase III study reported andpublished so far, and finally the results of a recently reported retrospectiveinternational multicenter study. With this new alternativetherapeutic approach, overall mean survival is 40% at 36months, and 20% at 5 years.Based on these results, this new therapeutic approach is proposedas the treatment of choice for these unfortunate patients

Influence of age and gender on quality-of-life outcomes after cholecystectomy.

Few studies have assessed the role of sociodemographic characteristics on outcomes after a cholecystectomy. Our goal was to evaluate the influence of age and gender on the health related quality of life (HRQoL) changes after cholecystectomy in this prospective observational study of consecutive patients undergoing cholecystectomy. Patients completed the SF-36 and the Gastrointestinal Quality of Life Index (GIQLI) before intervention and 3 months later. The influence of age, gender, and the pre-intervention health status on the HRQoL changes was studied by multivariate regression analysis. Older patients had poorer HRQoL and their post-intervention improvement was lower than younger patients. Compared with men, women had worse health status before the intervention measured with both HRQoL tools. In the unadjusted analysis women had greater improvements than men, measured by the GIQLI, but not with the SF-36. However, after controlling for other relevant variables, the SF-36 measured lower improvements in women more often than men, but the GIQLI showed similar results for both. For men and women, the lower the pre-intervention health status the higher the post-operative improvement. Women presented with worse health status before the intervention and less improvement post-operatively after adjustments. The pre-intervention health status has an important role explaining changes after the intervention. A gender-related difference exists between what a generic and a disease-specific HRQoL instrument captures when measuring HRQoL improvement after cholecystectomy.

Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat.

Phosphodiesterase 5 (PDE5) inhibitors prevent the normal hydrolysis of cGMP. As the resulting cGMP accumulation facilitates penile smooth muscle relaxation, PDE5 inhibitors can partially reverse deficiencies in the nitric oxide (NO)/cGMP pathway to treat erectile dysfunction (ED). However, approximately 30-40% of men with ED do not respond to drug therapy. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5 inhibitors. Decreased expression or activity of neuronal or endothelial NO synthase (NOS), impaired NO release, or NO destruction will preclude sufficient cGMP formation to permit PDE5 inhibitor efficacy. This article discusses the possible reasons for unresponsiveness and strategies to overcome it. Therapeutic approaches proposed to increase available NO in penile tissue include facilitating NO release by using alpha-2 antagonists, enhancing NO synthesis by providing more substrate for the reaction, and using antioxidants to inhibit NO breakdown by reactive oxygen species.

Sustained efficacy and tolerability with vardenafil over 2 years of treatment in men with erectile dysfunction.

This randomised, double-blind study assessed the long-term efficacy and tolerability of vardenafil 10 and 20 mg in men with erectile dysfunction (ED). A total of 566 men who completed an initial 12-month treatment period entered a 12-month extension. In these men, both doses of vardenafil produced improvement in scores for the 'erectile function' Domain of the International Index of Erectile Function, evident from week 4 and maintained through 2 years. Sexual Encounter Profile diary responses indicated that following treatment, penetration was achieved on 92-94% of attempts and erections that lasted long enough for successful intercourse were achieved on 87-89% of attempts. In response to the General Assessment Question, 90-92% of patients reported improved erections with vardenafil. Most treatment-emergent events were mild and transient with no cardiovascular safety concerns. These results support the long-term efficacy, reliability and tolerability of vardenafil 10 and 20 mg in men with ED.

Predictors of improvement in health-related quality of life in patients undergoing cholecystectomy.

BACKGROUND: Few studies have assessed health-related quality of life (HRQoL) among patients undergoing cholecystectomy. This study aimed to determine clinical variables that predict changes in HRQoL following cholecystectomy. METHODS: This was a prospective study of consecutive patients undergoing elective cholecystectomy for gallstones in six hospitals. Patients were asked to complete two questionnaires-the Short Form 36 (SF-36) and the Gastrointestinal Quality of Life Index (GIQLI)-before and 3 months after cholecystectomy. Multivariate linear regression models were used to examine factors potentially contributing to changes in HRQoL. RESULTS: Patients with symptomatic cholelithiasis and low surgical risk experienced the highest HRQoL gains in several SF-36 and GIQLI domains, with significant improvements in physical function detected by both instruments, compared with asymptomatic individuals at high surgical risk. Patients with asymptomatic cholelithiasis or high surgical risk experienced least improvement. CONCLUSION: These data indicate that cholecystectomy is appropriate for patients with symptomatic cholelithiasis and low surgical risk. In terms of HRQoL, the risk to benefit ratio seems poor for patients with asymptomatic gallstones.

Vardenafil reverses erectile dysfunction induced by paroxetine in rats.

Selective serotonin reuptake inhibitors (SSRIs) are associated with a high incidence of impotence. Paroxetine is an extensively used SSRI that has been shown to impair erectile function in patients, to induce erectile dysfunction and to inhibit nitric oxide synthase (NOS) activity and NO production in animal models. NO is a key mediator of penile erection. Vardenafil is a type 5 phosphodiesterase inhibitor that potentiates NO-mediated responses in isolated trabecular smooth muscle and penile erection in men in clinical trials. The aim of this study was to evaluate the effects of vardenafil on the impairment of erectile responses produced by paroxetine in the rat model. Application of cavernosal nerve electrical stimulation (CNES) produced frequency-related intracavernosal pressure (ICP) increases, which were inhibited by the NOS inhibitor N(G)-nitro-L-arginine (0.3 mg/kg) and potentiated by vardenafil (0.3 mg/kg). Acute paroxetine treatment (10 mg/kg) significantly reduced ICP-responses to CNES. This inhibition was completely reversed by vardenafil (0.3 mg/kg) administration. The results show that the erectile dysfunction induced by paroxetine in rats can be effectively treated with vardenafil, suggesting that the use of this compound could be a reasonable therapeutic approach to treating erectile dysfunction associated with SSRI administration.

Vardenafil enhances clitoral and vaginal blood flow responses to pelvic nerve stimulation in female dogs.

The relaxation of the smooth muscle in the vagina and clitoris and the increase of blood flow into these organs is thought to be essential in the female sexual response. Vardenafil is a type 5 phosphodiesterase (PDE5) inhibitor that potentiates the nitric oxide (NO)/cGMP pathway facilitating penile smooth muscle relaxation and improving penile erection in men. Although the potentiation of the NO/cGMP pathway through PDE5 inhibitors can clearly enhance blood flow into the penis and is used in the therapy of male sexual dysfunction, there is controversy about the efficacy of these agents in improving female sexual function. The aim of this work was to evaluate the effects of vardenafil on the increase of blood flow into the vagina and clitoris induced by pelvic nerve electrical stimulation (PNES) in a female dog model. Application of PNES produced consistent and frequency-related increased blood flow into the vagina and clitoris of anesthetized female dogs. The magnitude and duration of the blood flow responses to PNES were variable among the different animals but remained stable over time within the same animal. The intravenous administration of vardenafil (1 mg/kg) significantly potentiated the increases in blood flow produced by PNES into the vagina (381.4 and 206.2% of control response at 5 and 10 Hz, respectively, P<0.01, n=6) and clitoris (379.4 and 238.5% of control response at 5 and 10 Hz, respectively, P<0.01, n=6) 20 min after administration. The significant enhancement of PNES-induced responses was maintained 50 min (224.5 and 181.0%, P<0.01 in vagina; 294.8 and 258.9%, P<0.05 in clitoris) and 80 min after vardenafil administration (209.5 and 156.9%, P<0.05 in vagina; 268.9 and 194.9%, P<0.05 in clitoris). Here we present a feasible model for research into female sexual function. Our results show that vardenafil effectively potentiates the blood flow responses to PNES in the genitalia of female dogs. These results emphasize the role of the NO/cGMP pathway in the local vasodilatory response in female sexual organs and provide a rationale for testing PDE5 inhibitors, such as vardenafil, as a treatment for certain forms of female sexual dysfunction.

Quality-of-life outcomes with laparoscopic vs open cholecystectomy.

BACKGROUND: Few studies have assessed the health outcomes of patients who underwent cholecystectomy. The goal of this study was to evaluate the health-related quality-of-life (HRQoL) improvement of patients undergoing laparoscopic versus open cholecystectomy. METHODS: A prospective observational study was performed of consecutive patients on waiting lists to undergo cholecystectomy for nonmalignant disease in six hospitals. Patients were asked to complete two questionnaires that measure (HRQoL)-the SF-36 and the Gastrointestinal Quality of Life Index (GIQLI)-before the intervention and 3 months later. RESULTS: Improvement after surgery, measured by the SF-36 and GIQLI, was similar for both surgical techniques. The SF-health transition item showed a perception of worse health, compared to 1 year previously, for those who underwent open surgery and complications were also higher. CONCLUSIONS: HRQoL improvement at 3 months was relevant and similar for both surgical techniques, although the health transition perception was worse for those who underwent open surgery.

Development of explicit criteria for cholecystectomy.

OBJECTIVE: Consensus development techniques were used in the late 1980s to create explicit criteria for the appropriateness of cholecystectomy. New diagnostic and treatment techniques have been developed in the last decade, so an updated appropriateness of indications tool was developed for cholecystectomy in patients with non-malignant diseases. The validity and reliability of panel results using this tool were tested. METHODS: Criteria were developed using a modified Delphi panel judgement process. The level of agreement between the panelists (six gastroenterologists and six surgeons) was analysed and the ratings were compared with those of a second different panel using weighted kappa statistics. RESULTS: The results of the main panel were presented as a decision tree. Of the 210 scenarios evaluated by the main panel in the second round, 51% were found appropriate, 26% uncertain, and 23% inappropriate. Agreement was achieved in 54% of the scenarios and disagreement in 3%. Although the gastroenterologists tended to score fewer scenarios as appropriate, as a group they did not differ from the surgeons. Comparison of the ratings of the main panel with those of a second panel resulted in a weighted kappa statistic of 0.75. CONCLUSIONS: The parameters tested showed acceptable validity and reliability results for an evaluation tool. These results support the use of this algorithm as a screening tool for assessing the appropriateness of cholecystectomy.

Molecular mechanisms for the regulation of penile smooth muscle contractility.

Relaxation of penile smooth muscle (arterial and trabecular) initiates and maintains penile erection. Relaxation of smooth muscle is viewed as a 'resetting' of contractile machinery by resumption of a precontractile state accomplished by lowering cytosolic Ca(+2) and/or by a decrease in sensitivity of the contractile machinery to Ca(+2). There are various mechanisms whereby cytosolic Ca(+2) can be reduced and relaxation achieved, but in general, all pathways depend on the accumulation of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) or activation of K channels with hyperpolarization. Another mechanism, activation of Na(+)/K(+) adenosine triphosphatase (ATPase) by nitric oxide, has been shown to be involved in relaxation of trabecular smooth muscle. Since Na(+)/K(+) ATPase is electrogenic, its stimulation would cause hyperpolarization. Hyperpolarization will prevent the opening of voltage-dependent calcium channels. Guanylate cyclase, which catalyzes the conversion of guanosine triphosphate to cGMP, is activated by nitric oxide. cGMP activates protein kinase G, which through multiple phosphorylations facilitates calcium sequestration and reduces the entry of calcium into the cell. Other muscle relaxants act by way of a cAMP-dependent mechanism such as prostaglandin E, vasoactive intestinal polypeptide, and catecholamines (via beta-receptors). These substances react with membrane receptors coupled to a GS-type protein that stimulates adenylate cyclase, which catalyzes the accumulation of cAMP. DOI: 10.1038/sj/ijir/3900790

Differential effects of serotonin reuptake inhibitors on erectile responses, NO-production, and neuronal NO synthase expression in rat corpus cavernosum tissue.

Increased incidence of impotence is associated with some selective serotonin-reuptake-inhibitors (SSRIs), but the pathophysiological mechanism is unknown. Paroxetine and citalopram are extensively used SSRIs, but only paroxetine has been shown to inhibit nitric oxide synthase (NOS) activity. NO is a key mediator of penile erection. Thus, the aim of this study was to determine the effects of paroxetine and citalopram on erectile function and NO production, in a rat model. Application of cavernosal nerve electrical stimulation produced frequency-related intracavernosal pressure (ICP) increases, which were inhibited by the NOS inhibitor, N(G)-nitro-L-arginine (0.3 mg x kg(-1)). Acute or chronic (2 weeks) paroxetine-treatment (10 mg x kg(-1)) reduced ICP-responses, while citalopram did not. Paroxetine, but not citalopram, significantly reduced nitrite+nitrate plasma levels by 61.4% and inhibited penile neuronal NOS (nNOS) protein expression by 31.2% after chronic treatment. The results show that paroxetine inhibits erectile responses in rats. We propose that this effect is due to reduced NO production and nNOS expression.

Traducción y validación del índice de calidad de vida gastrointestinal (GIQLI) / Translation and valida tion of the Gastrointestinal Quality of Life Index (GIQLI)

Objetivo: traducir al español y validar el GIQLI, un cuestionario de medición de calidad de vida relacionada con la salud para patología gastrointestinal Pacientes y métodos: en el estudio se incluyen todos los pacientes con diagnóstico de colelitiasis, en lista de espera para ser intervenidos de colecistectomía, en tres hospitales públicos. A todos los pacientes se les pidió que cumplimentaran los cuestionarios GIQLI y SF-36 antes de la intervención y a los 3 meses de la misma. Se estudió la validez, fiabilidad y sensibilidad al cambio del GIQLI. Resultados: completaron ambos cuestionarios, antes y después de la colecistectomía, 353 pacientes. El GIQLI fue capaz de detectar diferencias según nivel de gravedad, medido por el número de cólicos previos, entre aquéllos con menos de 6 cólicos (puntuación total del GIQLI: 102,7) o más de 6 (89,2). Las áreas del GIQLI correlacionaron bien con el SF-36 (coeficiente de correlación de Pearson de 0,58 a 0,79). La consistencia interna de sus áreas fue buena ( de Cronbach de 0,70 a 0,86). La sensibilidad al cambio, medida por la media de respuesta estandarizada, de las áreas del GIQLI fue de 0,45 a 0,82, mejor que la del cuestionario genérico SF-36 (0,20 a 0,56).Conclusiones: la traducción de GIQLI al español proporciona una nueva herramienta de medición de la cálida de vida, para su uso en patología gastrointestinal. Nuestros resultados apoyan la validez, fiabilidad y sensibilidad al cambio de este cuestionario (AU)

Prevalence and independent risk factors for erectile dysfunction in Spain: results of the Epidemiologia de la Disfuncion Erectil Masculina Study.

PURPOSE: We determined the prevalence of and risks factors for erectile dysfunction in Spain in a cross-sectional study. MATERIALS AND METHODS: A total of 2,476 noninstitutionalized Spanish men 25 to 70 years old were interviewed at home and answered a self-administered questionnaire of 71 items, including 2 instruments to define erectile dysfunction, a simple self-assessment question to estimate erectile function and the International Index of Erectile Function. Data on disease, medication and toxic habits were also obtained. RESULTS: With an overall participation rate of 75% the prevalence of erectile dysfunction according to the simple question was 12.1%. According to the erectile function domain of the International Index of Erectile Function the overall prevalence was 18.9%. Several independent risk factors were significantly associated with the probability of erectile dysfunction. Some differences arose according to the tool used to define the condition. However, there was a strong relationship of patient age with frequency or severity no matter which instrument was used to define erectile dysfunction. Diabetes (age adjusted odds ratio 4), high blood pressure (odds ratio 1.58), high cholesterol (1.63), peripheral vascular disorder (2.63), lung disease (3.11), prostate disease (2.93), cardiac problems (1.79), rheumatism (2.37) and allergy (3.08) were significantly associated with erectile dysfunction. Drug intake, which respondents called medication for nerves and sleeping pills, correlated strongly (odds ratio 2.78 and 4.27, respectively), as did tobacco use (2.5) and alcohol consumption (1.53). CONCLUSIONS: This study provides data on the prevalence of and risks factors for erectile dysfunction in Spain. The relationship of erectile dysfunction with certain risk factors, such as cardiovascular risk factors and drugs intake, are well known and our study corroborates these associations. Other associations with erectile dysfunction, such as prostate disease, allergy and rheumatism, support findings in previous reports, although to our knowledge the pathophysiological mechanisms remain unclear. Estimating the strength of the association of erectile dysfunction with distinct risk factors in terms of odds ratios enabled us to identify the factors to pursue when seeking to prevent erectile dysfunction. Furthermore, the relationship of tobacco with erectile dysfunction, which has been controversial in previous series, was well characterized in our study.

Combination of phentolamine and L-arginine or sildenafil synergistically improves neurogenic relaxation of rabbit corpus cavernosum smooth muscle.

OBJECTIVES: To analyze the effects of combining an alpha-adrenergic receptor antagonist, phentolamine, with an enhancer of the nitric oxide/cyclic guanosine monophosphate pathway (L-arginine or sildenafil) on neurogenic relaxations of rabbit corpus cavernosum (RCC). METHODS: Studies were performed on isolated RCC tissue in organ chambers. Transmural electrical stimulation (TES) was applied at increasing frequencies (0.5 to 6 Hz) on endothelin-contracted RCC strips, and the responses were evaluated. RESULTS: The activation of alpha(2)-adrenergic receptors with UK 14304 (0.3 microM) significantly inhibited the relaxation induced by TES in RCC strips in which adrenergic neurotransmission was blocked with guanethidine (10 microM). The relaxant responses produced by TES application on RCC strips without guanethidine were not significantly affected by the treatment with L-arginine or sildenafil but were significantly augmented by phentolamine (2.7-fold increase in maximum relaxation). Furthermore, the combinations of phentolamine with L-arginine or sildenafil markedly increased the relaxations evoked by the application of TES in RCC tissue, significantly more than those obtained in the presence of phentolamine alone (4.5 or 4.7-fold increase of maximum relaxation, respectively). CONCLUSIONS: Our results demonstrated a synergistic interaction between the alpha-adrenergic blockade and the potentiation of the nitric oxide/cyclic guanosine monophosphate pathway to increase neurogenic relaxation of trabecular smooth muscle relaxation. This fact suggests that the combination of alpha-adrenergic receptor blockade with L-arginine or sildenafil could represent a therapeutic advantage in the treatment of erectile dysfunction.

The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil.

We investigated the potency and the selectivity profile of vardenafil on phosphodiesterase (PDEs) enzymes, its ability to modify cGMP metabolism and cause relaxation of penile smooth muscle and its effect on erections in vivo under conditions of exogenous nitric oxide (NO) stimulation. PDE isozymes were extracted and purified from human platelets (PDE5) or bovine sources (PDEs 1, 2, 3, 4 and 6). The inhibition of these PDEs and of human recombinant PDEs by vardenafil was determined. The ability to potentiate NO-mediated relaxation and influence cGMP levels in human corpus cavernosum strips was measured in vitro, and erection-inducing activity was demonstrated in conscious rabbits after oral administration together with intravenous doses of sodium nitroprusside (SNP). The effects of vardenafil were compared with those of the well-recognized PDE5 inhibitor, sildenafil (values for sildenafil in brackets). Vardenafil specifically inhibited the hydrolysis of cGMP by PDE5 with an IC50 of 0.7 nM (6.6 nM). In contrast, the IC50 of vardenafil for PDE1 was 180 nM; for PDE6, 11 nM; for PDE2, PDE3 and PDE4, more than 1000 nM. Relative to PDE5, the ratios of the IC50 for PDE1 were 257 (60), for PDE6 16 (7.4). Vardenafil significantly enhanced the SNP-induced relaxation of human trabecular smooth muscle at 3 nM (10 nM). Vardenafil also significantly potentiated both ACh-induced and transmural electrical stimulation-induced relaxation of trabecular smooth muscle. The minimum concentration of vardenafil that significantly potentiated SNP-induced cGMP accumulation was 3 nM (30 nM). In vivo studies in rabbits showed that orally administered vardenafil dose-dependently potentiated erectile responses to intravenously administered SNP. The minimal effective dose that significantly potentiated erection was 0.1 mg/kg (1 mg/kg). The selectivity for PDE5, the potentiation of NO-induced relaxation and cGMP accumulation in human trabecular smooth muscle and the ability to enhance NO-induced erection in vivo indicate that vardenafil has the appropriate properties to be a potential compound for the treatment of erectile dysfunction. Vardenafil was more potent and selective than sildenafil on its inhibitory activity on PDE5.

Translation and validation of the gastrointestinal Quality of Life Index (GIQLI).

OBJECTIVE: To translate into Spanish and validate the GIQLI, a health related quality of life questionnaire for gastrointestinal diseases. PATIENTS AND METHODS: All patients with a diagnosis of cholelithiasis, on waiting list to undergo a cholecystectomy, from three public hospitals, were included in this study. All patients were requested to fulfill the GIQLI and the SF-36 before and three months after the intervention. The validity, reliability and responsiveness of the GIQLI were studied. RESULTS: 353 patients completed both questionnaires before and after the intervention. The GIQLI was able to discriminate among levels of severity, measured by the number of previous biliary colics, between those with less (total GIQLI score: 102.7) or more than 6 colics (89.2). GIQLI domains correlated with those of the SF-36 (Pearson correlation coefficient from 0.58 to 0.79). Internal consistency of its domains was good (Cronbach alpha from 0.70 to 0.86). Responsiveness, measured by the standardized response mean, of the GIQLI ranged between 0.45 to 0.82, better than the generic questionnaire SF-36 (0.20 a 0.56). CONCLUSIONS: GIQLI translation into Spanish provides with a new tool to measure quality of life on gastrointestinal diseases. Our results support the validity, reliability and responsiveness of the GIQLI Spanish version.

Rationale for the combination of PGE(1) and S-nitroso-glutathione to induce relaxation of human penile smooth muscle.

Many men with erectile dysfunction have been successfully treated with intracavernosal injection of prostaglandin E(1) (PGE(1)) but this treatment is ineffective in 30 to 40% of patients. The goals of this study were to characterize PGE(1)-induced relaxation of isolated human penile smooth muscle (penile arteries and trabecular strips), correlating this in vitro response with the clinical response to this drug, and to evaluate the effects of the combination of PGE(1) with S-nitrosoglutathione (SNO-Glu) on relaxation of isolated human penile smooth muscle. Large variability in the EC(50) and maximal relaxation induced by PGE(1) was observed between tissues of different patients. Patients with poor clinical response to intracavernosal alprostadil (PGE(1)) had significantly larger EC(50) values and smaller maximal relaxation compared with patients with partial or complete clinical response to this drug. SNO-Glu consistently produced complete or near complete relaxation of human corpus cavernosum strips and penile arteries, even when the tissue responded poorly to PGE(1). In trabecular strips, the combination of PGE(1) and SNO-Glu in a 1:100 ratio demonstrated a synergistic relaxation effect. The combination of PGE(1) and SNO-Glu simultaneously increased the levels of both cAMP and cGMP in human corpus cavernosum tissue. Our results suggest that the clinical effectiveness of intracavernosal administration of PGE(1) is related to the variability of the relaxation responses of human trabecular tissue and penile arteries to this drug. The synergistic interaction of PGE(1) and SNO-Glu makes this combination an effective method to cause penile smooth muscle relaxation, a necessary step to initiate and maintain penile erection.