endothelin-1 and Erectile-Dysfunction

Lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are highly prevalent in aging men and both of the conditions have a significant impact on the quality of life. In the past few years, various epidemiological trials were conducted to assess the association between LUTS and ED. These studies showed that LUTS, particularly the voiding symptoms, nocturia and the others caused by LUTS, independently increased the incidence of ED. There are some factors involved in the link between LUTS and ED: (1) rho-kinase expression/activity increased; (2) nitric oxide release decreased and corpus cavernosum smooth muscle contraction strengthened due to endothelin-1; (3) the composition of myosin isoform altered; (4) sympathetic hyperactivity and innervation of the corpus cavernosum smooth muscles decreased. These findings concerning the relationship between LUTS and ED have offered some new insights into the evaluation and treatment of patients with these conditions. The present paper briefly reviews the recent studies of the association between LUTS and ED.

Topics: Adult; Aged; Aged, 80 and over; Endothelin-1; Erectile Dysfunction; Humans; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Myosins; Nitric Oxide; Penis; Protein Serine-Threonine Kinases; rho-Associated Kinases; Urologic Diseases

Erectile dysfunction is a familiar complication of diabetes mellitus, which results from combined factors of impairment to the vascular structure of the penis, the pathological changes in neural system and neural transmitters, and endocrine disorders. There are numerous therapeutic options for the treatment of diabetic erectile dysfunction, including medicines like PDE5 inhibitors, insulin, androgen, surgical therapy and gene therapy.

Topics: Androgens; Diabetes Complications; Diabetic Neuropathies; Endothelin-1; Erectile Dysfunction; Humans; Male; Nitric Oxide

Erectile dysfunction (ED) reduces the quality of life. It is estimated that 52% of men have some degree of ED, which is associated with ageing. While it is clear that there are a variety of current treatment options for ED, each of these has drawbacks and contraindications. A better understanding of the physiological mechanisms involved in penile erection will provide new ways to treat ED. This review not only focuses on the vasoconstrictors and vasodilators that control the state of contraction and relaxation of the corpora cavernosa smooth muscle, but also presents a novel Ca(2+)-sensitising pathway that contributes to maintaining the penis in the non-erect state. Studies have shown that inhibition of the RhoA/Rho-kinase signalling pathway induces penile erection. Further understanding of this RhoA/Rho-kinase pathway may provide a novel alternative treatment for ED.

Topics: Adrenergic Agonists; Adult; Aged; Aging; Amides; Angiotensin II; Calcium Signaling; Cyclic AMP; Endothelin-1; Erectile Dysfunction; Forecasting; Humans; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Nitric Oxide; Penis; Protein Serine-Threonine Kinases; Pyridines; rho-Associated Kinases; rhoA GTP-Binding Protein; Vasoactive Intestinal Peptide

The importance of signaling pathways in penile smooth muscles involved in normal erection and erectile dysfunction (ED) is discussed based on a review of the literature.. Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents but also by visual, olfactory and imaginary stimuli. The generated nervous signals will influence the balance between the contractant and relaxant factors, which control the degree of contraction of penile smooth muscles and, thus, determine the functional state of the penis. The different steps involved in neurotransmission, impulse propagation and intracellular transduction of neural signals may be changed in different types of erectile dysfunction.. Recent findings have suggested an important role for RhoA/Rho kinase in the regulation of cavernosal smooth muscle tone and that changes in this pathway may contribute to ED in various patient subgroups, eg diabetes and vascular disease. Neurogenic nitric oxide is still considered the most important factor for immediate relaxation of penile vessels and corpus cavernosum. However, endothelially generated nitric oxide seems essential for maintaining erection. Endothelial dysfunction can contribute to ED in several patient subgroups. In addition, in conditions associated with reduced function of nerves and endothelium, such as aging, hypertension, smoking, hypercholesterolemia and diabetes, circulatory and structural changes in the penile tissues can result in arterial insufficiency and defect muscle relaxation.. Different types of ED often have overlapping pathophysiologies but may also have common pathways contributing to ED. Such pathways may be potential treatment targets.

Topics: Amides; Animals; Diabetes Mellitus; Endothelin-1; Erectile Dysfunction; Humans; Hypothalamus; Male; Muscle Contraction; Muscle Relaxants, Central; Muscle, Smooth; Nitric Oxide; Norepinephrine; Penile Erection; Phosphorylation; Pyridines; Receptors, Endothelin; rho GTP-Binding Proteins

Erectile dysfunction (ED) is a common problem, particularly in older men. The production of penile erection involves an interplay between autonomic nerves and locally released vasoactive mediators. Endothelin-1 (ET-1) is a peptide released from endothelium in the corpus cavernosum, which causes smooth muscle contraction. Recent studies have investigated the physiological significance of ET-1 in the control of erectile function and it may play a role in detumescence. There is also much evidence to link ET-1 to risk factors for ED. ET-1 antagonists may prove beneficial in the treatment of ED and also in prevention of long term deterioration of erectile function. These antagonists may also find a role when used in combination with agents, which are established for the treatment of ED.

Topics: Animals; Antihypertensive Agents; Bosentan; Diabetes Complications; Diabetes Mellitus; Endothelin-1; Erectile Dysfunction; Humans; Hypercholesterolemia; Hypertension; Male; Myocardial Ischemia; Neural Pathways; Nitric Oxide; Penile Erection; Risk Factors; Smoking; Sulfonamides

To investigate the effects of prolonged inhibition of phosphodiesterase type-5, using once-daily long-acting phosphodiesterase type-5 inhibitor (tadalafil) on erectile function and biomarkers of endothelial function in male patients with systemic sclerosis (SSc) and erectile dysfunction (ED).. In an open-label study, 14 nonconsecutive male patients with SSc with different degrees of ED were enrolled into the study irrespective of their clinical response to tadalafil, and received once-daily tadalafil 10 mg for 12 weeks. Primary endpoints were variations from baseline of penile arterial inflow [peak systolic velocity (PSV, cm/s); measured with dynamic color duplex ultrasound] and the erectile function domain score (measured with the International Index of Erectile Function questionnaire). Secondary endpoints were variations from baseline of morning erections (determined by modified question 13 of the Structured Interview on Erectile Dysfunction questionnaire) and plasma concentrations of endothelin-1 (ET1).. The PSV and the erectile function domain score were significantly improved by once-daily tadalafil (from 21.3 +/- 6.4 to 30.0 +/- 7.0 cm/s and from 13.0 +/- 6.8 to 17.0 +/- 9.0 vs baseline, respectively; p <0.05). Question 13 scores decreased dramatically after treatment compared with baseline (from 2.2 +/- 0.2 to 0.8 +/- 0.5 arbitrary units; p < 0.001), and plasma ET1 levels decreased (from 24 +/- 15 to 9.8 +/- 7.4 pg/ml; p < 0.05).. In men with SSc-related ED, once-daily tadalafil improved both erectile function and vascular measures of cavernous arteries. Increases in morning erections and decreases in plasma ET1 levels were found, which may play a potential role in preventing progression of penile fibrosis and erectile dysfunction.

Topics: Adult; Carbolines; Disease Progression; Endothelin-1; Erectile Dysfunction; Health Surveys; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Scleroderma, Systemic; Tadalafil

To evaluate the protective role of bosentan (BOS), an endothelin-1 (ET-1) receptor antagonist, and to show the changes in rats with experimentally induced diabetic erectile dysfunction (ED), a total of 24 albino Wistar rats were allocated into four groups. Group 1 was the healthy group and Group 2 had diabetes mellitus (DM) induced by intraperitoneal injection of 60 mg kg

Topics: Animals; Apomorphine; Bosentan; Diabetes Mellitus, Experimental; Dopamine Agonists; Endothelin Receptor Antagonists; Endothelin-1; Erectile Dysfunction; Humans; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Penile Erection; Penis; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Sulfonamides; Tumor Necrosis Factor-alpha

Erectile dysfunction (ED) is a predictor or marker of coronary artery disease in patients at high risk of cardiovascular diseases. The aim of this study was to investigate the prevalence of ED in patients with acute myocardial infarction (AMI) and after 2 years of follow-up, and to determine the association between ED and the concentrations of the markers of inflammation, endothelial dysfunction and oxidative stress which were measured on the third day after hospital admission.. The study included 80 patients aged 62.25 ± 10.47 years. The primary endpoints of interest were re-hospitalization due to cardiovascular causes and death during the 2 year period after hospital-ization. The Sexual Health Inventory for Men (SHIM) was assessed at the point of hospital discharge and 24 months thereafter.. 40.1% of patients had some degree of ED. The percentage of patients without ED increased (13.2%), while the percentage of patients with severe ED significantly decreased (14.7%) after 2 years. Patients with ED had significantly higher B-type natriuretic peptide (BNP) levels and decreased levels of nitric-oxide. During the 2 years of follow-up, 9 patients died (6.5% without ED, 68.6% with ED) (c2 = 7.19, p = 0.015). During the same time period, 22 (27.5%) patients were re-hospitalized due to cardiovascular causes, of whom 59.1% had ED at hospital admission (p < 0.05).. Low levels of nitric-oxide were the best predictors of ED during AMI and after 2 years. ED predicted the worst outcomes of AMI: death and re-hospitalization. Lifestyle changes and nitric- -oxide donors could assist in the treatment of ED and in the improvement of long-term prognosis for AMI. (Cardiol J 2017; 24, 4: 393-402).

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Biomarkers; Endothelin-1; Endothelium, Vascular; Erectile Dysfunction; Humans; Inflammation Mediators; Male; Middle Aged; Nitric Oxide; Non-ST Elevated Myocardial Infarction; Oxidative Stress; Patient Readmission; Penile Erection; Prevalence; Prospective Studies; Risk Factors; Serbia; ST Elevation Myocardial Infarction; Surveys and Questionnaires; Time Factors; Treatment Outcome

Investigate the effects of chronic ethanol consumption on erectile function and on the corpus cavernosum (CC) reactivity to endothelin-1 (ET-1).. Male Wistar rats were treated with ethanol (20% v/v) for six weeks.. Ethanol-treated rats showed impaired erectile function represented by decreased intracavernosal pressure/mean arterial pressure (ICP/MAP) responses. Ethanol consumption increased the contractile response induced by ET-1 in the isolated CC. Tiron increased ET-1-induced contraction in CC from control and ethanol-treated rats. No differences in the maximal contraction to ET-1 were observed after incubation of CC with PEG-catalase. SC560 and SC236 increased ET-1-induced contraction in CC from ethanol-treated rats. Y27632 reduced the contraction induced by ET-1 in CC from control and ethanol-treated rats. Ethanol increased plasma TBARS, superoxide anion (O2(-)) levels and intracellular reactive oxygen species (ROS) generation in the rat CC. Reduced hydrogen peroxide (H2O2) levels in CC and increased catalase (CAT) activity in plasma and CC were detected after treatment with ethanol. Ethanol decreased superoxide dismutase (SOD) activity in the rat CC. Increased expression of COX-1 was observed in CC from ethanol-treated rats. Treatment with ethanol decreased COX-2 expression but did not alter the expression of Nox1, RhoA and p-RhoA (ser(188)) in the rat CC.. The major new findings of our study are that ethanol consumption induces erectile dysfunction (ED) and increases the contraction induced by ET-1 in the rat CC by a mechanism that involves decreased generation of H2O2 and vasodilator prostanoids as well as increased activation of the RhoA/Rho-kinase pathway.

Topics: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; Animals; Arterial Pressure; Catalase; Central Nervous System Depressants; Cyclooxygenase 1; Cyclooxygenase 2; Endothelin-1; Erectile Dysfunction; Ethanol; Hydrogen Peroxide; Male; Muscle Contraction; Oxidative Stress; Penis; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxides; Thiobarbituric Acid Reactive Substances

Endothelin 1 (ET-1) levels and receptors are up-regulated in the erectile tissue of diabetic patients and animal models of erectile dysfunction (ED).. The present study assessed the role of ET-1 receptors in the impaired adrenergic vasoconstriction and nitrergic relaxation of penile arteries from a rat model of insulin resistance.. The effect of ET receptor antagonists was evaluated on the contractile responses to electrical field stimulation (EFS) of penile arteries from obese Zucker rats (OZRs) compared with lean Zucker rats (LZRs). ET receptor expression was determined by immunohistochemistry.. Changes in neural nitrergic relaxation and adrenergic vasoconstriction and the expression of ET receptors in perivascular nerves were assessed.. ET-1 (10(-10)  M) enhanced EFS-induced vasoconstriction, and treatment with the adrenergic neurotoxin guanethidine reduced the contractions induced by ET-1 in penile arteries from both LZRs and OZRs, thus supporting the hypothesis that ET-1 releases noradrenaline from adrenergic nerves. ET-1 antagonized neural nitric oxide (NO)-mediated relaxant responses in LZR arteries, antagonizing relaxations induced by the NO donor S-nitroso-N-acetylpenicillamine to a larger extent in arteries from OZRs. ET(A) and ET(B) receptors were expressed in perivascular fibers colocalized with the neuronal marker protein gene product 9.5 in penile arteries from OZRs. The ET(A) receptor antagonist BQ-123 reversed the enhancing effect of ET-1 on the vasoconstriction elicited by EFS and the ET-1-induced inhibition of nitrergic relaxations in LZRs, restoring them to control levels in penile arteries of OZRs.. ET-1 enhances adrenergic vasoconstriction through presynaptic ET(A) receptors and antagonizes neural NO-mediated relaxation through postsynaptic smooth muscle ET(A) receptors in penile arteries from OZRs, which likely contributes to the augmented vasoconstriction and blunted nitrergic relaxation of erectile tissue under conditions of insulin resistance.

Topics: Adrenergic Agents; Animals; Arteries; Endothelin A Receptor Antagonists; Endothelin-1; Erectile Dysfunction; Guanethidine; Insulin; Insulin Resistance; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Neurotoxins; Nitric Oxide; Obesity; Penile Erection; Penis; Peptides, Cyclic; Rats, Zucker; Receptor, Endothelin A; Vasoconstriction; Vasodilation; Vasodilator Agents

Erectile dysfunction is considered as an early sign of subclinical vascular disease and endothelial dysfunction and a highly prevalent condition in diabetic patients.. The current study assessed whether impaired vascular effects of endothelin (ET)-1 may contribute to the vascular dysfunction of penile arteries from a rat model of insulin resistance.. The effect of ETA and ETB receptor antagonists was assessed on the intracellular Ca(2+) [Ca(2+) ]i and contractile responses to ET-1 in penile arteries from obese Zucker rats (OZR) and lean Zucker rats (LZR), and ET receptor expression in the arterial wall was assessed by immunohistochemistry.. Changes in ET-1 [Ca(2+) ]i and vasoconstriction and ET receptor expression were evaluated in penile arteries from insulin-resistant rats.. ET-1-induced vasoconstriction was associated with a higher increase in smooth muscle [Ca(2+) ]i in penile arteries from OZR compared with LZR. Removal of the endothelium inhibited and enhanced contractions to the lowest and highest doses of ET-1, respectively, mainly in OZR. The selective ETA receptor antagonist BQ-123 inhibited ET-1 vasoconstriction and [Ca(2+) ]i response in both LZR and OZR. The ETB receptor antagonist BQ-788 had little effect in healthy arteries but markedly inhibited ET-1-induced increases in [Ca(2+) ]i and vasoconstriction in arteries from OZR. ETA receptors were located on the smooth muscle and endothelium of penile arteries, whereas ETB receptors were found on the arterial endothelium in LZR and OZR, and also on the smooth muscle in OZR, immunostaining for both receptors being higher in OZR.. Penile arteries from OZR exhibit an impaired ET-1 Ca(2+) signaling along with changes in the ET receptor profile. Thus, whereas ET-1 contraction and the associated [Ca(2+) ]i increase are mediated by smooth muscle ETA receptors in healthy arteries, ETB receptors contribute to contraction and are coupled to the augmented ET-1 [Ca(2+) ]i response under conditions of insulin resistance.

Topics: Animals; Arteries; Calcium Signaling; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Erectile Dysfunction; Humans; Impotence, Vasculogenic; Insulin Resistance; Male; Muscle, Smooth, Vascular; Penis; Rats; Rats, Zucker; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction

Phosphodiesterase type 5 inhibitors are potent in relieving erectile dysfunction (ED), however, they are less satisfactory in diabetic patients, probably due to the pro-inflammatory biomarkers caused by diabetes. Therefore, it was interesting to compare the effects of sildenafil with strontium fructose 1,6-diphosphate (FDP-Sr) on cavernosal vascular activity and expressions of pro-inflammatory biomarkers in diabetic rats.. Male Sprague-Dawley rats were injected with streptozocin (60 mg/kg, i.p.) to develop diabetes. The animals were diabetic for eight weeks with sildenafil (12 mg/kg per day) or FDP-Sr (200 mg/kg per day) being administered for the last four of those eight weeks.. Sildenafil was more effective in relieving reduced vascular dilatation (relevant to ED), but less in attenuating over-expressions of NADPH oxidase p22, p47 and p67 subunits, and ET(A/B) R (endothelin receptor type A and type B) in the diabetic cavernosum. In contrast, FDP-Sr was less effective in improving ED, but more effective in normalizing the abnormal NADPH oxidase and ET(A/B) R.. The activated NADPH oxidase and upregulated ET(A) R and ET(B) R due to diabetic lesions played a minor or moderate role in ED. By offering extra ATP, FPD-Sr suppressed these abnormalities, however, sildenafil did not. A combined therapy of sildenafil with FDP-Sr may be more effective in relieving ED in diabetic patients through normalizing pro-inflammatory cytokines and improving the nitric oxide/cGMP pathway in the cavernosum.

Topics: Animals; Blood Glucose; Blotting, Western; Diabetes Mellitus, Experimental; Disease Models, Animal; Endothelin-1; Erectile Dysfunction; Fructosediphosphates; Male; Malondialdehyde; NADPH Oxidases; Piperazines; Protein Kinase C-epsilon; Purines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sildenafil Citrate; Sulfones; Superoxide Dismutase; Up-Regulation; Vasodilator Agents

Erectile dysfunction (ED) is an early manifestation of arteriosclerosis associated with endothelial damage/dysfunction and to a blunted ability of cultured mononuclear circulating cells (MNCs) to differentiate circulating angiogenic cells (CACs), putatively involved in endothelial damage repair. Here we explored effects of human serum (HS) from patients with ED and cardiovascular risk factors (VRFs) but no clinical atherosclerosis, on cultured MNCs of healthy men to differentiate CACs and to form colonies. Effect of HS on number of CACS and of colony forming units (CFUs) was correlated with circulating markers of endothelial damage and with angiogenic modulators. MNCs from healthy men were cultured in standard conditions or with 20% HS from 35 patients with ED and from 10 healthy men. CACs were identified after 7 days of culture by uptake of acetylated low-density lipoprotein with concomitant binding of Ulex europaeus agglutinin I. CFUs were counted after 5 days of culture. Enzyme-linked immunosorbent assays assessed plasmatic soluble (s) form of E-selectin, Endothelin (ET)-1, tissue type plasminogen activator (tPA), vascular endothelial growth factor (VEGF)(165) and sVEGF receptor (R)-1. The number of CACs and of CFUs from healthy men was reduced after culturing MNCs with HS compared to standard medium. The inhibitory effect was significantly higher with HS from ED patients with higher or lower VRF exposure compared to healthy men. Inhibition was positively correlated with VRFs exposure, with ED severity, with common carotid artery intima media thickness measured using B-mode ultrasound, and to a lesser extent with plasmatic sE-Selectin, sET-1 and sVEGFR-1. Dysfunction of cells involved in vascular homoeostasis is induced by soluble factors still unknown and already present in a very initial systemic vascular disease in men with ED and VRFs.

Topics: Adult; Aged; Cardiovascular Diseases; Carotid Intima-Media Thickness; E-Selectin; Endothelin-1; Endothelium, Vascular; Erectile Dysfunction; Humans; Leukocytes, Mononuclear; Lipoproteins, LDL; Male; Middle Aged; Risk Factors; Stem Cells; Tissue Plasminogen Activator; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

To investigate the impact of daily sildenafil on levels of soluble molecular markers of endothelial function in men with erectile dysfunction.. Patients aged >18 years with erectile dysfunction of vascular etiology for >6 months, either alone or in combination with disease states strongly associated with endothelial dysfunction such as diabetes/metabolic syndrome, hypertension and coronary artery disease, received sildenafil 25 mg orally for 4 weeks. Markers of endothelial function were measured in plasma at baseline and at end of treatment using standard methods and commercially available kits.. Altogether, 112 men with mean (SD) age of 60.6 (7.3) years completed the protocol. Sildenafil 25 mg daily for 4 weeks significantly reduced endothelin-1 levels compared with baseline (2.83+/-1.63 vs 3.24+/-1.90 pg/ml, p<0.001). Significant changes were also observed for nitric oxide (35.12+/-21.14 vs 31.91+/-16.28 pmol/lt, p=0.01) and cyclic guanosine monophosphate (3.79+/-2.37 vs 2.70+/-1.34 pmol/ml, p<0.001) levels, but not for any of the other biomarkers measured. Erectile function was significantly improved.. Daily sildenafil ameliorates endothelial function as assessed by levels of biomarkers of endothelial function in patients with erectile dysfunction. This is in agreement with other studies showing similar benefits with phosphodiesterase-5 inhibitor treatment. The clinical implications of this finding warrant further investigation.

Topics: Administration, Oral; Biomarkers; Cyclic GMP; Drug Administration Schedule; Endothelin-1; Endothelium, Vascular; Erectile Dysfunction; Humans; Male; Middle Aged; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

The cavernosal tissue is highly responsive to endothelin-1 (ET-1), and penile smooth muscle cells not only respond to but also synthesize ET-1.. Considering that ET-1 is directly involved in end-organ damage in salt-sensitive forms of hypertension, we hypothesized that activation of the ET-1/ET(A) receptor pathway contributes to erectile dysfunction (ED) associated with mineralocorticoid hypertension.. Wistar rats were uninephrectomized and submitted to deoxycorticosterone acetate (DOCA)-salt treatment for 5 weeks. Control (Uni [uninephrectomized control]) animals were uninephrectomized and given tap water. Uni and DOCA-salt rats were simultaneously treated with vehicle or atrasentan (ET(A) receptor antagonist, 5 mg/Kg/day). Cavernosal reactivity to ET-1, phenylephrine (PE), ET(B) receptor agonist (IRL-1620) and electric field stimulation (EFS) were evaluated in vitro. Expression of ROCKalpha, ROCKbeta, myosin phosphatase target subunit 1 (MYPT-1), and extracellular signal-regulated kinase 1/2 (ERK 1/2) were evaluated by western blot analysis. ET-1 and ET(A) receptor mRNA expression was evaluated by real-time reverse-transcriptase polymerase chain reaction. Voltage-dependent increase in intracavernosal pressure/mean arterial pressure (ICP/MAP) was used to evaluate erectile function in vivo.. ET(A) receptor blockade prevents DOCA-salt-associated ED.. Cavernosal strips from DOCA-salt rats displayed augmented preproET-1 expression, increased contractile responses to ET-1 and decreased relaxation to IRL-1620. Contractile responses induced by EFS and PE were enhanced in cavernosal tissues from DOCA-salt hypertensive rats. These functional changes were associated with increased activation of the RhoA/Rho-kinase and ERK 1/2 pathways. Treatment of rats with atrasentan completely prevented changes in cavernosal reactivity in DOCA-salt rats and restored the decreased ICP/MAP, completely preventing ED in DOCA-salt rats.. Activation of the ET-1/ET(A) pathway contributes to mineralocorticoid hypertension-associated ED. ET(A) receptor blockade may represent an alternative therapeutic approach for ED associated with salt-sensitive hypertension and in pathological conditions where increased levels of ET-1 are present.

Topics: Animals; Atrasentan; Blood Pressure; Desoxycorticosterone; Dose-Response Relationship, Drug; Endothelin B Receptor Antagonists; Endothelin-1; Erectile Dysfunction; Gene Expression; Hypertension; In Vitro Techniques; Male; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Penis; Pyrrolidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; rho-Associated Kinases; RNA, Messenger

We investigated the relationship between oxidative stress and diabetic erectile dysfunction.. A total of 23 patients with a mean +/- SD age of 56.7 +/- 5.6 years, a history of type 2 diabetes for 10.0 +/- 8.3 years and erectile dysfunction, as tested by the International Index of Erectile Function questionnaire, but without vascular and neurological complications, and 15 age matched patients with diabetes without erectile dysfunction were recruited. Circulating monocyte oxidative activity by cytofluorometry, and endothelin-1, intercellular adhesion molecule-1, plasminogen activator inhibitor-1 by enzyme linked immunosorbent assay were evaluated in all patients in the study.. Monocyte free radical production, and total and low density lipoprotein cholesterol were higher in patients with than in those without erectile dysfunction (p <0.03, <0.02 and <0.05, respectively). In all patients the International Index of Erectile Function score inversely correlated with low density lipoprotein (p <0.05), while in patients with erectile dysfunction it negatively correlated with age (p <0.03), body mass index (p <0.02), endothelin-1 (p <0.02) and intercellular adhesion molecule-1 (p <0.05). Endothelin-1, intercellular adhesion molecule-1 and plasminogen activator inhibitor-1 were not different in patients with diabetes with and without erectile dysfunction.. In men with type 2 diabetes who have erectile dysfunction but are asymptomatic for cardiovascular disease oxidative activation of monocytes is increased and it is related to other risk factors of endothelial dysfunction.

Topics: Diabetes Complications; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Erectile Dysfunction; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; Monocytes; Plasminogen Activator Inhibitor 1; Reactive Oxygen Species

To determine the alterations in the plasma levels of endothelin-1, angiotensin II, nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in the venous and cavernosal blood of patients with organic and psychogenic erectile dysfunction (ED).. The study included 32 patients complaining of ED; they were subdivided into two equal groups with either organic or psychogenic ED. Fifteen healthy potent age-matched male volunteers were enrolled as a control group. For each patient, venous and cavernosal blood samples were obtained, while venous blood was obtained from the controls.. There were significantly greater mean plasma levels of endothelin-1 and angiotensin II, and significantly lower mean plasma levels of NO and PGE(2), in the venous blood of patients with ED than in the controls. Patients with organic ED had significantly higher levels of endothelin-1 and significantly lower levels of NO in both venous and cavernosal blood than had those with psychogenic ED. There were significant positive correlations in both venous and cavernosal blood between endothelin-1 and angiotensin II, and between NO and PGE(2) in all patients with ED and the two subgroups. There were significant negative correlations between venous and cavernosal endothelin-1 and NO, endothelin-1 and PGE(2), angiotensin II and NO, and between angiotensin II and PGE(2).. The present results suggest that endothelin-1 could be a clinical marker of diffuse endothelial disease manifested by ED. As angiotensin-converting enzyme (ACE) activity controls angiotensin II there might be a rationale for the use of ACE inhibitors to prevent or treat ED. NO and PGE(2) may provide new strategies for the pharmacological treatment of ED.

Topics: Adult; Angiotensin II; Case-Control Studies; Dinoprostone; Endothelin-1; Erectile Dysfunction; Humans; Male; Middle Aged; Nitric Oxide; Penis; Sexual Dysfunctions, Psychological; Vasodilation

Corpus cavernosum smooth muscle (CCSM) from rabbits made diabetic for 6 months as a result of alloxan injection exhibited increased sensitivity (3vs 9 nM EC(50)) and generated 20-50% greater force to endothelin-1 (ET-1) compared to CCSM from normal rabbits. In contrast, the force produced by the CCSM in response to KCl and phenylephrine was not significantly altered in diabetic CCSM. The increased ET-1 sensitivity is associated with a two to three-fold upregulation of ET receptor A at both mRNA and protein levels in diabetic CCSM. ET-1-induced CCSM contraction is largely dependent upon Rho-kinase (ROK), since it is almost completely blocked by Y-27632 (a highly selective ROK inhibitor). Furthermore, expression of ROKbeta isoform is selectively upregulated in CCSM from diabetic rabbits. Thus, an increased CCSM tone, modulated by sensitization of the endothelin-mediated contractile pathway via ROK, may be a key component of the molecular mechanism of diabetes-induced erectile dysfunction.

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Endothelin-1; Erectile Dysfunction; Fluorescent Antibody Technique; Gene Expression Regulation, Enzymologic; Intracellular Signaling Peptides and Proteins; Male; Muscle Contraction; Muscle, Smooth; Penis; Protein Serine-Threonine Kinases; Rabbits; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; rho-Associated Kinases; rhoA GTP-Binding Protein

The imbalance between vasoconstrictors and vasodilators may play an important role in the pathogenesis of erectile dysfunction (ED). A total of 36 patients with ED, organogenic [diabetic (n=12) and nondiabetic (n=12)] and psychogenic (n=12) etiology, and 12 healthy adult men as controls were included. The levels of endothelin-1 (ET-1), growth hormone (GH), angiotensin-converting enzyme activity (ACE), nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) were determined in the flaccid penis cavernosal blood of patients and in cubital blood of patients and controls. In psychogenic ED, systemic ACE activity was elevated compared to controls (P<0.05). In diabetic and nondiabetic ED patients, systemic levels of ET-1 (P<0.0001 for both) and ACE activity (P<0.01 and <0.05) were higher while GH (P<0.0001 and <0.001), NO (P<0.0001 for both) and cGMP (P<0.01 for both) levels were lower compared to controls. In diabetic patients, systemic and cavernosal ET-1 levels (P<0.0001 for both) and cavernosal ACE activity levels (P<0.05) were significantly elevated while systemic and cavernosal NO (P<0.0001 for both) and GH (<0.001 and <0.05) levels were declined compared to psychogenic. In nondiabetic patients, systemic and cavernosal ET-1 levels (P<0.0001 for both) were significantly elevated while systemic and cavernosal NO (P<0.0001 for both) and systemic GH levels (P<0.05) were declined compared to psychogenic. Systemic NO was positively correlated with GH in psychogenic (r=0.616, P<0.05), diabetic (r=0.583, P<0.05) and nondiabetic (r=0.615, P<0.05) patients and correlated positively with cGMP (r=0.605, P<0.05) but negatively with ACE activities (r=-0.585, P<0.05) in diabetic patients. In conclusion, plasma levels of ET-1, ACE activities are elevated and associated with reduction of GH, NO and cGMP levels in the systemic and cavernous blood of ED patients. This disturbance may indicate endothelial dysfunction that may hind at their significance in the pathophysiology of ED.

Topics: Adult; Cyclic GMP; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Erectile Dysfunction; Human Growth Hormone; Humans; Male; Middle Aged; Nitric Oxide; Penis; Peptidyl-Dipeptidase A; Sexual Dysfunctions, Psychological; Vasoconstriction; Vasodilation

The objectives of this work were to: (1) Determine if prostate and penile tissue levels of endothelin-1 (ET-1) are increased in a rat following pelvic irradiation. (2) Determine if an ETa receptor antagonist (BQ-123) potentiates erectile function in these irradiated animals. Rats were divided into three study groups: control, 1000 cGy and 2000 cGy. The experimental groups received a single dose of radiation to the pelvic region. A time course was established to measure the effects of irradiation on prostate and penile tissue levels of endothelin-1 (ET-1)-like immunoreactivity. The effect of intracavernous injection of BQ-123 (25 microg/30 microl) was evaluated by measuring intracavernous pressure (ICP) following cavernous nerve electrical field stimulation. In the 2000 cGy group, a significant rise in ET-1-like immunoreactivity tissue levels was observed at 20 days. A significant decrease in ICP was recorded in the 1000 and 2000 cGy irradiated rats compared to the control group. Only the 2000 cGy group had a significant improvement in erectile function following BQ-123 administration. A significant improvement was observed 20 min post-administration, lasted 90 min, and was back to pre-administered levels at 120 min. The conclusion made was that radiation-induced impotence in irradiated rats is associated with an increased production of ET-1. Preliminary results are suggestive that ETa receptor antagonist may be of use to reverse such radiation-induced impotence in these irradiated animals.

Topics: Animals; Electric Stimulation; Endothelin Receptor Antagonists; Endothelin-1; Erectile Dysfunction; Injections; Male; Pelvis; Penile Erection; Penis; Peptides, Cyclic; Pressure; Prostate; Radiation Injuries; Radiography; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Time Factors

The role of the sympathetic adrenergic nerves in mediating the constant tone of penile flaccidity and returning the erect penis to its flaccid state is fairly well established. However, it is not yet known whether additional nonadrenergic transmitters are involved in this process. The peptide endothelin-1 (ET-1) may be one of the factors contributing to such a control. Moreover, it has been speculated by various authors that ET-1 might be involved in the pathophysiology of erectile dysfunction. The present study was undertaken to determine whether or not there is a difference in the courses of ET-1/-2 plasma levels registered in systemic and cavernous blood cavities taken from healthy males and patients with ED during different penile conditions (flaccidity, tumescence/rigidity, detumescence). Thirty-two healthy adult males and 25 patients were exposed to visual and tactile erotic stimuli in order to elicit penile tumescence and, in the group of healthy volunteers, rigidity. Whole blood was aspirated from the corpus cavernosum and the cubital vein, and ET-1/-2 was determined in plasma aliquots by means of an enzyme-linked immunoassay (ELISA). Mean systemic and cavernous plasma level of ET-1/-2 in blood samples obtained from the volunteers was 0.2-0.7 fmol/ml. In the healthy males, no changes in ET-1/-2 levels were observed in the systemic and cavernous blood during penile tumescence, rigidity and detumescence. In the group of patients, mean plasma ET-1/-2 levels in the phase of penile flaccidity and detumescence were found to be higher in the systemic circulation than in the cavernous blood (flaccidity: 0.52+/-0.38 fmol/ml vs. 0.48+/-0.46 fmol/ml, respectively; detumescence: 0.53+/-0.33 fmol/ml vs. 0.27+/-0.11 fmol/ml, respectively). No differences in the plasma courses of ET-1/-2 were found between patients with an organogenic and psychogenic etiology of ED. In the phase of detumescence, the mean ET-1/-2 level was lower in the cavernous blood cavities taken from the patients than in the samples obtained from the healthy males. Our study revealed a difference in the profiles of ET-1/-2 registered in the cavernous blood of healthy subjects and patients with erectile dysfunction. Nevertheless, since this difference seems to be of no physiological significance, our data counteract the hypothesis of an ultimate importance of ET-1 in the control of penile flaccidity and detumescence and do not support speculations regarding an involvement of ET-1 in the pathop

Topics: Adult; Case-Control Studies; Endothelin-1; Endothelins; Erectile Dysfunction; Humans; Male; Middle Aged; Penile Erection; Penis; Peptide Fragments; Reference Values

The role of the sympathetic adrenergic nerves in mediating the constant tone of penile flaccidity and returning the erect penis to its flaccid state is fairly well established. However, it is not yet known whether additional nonadrenergic transmitters are involved in this process. The peptide endothelin-l (ET-1) may be one of the factors contributing to such a control. Moreover, it has been speculated that ET-1 might be involved in the pathophysiology of penile erection. The present study was undertaken to determine whether or not there is a difference in the courses of ET-1/-2 plasma levels recorded in systemic and cavernosal blood taken from healthy males and patients with erectile dysfunction (ED) during different penile conditions (flaccidity, tumescence/rigidity, detumescence). The study groups comprised 33 healthy adult males and 25 patients. The subjects were exposed to visual and tactile erotic stimuli in order to elicit penile tumescence and, in the group of healthy volunteers, rigidity. Whole blood was aspirated from the corpus cavernosum and the cubital vein, and ET- 1/-2 was determined in plasma aliquots by means of an enzyme-linked immunosorbent assay (ELISA). Mean systemic and cavernosal plasma levels of ET- 1/-2 in blood samples obtained from the volunteers was 0.2-0.7 fmol/ml. In the healthy males, no changes in ET-1/-2 levels were observed in the systemic and cavernosal blood during penile tumescence, rigidity and detumescence. In the patients, mean plasma ET-1/-2 levels during penile flaccidity and detumescence were found to be higher in the systemic circulation than in the cavernosal blood (flaccidity 0.52 +/- 0.38 fmol/ml vs 0.48 +/- 0.46 fmol/ml, respectively: detumescence 0.53 +/- 0.33 fmol/ml vs 0.27 +/- 0.11 fmol/ ml, respectively). No differences in the plasma courses of ET-1/-2 were found between patients with an organogenic and those with a psychogenic aetiology of ED. During detumescence, the mean ET-1/-2 level was lower in the cavernosal blood taken from the patients than in the samples obtained from the healthy males. Our study revealed a difference in the profiles of ET-l/-2 in the cavernosal blood of healthy subjects and patients with erectile dysfunction. Nevertheless, since this difference seemed to be of no physiological significance, our findings contradict the hypothesis of the ultimate importance of ET-1 in the control of penile flaccidity and detumescence and do not support speculations regarding the involvement of E

Topics: Adult; Case-Control Studies; Endothelin-1; Endothelins; Enzyme-Linked Immunosorbent Assay; Erectile Dysfunction; Humans; Male; Middle Aged; Penile Erection; Penis; Peptide Fragments; Reference Values; Regional Blood Flow

Erectile dysfunction (ED) is a common problem that significantly affects the quality of life. Benign prostatic hyperplasia (BPH) is the commonest known benign proliferative disorder. Recently there has been growing evidence to suggest that patients with high BPH symptom scores have an increased incidence of ED. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is thought to play an important role as a modulator of erectile physiology and dysfunction. We investigated whether there are any changes in the density and distribution of ET-1 and its receptor subtypes in the corpora cavernosa (CC) of a rabbit model of partial bladder outflow obstruction (BOO). ET-1, endothelin-A- and -B- (ET(A) and ET(B)) receptor binding sites were primarily localized to the smooth muscle cells (SMC) of the CC and the endothelium lining the cavernosal space. ET(B)-receptor binding sites were significantly decreased (p = 0.04) in the 6-week BOO cavernosal tissue. ET-1 may play a role in the pathophysiology of ED associated with BPH. This may be partly a result of enhanced vasoconstrictor actions and SMC proliferation secondary to a reduction in ET(B)-receptors. Further work is needed to evaluate this possibility.

Topics: Animals; Binding Sites; Endothelin-1; Erectile Dysfunction; Male; Muscle, Smooth, Vascular; Penis; Rabbits; Receptor, Endothelin B; Receptors, Endothelin; Urinary Bladder Neck Obstruction

In the present study venous plasma concentrations of testosterone (T), nitric oxide (NO) and endothelin 1-2 (ET1-2) in the flaccid penis and brachial blood were measured in men with psychogenic impotence. T and NO were significantly lower in the penile venous blood, while ET1-2 showed no statistical difference. These data support the hypothesis of testosterone dependence of penile nitric oxide synthesis (NOS).

Topics: Adult; Arteries; Brachiocephalic Veins; Endothelin-1; Endothelin-2; Erectile Dysfunction; Humans; Male; Middle Aged; Nitric Oxide; Penis; Testosterone

We evaluated plasma concentration of endothelin-1 in diabetic and nondiabetic men complaining of erectile dysfunction, and the variation of endothelin-1 in cavernous body blood during intracavernous injection of prostaglandin E1.. We evaluated plasma concentrations of endothelin-1 in venous blood of 20 men with erectile dysfunction, 10 with and 10 without diabetes. Plasma concentration of endothelin-1 was also evaluated in the cavernous body blood of the 20 men with erectile dysfunction, during erection induced by intracavernous injection of 10 micrograms prostaglandin E1. A severe vasculogenic component of erectile dysfunction was excluded in all patients.. Basal plasma concentration of endothelin-1 in the cubital vein was increased in nondiabetic (1.13 +/- 0.4 pg./ml.) and in diabetic (1.80 +/- 0.2 pg./ml.) patients with erectile dysfunction, compared to control men (0.64 +/- 0.1 pg./ml.) (p < 0.0005 and p < 0.0001, respectively), and in diabetic compared with nondiabetic patients (p < 0.002). No difference and close correlation were observed in the concentration of endothelin-1 in the cavernous body blood evaluated 5 minutes and 30 minutes after injection of prostaglandin E1 (r = 0.89, p < 0.0001, y = 0.98 x + -0.066). The concentration of endothelin-1 in the cavernous body blood evaluated 30 minutes after injection of prostaglandin E1 did not show any difference compared to peripheral venous concentration of the peptide in the 2 patient groups. Concentrations of endothelin-1 in the peripheral vein and the cavernous body blood were not different in patients with a full erection compared with incomplete penis erection after injection of prostaglandin E1 in the cavernous body.

Topics: Adult; Diabetes Complications; Diabetes Mellitus; Endothelin-1; Erectile Dysfunction; Humans; Male; Middle Aged

Diabetes Mellitus (DM) is a major risk factor for erectile dysfunction in both patients and animal models. The pathogenesis of this dysfunction has not been fully elucidated. However, alterations in the synthesis of a number of vasoactive compounds, such as nitric oxide (NO) and prostacyclin (PGI2), have been reported in various diabetic tissues. The interaction between NO, PGI2 and endothelin-1 (ET-1), a powerful vasoconstrictor and smooth muscle cell mitogen, is thought to be important in maintaining vascular tone and the erectile process. We investigated the density and distribution of ET-1 and endothelin receptor subtypes in cavernosal tissue and assessed any changes brought about by DM in a rabbit model.. DM was induced in New Zealand White rabbits using alloxan. Penises were excised from the diabetic rabbits three months (n = 6) and six months (n = 6) after the induction of DM. Low and high resolution autoradiography was performed using radioligands for ET-1, endothelin A (ETA) and endothelin B (ETB) receptors and were analyzed densitometrically. The results were compared with those from six age-matched healthy control rabbits for each group. Immunohistochemical localization of ET-1 immunoreactivity was also performed, together with ultrastructural evaluation of the corpus cavernosum.. ET-1, ETA and ETB receptor binding sites were primarily localized to the smooth muscle cells of the corpus cavernosum and the endothelium lining the cavernosal spaces. A significant increase in ETB receptor binding sites was found only in cavernosal tissue six months after induction of DM, when compared with age-matched healthy controls. These receptor changes were accompanied by ultrastructural changes in the corpus cavernosum indicative of an early, atherosclerosis-like process.. The autoradiographic and immunohistochemical findings in this study suggest that ET-1 may have a role in the pathophysiology of diabetic ED. This peptide may be released in an autocrine fashion causing cavernosal smooth muscle cell (CSMC) contraction and/or proliferation.

Topics: Animals; Autoradiography; Binding Sites; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Endothelin-1; Erectile Dysfunction; Immunohistochemistry; Male; Penis; Rabbits; Receptor, Endothelin B; Receptors, Endothelin