RESUMEN
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.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Pene/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/farmacología , Canales de Potasio Calcio-Activados/metabolismo , Adulto , Anciano , Animales , Bencimidazoles/farmacología , Carbolinas/farmacología , GMP Cíclico/metabolismo , Diabetes Mellitus Experimental/complicaciones , Relación Dosis-Respuesta a Droga , Terapia por Estimulación Eléctrica/métodos , Disfunción Eréctil/etiología , Disfunción Eréctil/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Pene/irrigación sanguínea , Pene/metabolismo , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Piperazinas/administración & dosificación , Piperazinas/farmacología , Purinas/administración & dosificación , Purinas/farmacología , Ratas , Ratas Sprague-Dawley , Citrato de Sildenafil , Sulfonas/administración & dosificación , Sulfonas/farmacología , Tadalafilo , Vasodilatación/efectos de los fármacos , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacologíaRESUMEN
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.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Imidazoles/uso terapéutico , Inhibidores de Fosfodiesterasa/uso terapéutico , Piperazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa/efectos adversos , Piperazinas/efectos adversos , Sulfonas , Resultado del Tratamiento , Triazinas , Diclorhidrato de VardenafilRESUMEN
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.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Imidazoles/farmacología , Erección Peniana/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Animales , Estimulación Eléctrica , Disfunción Eréctil/inducido químicamente , Inyecciones Intravenosas , Masculino , Paroxetina , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina , Sulfonas , Triazinas , Diclorhidrato de VardenafilRESUMEN
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.
Asunto(s)
Clítoris/efectos de los fármacos , Plexo Hipogástrico/fisiología , Imidazoles/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Flujo Sanguíneo Regional/efectos de los fármacos , 3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Animales , Clítoris/irrigación sanguínea , Clítoris/inervación , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Perros , Estimulación Eléctrica , Femenino , Sulfonas , Triazinas , Vagina/irrigación sanguínea , Vagina/efectos de los fármacos , Vagina/inervación , Diclorhidrato de VardenafilRESUMEN
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
Asunto(s)
Contracción Muscular/fisiología , Músculo Liso/fisiología , Pene/fisiología , Disfunción Eréctil/fisiopatología , Humanos , MasculinoRESUMEN
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.
Asunto(s)
Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico/metabolismo , Erección Peniana/efectos de los fármacos , Pene/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Citalopram/farmacología , Citalopram/uso terapéutico , Estimulación Eléctrica , Disfunción Eréctil/tratamiento farmacológico , Masculino , Neuronas/efectos de los fármacos , Paroxetina/farmacología , Paroxetina/uso terapéutico , Pene/efectos de los fármacos , Pene/enzimología , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
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.
Asunto(s)
Disfunción Eréctil/epidemiología , Adulto , Factores de Edad , Anciano , Estudios Transversales , Complicaciones de la Diabetes , Disfunción Eréctil/etiología , Cardiopatías/complicaciones , Humanos , Hipercolesterolemia/complicaciones , Hipertensión/complicaciones , Enfermedades Pulmonares/complicaciones , Masculino , Persona de Mediana Edad , Prevalencia , Enfermedades de la Próstata/complicaciones , Factores de Riesgo , España/epidemiología , Enfermedades Vasculares/complicacionesRESUMEN
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.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Antagonistas Adrenérgicos alfa/farmacología , Arginina/farmacología , Relajación Muscular , Músculo Liso/efectos de los fármacos , Pene/efectos de los fármacos , Fentolamina/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Animales , Sinergismo Farmacológico , Estimulación Eléctrica , Masculino , Músculo Liso/fisiología , Pene/fisiología , Purinas , Conejos , Citrato de Sildenafil , SulfonasRESUMEN
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.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Imidazoles/farmacología , Isoenzimas/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Piperazinas/farmacología , Acetilcolina/farmacología , Animales , Bovinos , GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Humanos , Técnicas In Vitro , Isoenzimas/efectos de los fármacos , Masculino , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Fenómenos Fisiológicos del Sistema Nervioso/efectos de los fármacos , Nitroprusiato/farmacología , Erección Peniana , Pene/efectos de los fármacos , Pene/inervación , Pene/metabolismo , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Conejos , Sulfonas , Triazinas , Diclorhidrato de Vardenafil , Vasodilatadores/farmacologíaRESUMEN
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.
Asunto(s)
Alprostadil/farmacología , Glutatión/análogos & derivados , Glutatión/farmacología , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Donantes de Óxido Nítrico/farmacología , Compuestos Nitrosos/farmacología , Pene/efectos de los fármacos , Vasodilatadores/farmacología , GMP Cíclico/metabolismo , Sinergismo Farmacológico , Humanos , Masculino , Músculo Liso/irrigación sanguínea , Músculo Liso/metabolismo , Pene/irrigación sanguínea , Pene/metabolismo , S-Nitrosoglutatión , Resistencia Vascular/efectos de los fármacosRESUMEN
Relaxation of smooth muscle is viewed as a 'resetting' of contractile machinery and the resumption of a pre-contractile state is accomplished by lowering cytosolic Ca(2+) and/or by decreasing the sensitivity of the contractile machinery to Ca(2+). There are several mechanisms whereby cytosolic Ca(2+) can be reduced and relaxation achieved but, in general, all pathways depend upon the accumulation of cyclic nucleotides cAMP and cGMP or on the activation of K(+) channels resulting in hyperpolarization. Recently, activation of Na(+)/K(+) ATPase by nitric oxide has been shown to be involved in the relaxation of trabecular smooth muscle. Since Na(+)/K(+) ATPase is electrogenic, its stimulation would cause hyperpolarization and, in turn, would prevent the opening of voltage-dependent Ca(2+) channels. This manuscript briefly reviews the molecular mechanisms affected by muscle relaxants and vasodilators in the treatment of erectile dysfunction. International Journal of Impotence Research (2000) 12, Suppl 4, S34-S38.
Asunto(s)
Músculo Liso Vascular/fisiología , Pene/fisiología , Vasoconstricción/fisiología , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Electrofisiología , Humanos , Masculino , Músculo Liso Vascular/citología , Óxido Nítrico/fisiologíaRESUMEN
The neurotransmitters and vasoactive substances regulating tone in the smooth muscle of the penile arteries/arterioles and the trabeculae of the corpora cavernosa are critical mediators of the state of penile erection. Contemporary research reveals a coordinated, intricate interplay between the pathways of vasorelaxation and vasoconstriction representing a most efficient physiological mechanism to initiate and maintain penile erection. This paper will focus on the role of the adrenergic constrictor pathways in penile erection and, more specifically, on the pre-junctional adrenergic mechanisms that regulate smooth muscle constriction. All neurogenic constrictor responses are related to the release of norepinephrine from adrenergic nerves that act on post-junctional alpha-1 and pre-junctional and post-junctional alpha-2 receptor subtypes. Based on the current state of knowledge, there are at least three pre-junctional mechanisms regulating penile smooth muscle tone. First, norepinephrine release from the adrenergic nerves binds to the pre-junctional alpha-2 adrenoceptor on the adrenergic nerves and negatively regulates norepinephrine release. Blockade of this reaction by selective alpha-2 receptor antagonists (e.g. yohimbine or delequamine) will enhance norepinephrine release. Second, norepinephrine release from the adrenergic nerves binds to the pre-junctional alpha-2 adrenoceptor on the non-adrenergic, non-cholinergic (NANC) nerves and inhibits nitric oxide synthesis and release. Blockade of this reaction by selective alpha-2 receptor antagonists (e.g. yohimbine or delequamine) will enhance nitric oxide release, facilitating erection. Finally, cholinergic nerves pre-junctionally inhibit norepinephrine release from the adrenergic nerve and stimulate the NANC nerve to increase nitric oxide synthesis and release. These observations indicate that different neurotransmitters regulate the adrenergic neurotransmission pathway. Based on the above concepts for pre-junctional and post-junctional regulation of smooth muscle tone, the most efficacious strategy to reduce adrenergic activity and facilitate penile erection is to combine alpha-1 and alpha-2 adrenergic receptor antagonists. In this case, any enhancement of norepinephrine release is of little importance because the alpha-1 receptor antagonist will impede this vasoconstrictor response. This will also enhance the release of nitric oxide, which increases smooth muscle relaxation and decreases contraction resulting in penile erection.
Asunto(s)
Pene/inervación , Receptores Adrenérgicos alfa/fisiología , Sinapsis/fisiología , Animales , Humanos , Masculino , Músculo Liso/inervación , Músculo Liso/fisiología , Erección Peniana/fisiologíaRESUMEN
Ischemia-reperfusion injury, a common source of renal dysfunction in adults, is associated with tubular epithelial cell damage. Since fibroblast growth factors (FGF) attenuated tissue injury after transient myocardial ischemia, we hypothesized that acidic fibroblast growth factor (aFGF; FGF-1) would attenuate renal ischemia-reperfusion injury. We studied the effects of FGF-1 in a rat model of acute renal failure induced by bilateral renal ischemia (60 min) and 1, 2 or 7 days reperfusion. After FGF-1 administration at the onset of renal reperfusion, there was less functional impairment of the kidneys. The histological changes were not as severe as in controls. Increases in serum creatinine and blood urea nitrogen 24 h after reperfusion were attenuated by 35% (p< 0.01) and by 53% (p< 0.001), respectively, in FGF-1-treated animals compared to vehicle-treated rats. The ischemia/reperfusion-induced increase in tissue myeloperoxidase, a marker of neutrophil infiltration, was mitigated (67% reduction, p< 0.05) with FGF-1 treatment. As shown by histology, neutrophil infiltration and tubular cell necrosis in medulla were less pronounced (p< 0.0001 and p< 0.05, respectively) in animals receiving FGF-1. Furthermore, ischemia-induced apoptosis, prevalent in tubular cells of the cortex, was also attenuated by FGF-1-treatment (83% reduction, p< 0.0001). Pretreatment of animals with Nw-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase, abolished the attenuating effects of FGF-1 on neutrophil infiltration, suggesting that nitric oxide might participate in the anti-inflammatory effects of FGF-1 in this experimental design. Our data support a role for FGF-1 in attenuation of renal damage or failure after ischemia-reperfusion injury of the kidney, in part at least by inhibition of neutrophil infiltration.
Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/uso terapéutico , Isquemia/tratamiento farmacológico , Riñón/irrigación sanguínea , Daño por Reperfusión/prevención & control , Animales , Apoptosis/efectos de los fármacos , Factor 1 de Crecimiento de Fibroblastos , Isquemia/patología , Isquemia/fisiopatología , Riñón/efectos de los fármacos , Riñón/patología , Riñón/fisiopatología , Peroxidasa/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Although around 10% of men aged 40 to 70 years have complete erectile dysfunction, only a few seek medical help. As erectile dysfunction is frequently associated with a number of systemic illnesses and surgical treatments, a wide range of doctors should be aware of the condition in their patients. Current effective treatments include psychosexual counselling, vacuum erection devices, intracavernosal and transurethral drug delivery, and penile prostheses. Promising oral treatments are currently being investigated. Both doctors and the public need to be better informed about erectile dysfunction and its treatment.
Asunto(s)
Disfunción Eréctil , Erección Peniana/efectos de los fármacos , Inhibidores de Fosfodiesterasa/uso terapéutico , Piperazinas/uso terapéutico , Adulto , Anciano , Disfunción Eréctil/etiología , Disfunción Eréctil/psicología , Disfunción Eréctil/terapia , Humanos , Masculino , Persona de Mediana Edad , Erección Peniana/psicología , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Purinas , Citrato de Sildenafil , SulfonasRESUMEN
We have investigated the effect of oxidatively-modified low density lipoproteins (ox-LDL) on the contractility of rabbit trabecular smooth muscle. Low density lipoproteins (LDL) were isolated from fresh human plasma pooled from multiple donors and oxidized by exposure to copper. Corpus cavernosum strips from New Zealand White rabbits were studied in organ chambers for isometric tension measurement. Corporeal strips in which moderate tone was induced by phenylephrine, contracted when exposed to ox-LDL, but not when exposed to either native LDL (nLDL) or LDL protected from oxidation by butylated hydroxytoleune (BHT-LDL). Removal of the endothelium, or treatment of the corporeal strips with N(omega)-nitro-L-arginine (nitric oxide synthase inhibitor), methylene blue of LY83583 (guanylate cyclase inhibitors/superoxide producing agents), did not prevent ox-LDL-induced contraction. ox-LDL, dose-dependently, enhanced the contractile response of corporeal strips to low and moderate concentrations by phenylephrine. nLDL had no significant effect on phenylephrine-induced contraction of corporeal strips. ox-LDL, nLDL or BHT-LDL had no effect on relaxation induced by the endothelium-dependent dilator, acetylcholine, or the nitric oxide donor, nitroprusside. In conclusion, this present study demonstrates significant pro-contractile effects of ox-LDL on corporeal smooth muscle, this effect is independent of the endothelium or the nitric oxide/cGMP pathway. The pro-contractile effect of ox-LDL may interfere with penile smooth muscle relaxation, necessary for the initiation and maintenance of penile erection.
Asunto(s)
Lipoproteínas LDL/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , Pene/fisiología , Aminoquinolinas/farmacología , Animales , Hidroxitolueno Butilado/farmacología , Cobre/farmacología , Relación Dosis-Respuesta a Droga , Endotelio Vascular/fisiología , Inhibidores Enzimáticos/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Lipoproteínas LDL/administración & dosificación , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroarginina/farmacología , Fenilefrina/farmacología , Potasio/farmacología , ConejosRESUMEN
PURPOSE: To study the mechanism of chronic ischemia-induced increased cavernosal smooth muscle contraction in an animal model of vasculogenic erectile dysfunction. MATERIALS AND METHODS: New Zealand White rabbits were divided into control (n = 6, fed with a regular diet), hypercholesterolemic (n = 9, fed with a diet containing 0.5% cholesterol) and chronic cavernosal ischemia (CCI, n = 10, underwent balloon de-endothelialization of iliac arteries and received a diet containing 0.5% cholesterol) groups. After 16 weeks, the relationship between iliac artery blood flow and cavernosal smooth muscle contraction was studied. The roles of cyclooxygenase and nitric oxide (NO) pathways in chronic ischemia-induced increased smooth muscle contraction were also examined. RESULTS: Iliac artery blood flow in the CCI group was significantly reduced compared with the control and hypercholesterolemic groups. Hypercholesterolemia alone did not affect cavernosal smooth muscle contraction. Atherosclerosis-induced chronic cavernosal arterial insufficiency did not affect contraction to norepinephrine while causing a significant increase in electrical field stimulation-induced neurogenic contraction. Inhibition of the cyclooxygenase pathway by indomethacin decreased electrical field stimulation-induced contraction in all animals but failed to normalize the differences between CCI and control groups. In the presence of indomethacin, L-arginine decreased electrical field stimulation-induced contraction in the control and hypercholesterolemic groups but not in the CCI group. In the presence of indomethacin, treatment with nitric oxide synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), increased electrical field stimulation-induced contraction in all groups. This effect of L-NMMA on smooth muscle contraction was significantly greater in the control and hypercholesterolemic groups compared with the CCI group. After tissue treatment with L-NMMA, the magnitude of contraction in cavernosal tissue from control and hypercholesterolemic groups was similar to those observed in the CCI group. CONCLUSIONS: Mechanism of chronic ischemia-induced increased cavernosal smooth muscle contraction involves increased output of constrictor eicosanoids and impairment of the inhibitory influence of NO pathway in cavernosal tissue.
Asunto(s)
Contracción Muscular/fisiología , Músculo Liso/fisiología , Óxido Nítrico Sintasa/fisiología , Pene/fisiología , Prostaglandina-Endoperóxido Sintasas/fisiología , Animales , Arginina/farmacología , Arteriosclerosis/fisiopatología , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Hipercolesterolemia/fisiopatología , Indometacina/farmacología , Isquemia/fisiopatología , Masculino , Contracción Muscular/efectos de los fármacos , Pene/irrigación sanguínea , Pene/efectos de los fármacos , Conejos , Flujo Sanguíneo Regional , omega-N-Metilarginina/farmacologíaRESUMEN
There is growing evidence that the field of pharmacotherapy, particularly oral drugs, will be dominant in the future management of sexual dysfunction. Basic research has led to the understanding of the intracellular mechanisms that control penile smooth muscle contractility and therefore erection, opening a vast area for pharmacological intervention. Moreover, the importance of central neurohormonal mechanisms has made these pathways the target for new centrally acting drugs. Given these trends most patients suffering from erectile dysfunction will respond to pharmacological agents in the not so distant future.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Antagonistas Adrenérgicos alfa/uso terapéutico , Alprostadil/uso terapéutico , Apomorfina/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Humanos , Masculino , Relajación Muscular/efectos de los fármacos , Papaverina/uso terapéutico , Fentolamina/uso terapéutico , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Purinas , Citrato de Sildenafil , Sulfonas , Vasodilatadores/uso terapéuticoRESUMEN
PURPOSE: To determine the effects of hypercholesterolemia and atherosclerosis-induced chronic cavernosal arterial insufficiency on cavernosal smooth muscle tone, nitric oxide synthase (NOS) activity and cavernosal tissue synthesis of constrictor eicosanoids. To study whether inhibition of the cyclooxygenase pathway by indomethacin and tissue treatment with nitric oxide (NO) precursor L-arginine improve hypercholesterolemia and ischemia-induced impaired endothelium-dependent and neurogenic relaxation of cavernosal tissue. MATERIALS AND METHODS: New Zealand White rabbits were divided into control (n = 10, fed a regular diet), hypercholesterolemia (Hch, n = 13, fed a diet containing 0.5% cholesterol) and chronic cavernosal ischemia (CCI, n = 14) groups. The CCI group underwent balloon deendothelialization of iliac arteries and received a diet containing 0.5% cholesterol. After 16 weeks, we examined the effects of Hch and balloon de-endothelialization induced arterial occlusive disease on iliac arterial blood flow, reactivity of cavernosal tissue, cavernosal NOS activity and cavernosal tissue synthesis of constrictor eicosanoids. RESULTS: Histology revealed significant atherosclerotic arterial occlusive disease in the CCI group. Iliac artery blood flow in the CCI group was significantly reduced compared with the control and Hch groups. In the Hch and CCI groups, endothelium-dependent relaxation of cavernosal tissue to acetylcholine was significantly reduced compared with the control group. Electrical field stimulation-induced neurogenic relaxation and cavernosal NOS activity were significantly reduced in the CCI group but not in the Hch group. The basal release of cavernosal constrictor eicosanoids, prostaglandin F2alpha (PGF2alpha) and thromboxane A2 (TXA2) was significantly increased in the CCI group. Indomethacin increased endothelium-dependent relaxation in all groups and neurogenic relaxation in the CCI group, but failed to normalize the differences in relaxation between treated and control groups. In the presence of indomethacin, L-arginine improved endothelium-dependent relaxation of cavernosal tissue in the Hch group but did not normalize endothelium-dependent or neurogenic relaxations in the CCI group. Relaxation to NO donor sodium nitroprusside and papaverine was similar in cavernosal tissue from all groups. CONCLUSIONS: Impairment of endothelium-dependent relaxation by Hch occurs secondary to disruption of the NO formation in cavernosal endothelium. Improvement of endothelium-dependent relaxation by L-arginine may suggest lack of availability of L-arginine in cavernosal tissue from the Hch animals. Impairment of endothelium-dependent and neurogenic relaxation by CCI occurs secondary to disruption of the NO formation due to an alteration in the expression or activity of NOS and increased output of constrictor eicosanoids in cavernosal tissue. These studies show that Hch and atherosclerosis-induced chronic cavernosal arterial insufficiency, beyond decreasing cavernosal perfusion pressure, also adversely affect smooth muscle relaxation mechanisms in cavernosal tissue.
Asunto(s)
Impotencia Vasculogénica/fisiopatología , Relajación Muscular , Músculo Liso/fisiopatología , Pene/fisiopatología , Animales , Arteriosclerosis/fisiopatología , Modelos Animales de Enfermedad , Hipercolesterolemia/fisiopatología , Impotencia Vasculogénica/enzimología , Isquemia/fisiopatología , Masculino , Músculo Liso/enzimología , Óxido Nítrico Sintasa/metabolismo , Pene/irrigación sanguínea , Pene/enzimología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Conejos , Flujo Sanguíneo RegionalRESUMEN
PURPOSE: The extent to which hemodynamic erectile responses predict penile buckling forces has not previously been analytically investigated. An engineering study was performed to compare hemodynamic data with penile buckling force values. METHODS: Dynamic infusion pharmacocavernosometry studies in 21 impotent patients (age 43, range 24-62 y) were accomplished to obtain information during penile erection concerning hemodynamic values, penile buckling forces and their determinants: intracavernosal pressure, erectile tissue mechanical properties and penile geometry. RESULTS: In the 21 patients, discrepancies existed in several patients who demonstrated normal hemodynamic values (low flow-to-maintain and high equilibrium intracavernosal pressures) but elevated cavernosal compliance values and diminished penile buckling forces. There was poor correlation between cavernosal compliance and equilibrium intracavernosal pressure (r = -0.36); better correlation between compliance and expandability (r = -0.72) and best correlation between dimensionless compliance and the dimensionless product of expandability with equilibrium pressure (r = -0.88). These data implied that cavernosal compliance was dependent on multiple factors, not only equilibrium intracavernosal pressure. CONCLUSIONS: Hemodynamic indices which correlate with intracavernosal pressure alone do not predict penile buckling forces since the latter are dependent not only on intracavernosal pressure but also on penile geometry and erectile tissue properties. The most relevant tissue property in predicting adequate penile buckling forces is cavernosal expandability. A new impotence classification system and diagnostic algorithm based on the determinants of penile rigidity and not exclusively on hemodynamic responses in proposed.
Asunto(s)
Ingeniería Biomédica , Disfunción Eréctil/fisiopatología , Hemodinámica , Erección Peniana , Pene/irrigación sanguínea , Pene/fisiopatología , Adulto , Fenómenos Biomecánicos , Presión Sanguínea , Disfunción Eréctil/clasificación , Humanos , Masculino , Persona de Mediana Edad , Modelos BiológicosRESUMEN
PURPOSE: The least investigated physical determinant of penile rigidity has been penile tissue material properties. The goals in this study (Part I) were to define two penile mechanical parameters, cavernosal expandability X and tunical distensibility VE/VF, determine their magnitudes in humans and develop an analytical expression for penile volume as a function of these two tissue characteristics and intracavernosal pressure. METHODS: Dynamic infusion pharmacocavernosometry was performed in 21 impotent patients (age 43 +/- 19 y) to provide human geometric, hemodynamic and structural data. A mathematically derived model of hemodynamic and structural-dynamic characteristics of penile erection was developed (Parts I, II, III) incorporating penile tissue mechanical qualities. RESULTS: Cavernosal expandability X provided a measure of the ability to approach maximum volume at relatively low intracavernosal pressures. Tunical distensibility VE/VF denoted the maximal erect to flaccid penile volume ratio. The magnitudes of X and VE/VF in the study population were 0.04-0.17 mmHg-1 and 1.7-5.0 respectively. CONCLUSIONS: Enabling penile volume to be derived as a function of tissue mechanical characteristics and pressure, allows for penile rigidity to be expressed (in Part II) as a function of pressure, geometry and tissue qualities.