Paulo Roberto de Brito Cunha
Estrada dos Três Rios, 654
Jacarepaguá, RIO, RJ
Consisting of a single layer of cells, the endothelium was considered as a simple covering tissue. The only information we have had was that it is the only cell presenting Weibel-Palade corpuscles (sequestrating the von Willebrand protein, the anti-hemophilic factor VIII, Selectin P and Interleukin 8). Today, we know that it is a single organ, the largest one of the mammalians, of circadian behavior, formed long before the first fetal hearth beat, with autacrine, paracrine and endocrine functions, covering the internal surface of the cardiac cavities, arteries, arterioles, venules, lymphatic and of the seminiferous tubules. Due to inexistence of the smooth muscular cell, the endothelium consists of a single structure of the capillaries and, particularly, of cavernous corps sinusoids (Protásio et al 2003).
The endothelium is able to synthesize the so called autacoids, because they are characterized by being produced, acting and degrading in situ, without having any distance action. There are vessel dilating autacoids: the nitric oxide (endothelium derived relaxing factor – EDRF), the endothelium derived hyperpolarizing factor (EDHF) and the prostacyclin; there are vessel constrictors: the angiotensin II, endoteline-1, thromboxane A2 and the oxygen free radicals (superoxide, hydrogen peroxide, hydroxyl radicals).
In a quite figured mode, we may compare the endothelium to the computer system managers, like the “Windows”, “DOS”, “Linux”, etc. Nothing happens in the mammalians without their participation. The endothelium is the “Mammalians System Manager”. The properties of the endothelium are: (a) to regulate the Thrombotic and fibrinolytic properties, (b) to mediate the antiinflammatory and immune mechanisms, (c) to regulate the adhesion of platelets and leucocytes, (d) to maintain the cavernous tissular structure, modulate the smooth vascular tonus, (e) to produce and release Nitric Oxide – NO, (f) to modulate the growth of the smooth muscular cell, (g) to regulate the oxidation of lipids, (h) to regulate the vascular permeability, (i) to promote the angiogenesis and vascular remodeling (Protásio et al 2003).
The physical, chemical and biologic phenomena, under normality or abnormality conditions, modulating the smooth vascular musculature tonus, stimulate the endothelium to produce active vessels responses or activate the endothelium to produce new substances.
We may highlight the production, under normality conditions, of nitric oxide (NO), a gas with average life of up to 20 seconds and with smooth muscular cell relaxing properties, by activating the guanylate cyclase, generating the GMPc, that will joint a specific and GMP-depending protein kinase to cause ionic changes in the calcium and potassium channels. Other relaxing substances of the smooth musculature are also produced under normality conditions. Among other ones, we can mention the prostaglandin, being responsible for the production of AMPc.
The tree isoforms of nitric oxide are composed by nNO, eNO, called constitutive and calcium-depending, and by the form-induced iNO, calcium independent and produced by the macrophages in the bacterial processes, being common in septic choke. The endothelium activators are the nNO (neuronal nitric oxide) produced, in essential mode, by the NANC nerve (non-adrenergic and non-cholinergic) and the eNO (endothelial nitric oxide) produced by the endothelium itself. The eNO is found in the caveolae of the endothelial cell in inactive form and strongly linked to calmoduline. The nNO increases the endothelial calcium concentration, breaking this NO-Calmoduline link and activates the eNOS (NO endothelial synthetase). The initial activation of the endothelium in the penile erection process occurs only by stimulus of the nNO. The production of NO requires a medium being rich in oxygen. Under conditions of cavernous tissular hypoxia a larger production of TGFb¹ occurs with blockage of the nitric oxide synthetase.
The AMPc is activated by the prostaglandin. The AMPc and the GMPc of the smooth muscular cell are blocking the calcium channels reducing it intracellular concentration and, in this way, determining the smooth muscular relaxation. The smooth muscular relaxation happens in an endothelium dependent way, requesting, therefore, an endothelial integrity grade. The shear stress (a mechanical cutting force exerted by the blood flow against the endothelium) has an important role to maintain the erection activating the NA-K-ATPase pump of electrogenic form and interfering in the calcium channels.
Summarizing: The erection requires an initial neural stimulus and is maintained by the shear stress of the blood on the endothelium.
We designate as atherosclerotic process all the inflammatory processes of the endothelium, differently from that formerly proposed. Therefore, it goes behind the concept that it means the simple deposition of oxidized fat on the vascular intimae in the endothelium.
PROFILING OF THE ENDOTHELIAL DYSFUNCTION, ERECTILE DYSFUNCTION AND CARDIOVASCULAR DISEASE
Erectile Dysfunction It is the incapacity to obtain and maintain an erection with sufficient quality to have sexual intercourse under satisfactory conditions.
Endothelial Dysfunction It is a chronic, progressive and systemic process, having as characteristics the inflammatory and fiber proliferative response of the arterial wall, caused by aggressions to the arterial surface. It is characteristically represented by the compromising of the smooth muscular relaxation.
Cardiovascular Diseases They are diseases compromising the cardiovascular system, having the atherosclerosis as the main etiology, which may result in myocardial infarct as it utmost consequence.
According to the NIH (National Institute of Health, United States), 1992, the erectile dysfunctions (ED) are of organic causes in 75%, with behavioral prevalence nearing 100%. The vascular lesions represent 70% of the EDs of organic causes. We may consider that 40% belong to the vascular causes itself and 30% to diabetes, in an indirect way (this last one determines as main lesion of the vascular intimae the hyaline atherosclerosis, being similar to the atherosclerosis being quite common in elderly). The endocrine causes, without becoming exclusively gonadal causes (hypo- / hyperthyroidism, prolactinoms, depression, etc.) represent 3%, the neurological causes 5%, the pelvic traumatic causes 6%, the dug interactions represent 15% and other ones represent 1% (Goldstein I. 2000; Ferrini MG et al 2004; Feldman et al 1994).
We know today that there is a strong association of the erectile dysfunction with the vascular risk factors and with the cardiovascular diseases, and that the common component is the compromise of the endothelial integrity (Kevin L. Billups). Obesity and dislipidemia are the main prevalence associated to the erectile dysfunction and to the coronary artery disease, if compared with diabetes, hypertension and smoke habit (Walczak MK et al 2002).
In men with ED and without treatment of the coronary artery disease, the severity of the penile vascular disease identified by Eco Doppler test (with pharmacological prove) is associated to increased levels of ultra sensitive reactive C-Protein, as well as this last one is associated to central obesity (Figure 1A and B). These chain rings allows us to primarily consider that the cardiovascular diseases, before being considered as ED comorbidities, may be endothelial dysfunction markers, it means: an integral part of the whole process. In the same way, the erectile dysfunction symptom may be also considered as an endothelial dysfunction marker (Dzau et al. 1997) (Ferrini MG et al. 2004) (Walczak MK et al 2002).
Following assessments as important methods of endothelial assessment:
· Mobility Assessment: Eco color Doppler of the carotids and vertebrae, flow mediated by the dilation of the brachial artery reactive hyperemia, contractile response of the smooth muscular cell due to the action of acetylcholine and Eco color Doppler of the cavernous arteries with pharmacological prove. The brachial artery reactive hyperemia (endothelium-dependent flow-mediated dilation – FMD) consists in the test best assessing the endothelial function, starting from the mobility assessment.
· Biochemical Assessment: Ultrasensitive reactive c-protein plasmatic levels, of fibrinogen, interleukins 1, 6, 8, of TFN-alfa, etc. For the Brazilian reality, due to the large economical advantages, the assessment of ultrasensitive reactive c-protein substitutes the penile test with eco color Doppler, with pharmacological prove (Telöken et al 2004)
Which are the benefits of investigate the ED as an endothelial marker? Far before representing a cardiovascular disease, the erectile dysfunction may be one of the first signs of sub-clinical atherosclerosis (understood, in the present case, as a vascular endothelial inflammatory process) (Jarasuniene D, Simaitis A 2003). The endothelial dysfunction precedes the clinical signs of the different phases from the atherosclerotic vascular diseases. Considering that it represents a prognostic index, the treatment of ED can and must be directed to the basic causes of the endothelial dysfunction, the therapeutic goal, particularly for the vascular risk factors (Protásio 2003). (Kevin L. Billups). We already can, starting from this point, state that the diseases formerly designated as comorbidities are, actually, an integral part of this process, the “system of cardiovascular diseases / dysfunctional erectile and / or endothelial”.
Multiple factors may be concurrent for the endothelial dysfunction (Shimokawa H.). The vascular oxidative stress (excess of free radicals production – Reactive Oxygen Species- ROS) causing the inactivation of eNO is the primary mechanical basis of the endothelial dysfunction (Protasio 2003). A free radical reduces the expression of the available NO and determines an inflammatory process as response, increasing the production of TGF-b, reducing the fibroblast apoptosis and increasing the myofibroblast, resulting in irreversible vascular fibrotic processes. Due to the fact that the endothelium is a single organ, we affirm that penile endothelial cells use the same metabolic pathway of all other endothelial cells to produce NO.
Which is the advantage to investigate the ED – even those not related one – in the age range presenting the largest prevalence? As an adjuvant in the early diagnosis of arterial hypertension, insulin resistance, diabetes, dyslipidemia, coronary disease, etc., the investigation of the erectile quality allows that the men is seen by the urologist as a whole (Whitehead ED y Klyde BJ 1990) (Wei M et al 1994). This methodology does not requires that the urologist is obliged to have full training and competence to treat cardiovascular diseases with larger complexity level (Barret-Connors E 2004). It does not require, in this propedeutic phase, the support of other experts. This methodology allows, even in an indirect way, a preventive actuation with all it social benefits.
Erectile dysfunction must be considered as a cardiovascular disease marker preceded by metabolic dysfunction (central obesity – assessed by an abdominal circumference larger then 102 cm; dyslipidemia – assessed by HDL level lower than 40mg% and of triglycerides higher than 150 mg%; arterial hypertension – higher than 130 x 85 mm Hg; insulin resistance and diabetes – assessed by glycemia higher than 100 mg%). It is also most commonly seen in men with several independent components of metabolic syndrome (Ogawa Y 2005). Atherosclerosis, vessel constriction and thrombosis are resulting from the oxidative stress. Eighty percent (80%) of the patients with ED setting are obese. Eighty two percent of the patients presenting diabetes are sedentary. In ED patients, the incidence of insulin resistance is three times higher, and 85% of the DM II is insulin resistant in the pre-diabetes phase. Being common in the sedentary individuals, the central type obesity indicates an endothelial affection, exiting a strong association of the sedentarism, increased ultrasensitive C-reactive protein, non-hepatic and non-alcoholic esteatosis and endothelial dysfunction (Yoon D et al 2005).
Obesity, Hypogonadism and ED. Which is the link between them? Adipous tissue functions as an endocrine gland. More than 100 families of proteins, as well as fatty acids and prostaglandins are secreted by the adipous tissue. The tumoral necrosis alpha factor (TNF-a), interleukin 6 (IL-6), interleukin-8 (IL-8), plasminogen activator inhibitor (PAI-1), angiotensin II, leptin and adiponectin are of particular interest (Hauner H. 2005; Strazzullo P. and Galleti F. 2004). Due to the increased consumption of NO, some adipocytokines determine an endothelial oxidative stress status and of chronic inflammation, with reduction of the smooth muscular relaxation and affecting the erectile response. The adiponectin circulates in high concentration and it plasmatic levels are higher in slim individuals, if compared to the levels of visceral or central obese individuals. The visceral adiposity has been considered as an independent marker of adiponectin levels. The adiponectin is reduced in central obese individuals, in the insulin resistance phase preceding the type II diabetes. Excepting the adiponectin, the plasmatic concentrations of other cytokines are increased in central obesity. The primary mechanism causing increased insulin sensitivity of the adiponectin is probably due to it involvement in the fatty acid oxidation of the triglycerides and in the inhibition of hepatic glycogenesis (Lihn AS et al 2005) (Ross R et al 2002).
Insulin resistance may be the main responsible condition for the accumulation of triglycerides in the hepatocytes. According to C. Ronald Kahn, M.D., and Cullen Taniguchi, M.D., Ph.D., from Joslin Diabetes Center (Cell Metab. 2006 May;3(5):343-53), the control of glycemic and lipids levels, differently from that being formerly proponed, use different subunits in the Phosphatidyl Inositol 3 Kinase (PI3K) pathway. Akt (serine treonin) is responsible for the glycemic control and PKC in the atypical form by the metabolism of lipids. This explains why some patients with hepatic fatty diseases do not present glycemic changes and others do not present lipids changes in the presence of type II diabetes. A large quantity of studies demonstrated the importance to use substances determining the increase of the sensitivity to insulin and of antioxidants or endothelial protectors. The adiponectin is reduced by the action of inflammatory cytokines, mainly by the tumoral necrosis alpha factor (TNF-a).
In a conclusive way, the adiponectin increases the sensitivity to insulin, further to it antiatherogenic and antiinflammatory effects. Associated to this fact, the increase of aromatasis in obsess individuals reduces the plasmatic levels of testosterone and of the libido and increases the estrogen (estradiol) levels, by means of an aromatization process. Further to the adiponectin, the adipocytokines visfatin and omentin increase the sensitivity to insulin, whereas the TNF-a, IL-6 and resistin increase the resistance to insulin (Lihn et al 2005). Primarily produced in the liver, the protein C-reactive is a protein of the acute inflammatory phase. The adipous tissue secretes IL-6, which regulates the production of PCR, being possible to result in a chronic systemic inflammation in individuals with corporal fat excess (Pilz S et al 2005).
Further to the suprarenal and testes, which are the main sources of sexual hormones, the adipous tissue participates of the activation, conversion and inactivation of steroids in an enzymatic way. Among the main enzymes, we can mention the cytochrome P450 aromatasis dependent and desidrogenase 17 beta-hydroxysteroid (17βHSD). Aromatasis is responsible for the conversion of androstenediona in estrone and of testosterone in estradiol. The 17βHSD mediates the conversion of androstenedion in testosterone and estrone in estradiol. Related to the aromatasis, the enzyme 17βHSD is found with lower concentration in the subcutaneous adipous tissue and with higher concentration in the central adipous tissue, implying in the larger production of androgen in central obesity (Belanger C et al). Seventy percent of elderly men, obese and with metabolic syndrome have total testosterone levels reduced in a significant way (< 400 ng/dl), according to Steven A Kaplan (AUA, Atlanta; 2006. Abstract 692). According to the same author, in the association of ED and diabetes a hypoadrenergic component may be also involved. The levels of testosterone, LH and SHBG are decreased and the plasmatic level of estradiol is increased in the metabolic syndrome of the men.
The first line treatment consists in the life style change. Exclude smoking, avoiding alcohol and energetic diet as well as execute regular physical activity results in the reduction of the mass of central body fat. This reduction is associated to the improvement of the erectile response in 30% of the individuals with ED (Esposito K and Giugliano D 2005). The participation of a professional – psychologist, etc. – is important in this phase to provide the necessary support to those being most commonly present in the human being that is the resistance to changes. It is important to mention that with the autoesteem being affected by the body shape, an obese individual suffers the traumatic consequences of the social discrimination. It is not uncommon that this discrimination is actively executed by some healthcare professionals. However, it must be pointed out that the extreme weight loss due to exclusively esthetical motives, like that observed in bariatric surgeries, can result in deficiency of zinc and, as consequence, determine hypogonadism and impotence due to the low production of testosterone. Ss there are no studies to safely establish if the hypogonadism is the cause or consequence of the metabolic syndrome, or if it is an integral part of the last one, the reposition of testosterone to reduce the central obesity is not covered by scientific truth.
The man, being collector and hunter, is not genetically adapted to sedentarism, the “Syndrome of Social Modernity”. Expressed by obesity, his genes remain in the Stone Age in spite of living in the current XXI century. The regular practice of physical activity – should be not confounded with physical exercise, mainly with the inefficacy of abdominal exercises – has as benefit the remarkable improvement of the endothelial function, in all phases of life. Due to the reduction, and as a chain reaction, of the central obesity and of the resistance to insulin, dyslipidemia, interleukin 6, TNF-alpha, leptin, ultrasensitive reactive C protein, oxidative stress and of the endothelial dysfunction we will have the increase of eNO synthesis, sensitivity to insulin, endothelial dependent vessel mobility response, erectile response, response to L-arginin and of the endothelial function (Esposito K y Giugliano D 2005) ( Ross R et al 2000) ( Lindstrom S 2003). Bing usually reduced in the endothelial inflammatory processes, the circulating number of endothelium precursor cells derived from bone marrow stem cells are increased in function of the physical activity (Rehman J). The chronic use of iPED5 determines the same benefits, favoring the angiogenesis. However, in individuals with BMI lower than 25 m²/kg – usually not belonging to DCV or DMC II risk groups – erectile dysfunction was considered as metabolic syndrome predictor. In men with ED and BMI of 25 m²/kg the probability of metabolic syndrome expression was increased in 2 times. This founding, in an erectile dysfunctional setting, causes a primary intervention in cardiovascular diseases, also in non-obese individuals, being formerly considered as included in the low vascular risk group (Kupelian, Varant; Shabsigh, Ridwan; Araujo, Andre B; O’Donnell, Amy B; McKinlay, John B).
In contrast, the diet aiming to avoid aggressions to the endothelium has it results limited to the phase of life in which it appears (Derby CA. et al 2000).
As a prophylactic measure, together with the intervention on the modifiable factors of vascular risk (sedentarism, smoking, abuse of alcohol, highly caloric diet, visceral obesity) we may use the antioxidant therapy, an excellent weapon to prevent pathologies of the smooth muscular cells and cavernous tissular fibrosis in erectile dysfunction (Espósito K et al 2003). The use of pomegranate (Punica Granatum L), (a fruit being originally from Iran) and of red wine, due to the high concentration of polyphenols, has demonstrated to be an excellent weapon (Aviram M et al 2004). Recent works also demonstrated, in vitro, the inhibitory action of PDE5 from the polyphenols contained in the red wine (Dell´Agli M et al 2005). In the same way, the grape juice resulted benefic to the endothelium (Protásio 2003). Resulting from his high concentration of catechins, the daily use of green tea (Camelia sinensis) reducing the corporal adiposity, suggests that the catechins may be useful in the prevention and improvement of the diseases called “modifiable vascular risk factors” or “life-style dependent”, mainly for the obesity present in the metabolic syndrome (Nagao T et al ).
The endothelial dysfunction precedes the vascular lesion in the early phase of hypo- / hypercholesterolemia (Tesfemariam B.). The main benefit resulting from the use of HMG-CoA reductase inhibitors (statins) is the normalization of the endothelium dependent smooth muscular relaxation. This phenomenon, occurring far before the reduction of plasmatic cholesterol levels, results from the larger bioavailability of nitric oxide and oxidative stress reduction. The ingestion of antioxidant complexes is particularly important (vitamins C, E, beta-carotene, chrome, manganese, selenium, etc.).
The chronic use of iPED5 as therapeutic method in the inflammatory phase resulting from several pathologies (ischemia, dyslipidemia, hyperglycemia, arterial hypertension, Peyronie disease, priapism, trauma, etc.) may be efficient for the reversion of the evolution of fibrotic processes from the cavernous body (Tejada IS). The use of Syldenafil, in high doses (100 mg) is able to increase the number of cavernous smooth muscular cells after radical surgery of the prostate (Schwartz et al J Urol. 2004). The penile fibrosis, characterized by the percentile increase of collagen and having the endothelial dysfunction as primary cause, is responsible for the permanent fail of the pharmacological treatment of erectile dysfunction (Tejada IS). It cannot be requested from the iPED5 more than those being requested from the endothelium.
In a consequent way and being not under demand, and primarily looking for an benefic intervention on the endothelial response, we associated antioxidants to the PDE5 inhibitors (iPED5) (Brito Cunha 2005). Several papers demonstrated that the continuous use of iPED5 is important in the recovery of the vascular endothelium, as a result of the increased number of endothelium precursor cells (Sommer F, Schulze W). The endothelium precursor cells are of fundamental importance in the recovery of the damaged endothelium and the increased number of the circulating cells indicates a reduction of the endothelium inflammatory processes. The number and migratory activity of the endothelium precursor cells derived from the bone marrow are inversely proportional to the vascular risk factors (Vasa M et al), for the oxidative stress. Differently, the inflammatory CECs (circulating endothelial cells), representing the mature endothelial cells separated from the endothelial single layer are increased as a result of the endothelial lesion (Goon PK, Boos CJ, Lip GY).
When investing in men overall health, the possibility to reassume the sexual activity is an important motivation factor in the treatment of obesity and their related issues. To prophylactically and primarily intervene on the vascular risk factors and their endothelial and cardiovascular consequences is to increase the possibilities of erectile function recovery and postpone the surge of cardiovascular diseases. To currently consider the treatment with oral PDE5 inhibitors as first line treatment not considering the necessity to identify the factors, being cardiovascular in their majority, is to impose the medium to justify the finality. To consider the failure of the oral treatment without intervene on the causes is to request from the drug more than it may be requested from the endothelium. To establish secondary treatments or even tertiary ones (vacuum pumps, intracavernous injections, penile implants, etc.) are, at least, an earliest determination of the patient’s sexual death. To deny the ED as an indicator of silent vascular disease, refusing the consideration that a patient presenting ED and without cardiovascular symptoms is, until it is proven in opposite way, an individual with cardiopathy setting, is a refuse of the II Consensus of Princeton about ED and Cardiac Risk, It is currently not believable to suppose that someone is denying the existence of a large sharing between the erectile dysfunction, cardiovascular disease and endothelial dysfunction.
Paulo Roberto de Brito Cunha
Estrada dos Três Rios, 654
Jacarepaguá, RIO, RJ
Author of the book “Disfunção Erétil e o Endotélio” [Erectile Dysfunction and the Endothelium]. Editora Gaunabara Koogan; Rio de Janeiro; 2005. Responsible for the Sexual Medicine Section of the Hospital General de Jacarepaguá in Rio de Janeiro; Head of the Andrology Department of the Brazilian Society of Urology – Sectional RJ (biennial 2003/2005 and 2006/2007); Effective member of following societies Brazilian Socity of Urology – SBU, Brazilian Association for the Study of Sexual Inadequation – ABEIS, International Society for Sexual Medicine – ISSM and Latin American Society of Sexual Medicine – SLAMS. Elected president of ABEIS for the biennial 10/11.
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