adrenomedullin and Erectile-Dysfunction

To assess the levels of adrenomedullin (a vasodilatory peptide) in penile blood before and after injection with papaverine in impotent men, and in the internal spermatic vein in infertile patients with varicocele, comparing the results with levels in the brachial vein in the same patients.. Intracavernosal levels of adrenomedullin were determined in 14 impotent men (with no vascular pathology, as assessed by colour Doppler ultrasonography) before and after papaverine-induced penile erection. The effect of needle puncture alone was assessed in eight control patients. The level of adrenomedullin was also measured in the internal spermatic vein and brachial vein in 14 infertile men with varicocele.. The mean (SD) intracavernosal adrenomedullin levels in the 14 impotent men were significantly different between the flaccid and papaverine-induced erectile state, at 93.5 (33.0) and 135.8 (34.9) pmol/mL, respectively, (P < 0.05). Needle puncture alone had no effect on adrenomedullin levels. In men with varicocele, the adrenomedullin level of 139.0 (34.3) pmol/mL within the internal spermatic vein was significantly higher than that in the brachial vein, at 103.9 (37.6) pmol/mL (P < 0.05).. Injection with papaverine increases adrenomedullin release into penile blood; this release may be responsible for the increase in penile blood flow and penile erection. Higher levels of adrenomedullin within the internal spermatic vein of patients with varicocele may result from the retrograde flow of venous blood from the left adrenal gland and kidney. Further studies are needed to determine the role of adrenomedullin in male infertility and impotence.

Topics: Adrenomedullin; Adult; Biomarkers; Erectile Dysfunction; Humans; Infertility, Male; Injections; Male; Middle Aged; Papaverine; Peptides; Varicocele; Vasodilator Agents

Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of patients, approximately 30%, do not respond to PDE5i treatment. Therefore, new treatment methods are needed. In this study, we identified a pathway that contributes to male erectile function. We show that mechano-regulated YAP/TAZ signaling in smooth muscle cells (SMCs) upregulates adrenomedullin transcription, which relaxed the SMCs to maintain erection. Using single-nucleus RNA sequencing, we investigated how penile erection stretches the SMCs, inducing YAP/TAZ activity. Subsequently, we demonstrate that YAP/TAZ plays a role in erectile function and penile rehabilitation, using genetic lesions and various animal models. This mechanism relies on direct transcriptional regulation of adrenomedullin by YAP/TAZ, which in turn modulates penile smooth muscle contraction. Importantly, conventional PDE5i, which targets NO-cGMP signaling, does not promote erectile function in YAP/TAZ-deficient ED model mice. In contrast, by activating the YAP/TAZ-adrenomedullin cascade, mechanostimulation improves erectile function in PDE5i nonrespondent ED model rats and mice. Furthermore, using clinical retrospective observational data, we found that mechanostimulation significantly promotes erectile function in patients irrespective of PDE5i use. Our studies lay the groundwork for exploring the mechano-YAP/TAZ-adrenomedullin axis as a potential target in the treatment of ED.

Topics: Adrenomedullin; Animals; Erectile Dysfunction; Humans; Male; Mice; Penile Erection; Penis; Rats; Retrospective Studies; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins

Erectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats.. The aim of this study is to explore a better treatment for ED, we examined whether combination of AM and angiopoietin-1 (Ang-1) was more effective to treat ED than treatment with AM alone or Ang-1 alone. We also compared the effect of the combination therapy with that of treatment with vascular endothelial growth factor-A (VEGF-A).. Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Adenoviruses expressing AM (AdAM), Ang-1 (AdAng-1), and VEGF-A (AdVEGF-A) were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology, and protein expression were analyzed 4 weeks after the injection of the adenoviruses.. Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of α-smooth muscle actin (SMA), VE-cadherin and type I collagen was assessed by Western blot analysis.. Infection with AdAM plus AdAng-1 more effectively restored erectile function than infection with AdAM alone or AdAng-1 alone. This combination therapy restored erectile function to a level similar to that observed in the age-matched Wistar rats. Expression of SMA and VE-cadherin increased more significantly in the AdAM plus AdAng-1-treated group than in the AdAM- or AdAng-1-treated group. Although AdVEGF-A infection restored erectile function significantly, it also caused enlargement of the trabeculae of the cavernous body, aberrant angiogenesis, and overproduction of type I collagen.. These results suggested that combination therapy with AM and Ang-1 potently restored erectile function and normal morphology of the cavernous body compared with VEGF-A administration. This combination therapy will be useful to treat ED patients with a severely damaged cavernous body.

Topics: Adrenomedullin; Angiopoietin-1; Animals; Antigens, CD; Cadherins; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Erectile Dysfunction; Humans; Immunohistochemistry; Male; Penile Erection; Penis; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A

Erectile dysfunction (ED) is a major health problem. It is known that diabetic patients are more refractory to common treatments for ED.. To explore the better treatment for ED, we examined the effects of adipose-derived stem cells (ASC) on ED using a diabetic rat model. We also analyzed the cytokines produced by ASC and implicated in ASC-induced restoration of erectile function.. Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. ASC or adenoviruses were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology and protein expression were analyzed 4 weeks after the injection of ASC or adenoviruses.. Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of proteins specific for vascular endothelial cells (VEC) was assessed by Western blot analysis.. ASC restored erectile function especially when they were cultured in medium containing growth factors for VEC. This restoration was associated with improvement in the histology of the cavernous body, and increased expression of VEC markers such as VE-cadherin and endothelial nitric oxide synthase (eNOS). When the expression of adrenomedullin (AM), a vasoactive peptide originally isolated from human pheochromocytoma tissue, was knocked down, the effect of ASC on ED was significantly diminished. Knockdown of AM was associated with decreased expressions of VE-cadherin and eNOS. Furthermore, overexpression of AM induced by adenovirus infection significantly improved erectile function in these diabetic rats. Overexpression of AM was associated with increased expressions of VE-cadherin and eNOS.. These results suggested that ASC have the potentials to restore erectile function and that AM produced by ASC plays a major role in the restoration of erectile function.

Topics: Adipose Tissue; Adrenomedullin; Animals; Diabetes Mellitus, Experimental; Erectile Dysfunction; Genetic Therapy; Humans; Male; Penile Erection; Rats; Rats, Wistar; Stem Cells

We have reported that adrenomedullin (AM)-induced vasodilation is at least in part nitric oxide (NO)-cGMP-dependent in the rat. Although it is well known that NO is much involved in the erectile function, it is controversial as to whether AM influences the erectile function. Thus, we examined the effects of AM on intracavernous pressure (ICP) during penile erection. The left carotid artery of rats was cannulated to monitor of mean arterial pressure (MAP). Bipolar electrodes were positioned on the cavernous nerve. The right cavernous body was cannulated with a needle connected to a pressure transducer to monitor ICP. Electrical stimulation (ES) increased ICP in a voltage-dependent manner. Elevation of ICP continued during ES. The intracavernous injection of 0.5 nmol AM significantly potentiated ES-induced increases in both maximal developed ICP/MAP and area under the curve (ICP trace; AUC). Since AM slightly lowered MAP, ICP was normalized by MAP. i.v. administration of N(omega)-nitro-L-arginine, a NO synthase inhibitor, markedly decreased AM/ES-induced ICP elevation. However, in the presence of E-4021, a cGMP-specific phosphodiesterase inhibitor, AM further increased both ICP/MAP and AUC. These results suggest that a NO-cGMP pathway is involved in the regulation of AM-induced rat cavernous vasorelaxation.

Topics: Adrenomedullin; Animals; Arginine; Cyclic GMP; Disease Models, Animal; Enzyme Inhibitors; Erectile Dysfunction; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Penile Erection; Peptides; Phosphodiesterase Inhibitors; Piperidines; Quinazolines; Rats; Rats, Wistar