RESUMEN
Men with type 2 diabetes mellitus (T2DM) and erectile dysfunction (ED) have greater risk of cardiovascular events than T2DM men without ED, suggesting ED as a predictor of cardiovascular events in diabetic men. However, molecular mechanisms underlying endothelial dysfunction in the diabetic penis explaining these clinical observations are not known. We evaluated whether the temporal relationship between ED and endothelial dysfunction in the systemic vasculature in T2DM involves earlier redox imbalance and endothelial nitric oxidase synthase (eNOS) dysfunction in the penis than in the systemic vasculature, such as the carotid artery. Rats were rendered T2DM by high-fat diet for 2 weeks, followed by an injection with low-dose streptozotocin. After 3 weeks, erectile function (intracavernosal pressure) was measured and penes and carotid arteries were collected for molecular analyses of eNOS uncoupling, protein S-glutathionylation, oxidative stress (4-hydroxy-2-nonenal, 4-HNE), protein expression of NADPH oxidase subunit gp91(phox) , endothelium-dependent vasodilation in the carotid artery, and non-adrenergic, non-cholinergic (NANC)-mediated cavernosal relaxation. Erectile response to electrical stimulation of the cavernous nerve and NANC-mediated cavernosal relaxation was decreased (p < 0.05), while relaxation of the carotid artery to acetylcholine was not impaired in T2DM rats. eNOS monomerization, protein expressions of 4-HNE and gp91(phox) , and protein S-glutathionylation, were increased (p < 0.05) in the penis, but not in the carotid artery, of T2DM compared to non-diabetic rats. In conclusion, redox imbalance, increased oxidative stress by NADPH oxidase, and eNOS uncoupling, occur early in T2DM in the penis, but not in the carotid artery. These molecular changes contribute to T2DM ED, while vascular function in the systemic vasculature remains preserved.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Endotelio Vascular/fisiopatología , Disfunción Eréctil/fisiopatología , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endotelio Vascular/metabolismo , Disfunción Eréctil/metabolismo , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/fisiología , Pene/inervación , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVE: This study sought to develop a novel animal model to study the impact of nerve-sparing radical hysterectomy (NSRH) on female genital blood flow. DESIGN: In vivo animal study. POPULATION: Thirty Sprague-Dawley female rats. MATERIALS AND METHODS: Female rats underwent either unilateral pelvic nerve (PN) crush (PNC; n = 9), or crush of both the PNs and all efferent nerves in the pelvic plexus ('clock-nerve crush', CNC; n = 9). Under anaesthesia, we electrically stimulated the crushed PN at 3 and 10 days after crush while monitoring blood pressure and recording clitoral and vaginal blood flows by laser Doppler. Uninjured PNs were stimulated as an internal control. Twelve additional rats were assigned either to bilateral PNC or sham surgery, and genital tissues were processed 10 days after injury for in vitro analysis. MAIN OUTCOME MEASURES: Genital blood flow, nNOS, eNOS, collagen I-III. RESULTS: Stimulation of the crushed PN in both groups subjected to PNC and CNC induced significantly lower peak genital blood flow at 3 and 10 days (P < 0.05) compared to stimulation of the non-crushed control PN. The immunofluorescence and Western blot analyses revealed that all injured rats exhibited more vaginal collagen III and collagen I than rats did that ad undergone sham surgeries (P < 0.05). PCN reduced nNOS expression in both clitoral and vaginal tissue. CONCLUSIONS: Based on our study it may be hypothesised that NSRH might cause reductions of genital blood flow and vaginal fibrosis due to neurapraxia of the pelvic nerve and reductions of nNOS nerve fibres in clitoral and distal vaginal tissue. TWEETABLE ABSTRACT: Pelvic nerve neurapraxia during nerve-sparing radical hysterectomy could lead to sexual arousal dysfunction.
Asunto(s)
Plexo Hipogástrico/lesiones , Histerectomía/efectos adversos , Histerectomía/métodos , Traumatismos de los Nervios Periféricos/prevención & control , Vagina/irrigación sanguínea , Vagina/patología , Animales , Western Blotting , Clítoris/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Estimulación Eléctrica , Femenino , Fibrosis , Técnica del Anticuerpo Fluorescente , Flujometría por Láser-Doppler , Modelos Animales , Óxido Nítrico Sintasa/metabolismo , Pelvis/inervación , Traumatismos de los Nervios Periféricos/complicaciones , Traumatismos de los Nervios Periféricos/etiología , Ratas Sprague-Dawley , Flujo Sanguíneo Regional , Vagina/metabolismoRESUMEN
Highly efficient mechanisms regulate intracellular calcium (Ca2+) levels. The recent discovery of new components linking intracellular Ca2+ stores to plasma membrane Ca2+ entry channels has brought new insight into the understanding of Ca2+ homeostasis. Stromal interaction molecule 1 (STIM1) was identified as a Ca2+ sensor essential for Ca2+ store depletion-triggered Ca2+ influx. Orai1 was recognized as being an essential component for the Ca2+ release-activated Ca2+ (CRAC) channel. Together, these proteins participate in store-operated Ca2+ channel function. Defective regulation of intracellular Ca2+ is a hallmark of several diseases. In this review, we focus on Ca2+ regulation by the STIM1/Orai1 pathway and review evidence that implicates STIM1/Orai1 in several pathological conditions including cardiovascular and pulmonary diseases, among others.
Asunto(s)
Humanos , Canales de Calcio/metabolismo , Señalización del Calcio/fisiología , Calcio/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Pulmonares/metabolismoRESUMEN
Highly efficient mechanisms regulate intracellular calcium (Ca2+) levels. The recent discovery of new components linking intracellular Ca2+ stores to plasma membrane Ca2+ entry channels has brought new insight into the understanding of Ca2+ homeostasis. Stromal interaction molecule 1 (STIM1) was identified as a Ca2+ sensor essential for Ca2+ store depletion-triggered Ca2+ influx. Orai1 was recognized as being an essential component for the Ca2+ release-activated Ca2+ (CRAC) channel. Together, these proteins participate in store-operated Ca2+ channel function. Defective regulation of intracellular Ca2+ is a hallmark of several diseases. In this review, we focus on Ca2+ regulation by the STIM1/Orai1 pathway and review evidence that implicates STIM1/Orai1 in several pathological conditions including cardiovascular and pulmonary diseases, among others.
Asunto(s)
Canales de Calcio/metabolismo , Señalización del Calcio/fisiología , Calcio/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Enfermedades Cardiovasculares/metabolismo , Humanos , Enfermedades Pulmonares/metabolismo , Proteína ORAI1 , Molécula de Interacción Estromal 1RESUMEN
Sexual dysfunction is a frequent complication of treated and untreated cardiovascular disease. In fact, approximately 30% of hypertensives have been found to suffer from erectile dysfunction (ED) resulting from arterial dysfunction. Recent evidence has suggested that ED may be an early indicator of subclinical cardiovascular disease. In women, the evidence is similar, but more limited, showing that in hypertensive patients there is an increased prevalence of sexual dysfunction involving decreased vaginal lubrication, decreased orgasm, and increased pain. Clouding the issue, however, is that some antihypertensive agents may induce sexual dysfunction in hypertensives with normal sexual function. In contrast to the chronic treatments used in hypertension, therapies for ED involve acute treatments (none currently approved for women) targeting vasodilation of penile arteries, resulting in erection. Common to the treatment of hypertension and ED is that the current therapies were not designed to target underlying disorders of local, neural, vascular, or endocrine origin. In fact, while blood pressure is lowered, and erectile responses are improved with the respective therapies, the causal abnormalities may progress thereby limiting the long-term effectiveness of the medication. Some antihypertensive agents have been shown to have additional effects beyond blood pressure reduction and their impact on sexual function is a key focus of this review. This review examines the current and future strategies for treatments of male and female sexual dysfunction and the potential for therapeutic modalities that go beyond the recovery of the responses by targeting the fundamental mechanisms common to both sexual dysfunction and cardiovascular disease.