Yousry Endothelial Vs Erectile Dysfunction

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the relation between endotelium dysfuction as a vascular etiology to penile erectile dysfunction

the relation between endotelium dysfuction as a vascular etiology to penile erectile dysfunction

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  • 1. ENDOTHELIAL DYSFUNCTION ( ED ) in ERECTILE DYSFUNCTION( ED ) ED = ED M.Y.ABDEL_MAWLA,MD Zagazig Faculty of Medicine,EGYPT
  • 2. Erectile DysFunction( ED )
  • 3. Male Genital Anatomy
    • Two paired corpora cavernosa (erectile bodies) and a single corpus spongiosum surrounding the urethra, all encased within Buck’s fascia
    • The erectile tissue is comprised of a network of vascular sinusoids surrounded by trabecular smooth muscle.
  • 4. Vascular Supply
    • The blood supply to the penis is derived from the pudendal artery which branches from the internal iliac (hypogastric) artery.
    • Cavernosal arteries course through the center of each corporal body and give rise to multiple helicine arteries which open into the lacunar spaces.
  • 5.
    • Two types of erections – a) Reflexogenic b) Psychogenic
    • Blood flow increases secondary to vasodilatation of the cavernosal arteries
    • Relaxation of smooth muscle dilates the lacunar spaces causing engorgement
    • Increased intracorporal pressure expands the trabecular wall against the tunica albuginea
    • Compression of the subtunical veins along with a reduction of venous blood flow results in elevated pressures in the lacunar spaces, “ veno-occlusive” mechanism
    Mechanism of Erection Flaccid penis - arterial pressure 20mm/Hg Fully erect - arterial pressure 80-100mm/Hg
  • 6. Neuroanatomy
    • The parasympathetic nervous system provides excitatory input causing vasodilation and erection. (autonomic)
    • The sympathetic nervous system provides input which results in detumescence , maintains flaccidity , and emission . (autonomic)
    • Somatic sensory nerves provide sensation of the penile skin, glans, and urethra. ( dorsal nerve ).
    • The motor pathway lies within the sacral nerves to the pudendal nerve and innervate the bulbocavernous and ischiocavernous muscles and allow for ejaculation.
  • 7. The Whole Picture
  • 8. Nitric Oxide(NO) /cGMP PATHWAY in CORPORA CAVERNOSA
    • Relaxation of the smooth muscle trabeculae of the corpus cavernosum (CC)  & the helicine arteries leads to blood filling of the sinuses, occlusion of the venous outflow& penile erection.
    • Nitric oxide (NO), generated by both nerves( n ) & the endothelial( e ) cells that cover the trabeculae of the CC, through stimulation of soluble guanylate cyclase and the generation of cyclic GMP play a dominant role in relaxation of smooth muscle in this tissue.
    • Acetylcholine stimulates the endothelial cells to produce NO , which penetrates into and activates the muscle cells causing relaxation .
    • Other signaling pathways : vasoactive intestinal polypeptide /cAMP may also be operative in relaxation of the CC.
  • 9. (L-NMMA) = N(G)-mono-methyl-L-arginine
  • 10. ( L-NMMA ) = N(G)-mono-methyl-L-arginine (L-NMMA) = N(G)-mono-methyl-L-arginine
  • 11.  
  • 12. Causes of Erectile Dysfunction( ED ) Endothelial dysfunction ED Smoking Hypogonadism Endocrine Disorders Hypertension Hyperlipidemia Alcohol abuse Drug abuse Anemia Trauma/surgery to pelvis or spine Peyronie’s disease Vascular surgery Depression
  • 13.  
  • 14. The Endothelium
  • 15. LUMEN Tunica adventitia Tunica media Tunica intima
  • 16. Vasoconstriction and dilatation Normal Vasoconstriction Vasodilatation
  • 17. Vasoconstriction Vasodilatation Vasoconstriction and dilatation ↓ Resistance to flow ↑ Resistance to flow
  • 18. Endothelial Apoptosis Normal Apoptosed
  • 19. The Endothelium As an Endocrine Organ
  • 20.
    • The inner lining of our bloods vessels is the Endothelium
    • It plays a central role in regulating the vasomotror tone & Local homeostasis & control of the coagulation process
    • Endothelial cells have ‘Sensors’ and release ‘Mediators ’
    • ‘ Mediators’ are the functional molecules on the cell surface
    The Vascular Endothelium
  • 21.
    • Nitric oxide (NO)
    • Cycloxygenase (CxO)
    • Endothelin-1 (ET-1)
    • Endothelium Depolarisation Factor (EDF)
    • Prostanoids
    • Angiotensin
    • Rho/Rho-kinase
    • Prostaglandin E &prostacyclin (cAMP pathway).
    Vascular Endothelial Mediators
  • 22.
    • Half-life of NO, is affected by its chemical reaction and inactivation by superoxide anion
    • NO is the most abundant free-radical in the body
    • It is the only biological molecule in high concentrations to out-compete superoxide dismutase for superoxide
    • NO has an anti-thrombogenic & anti-atherogenic role
    Nitric Oxide (NO)
  • 23.
    • Endothelial NO has the following actions
    • Smooth muscle relaxation and vasodilatation
    • Essential for regulation of blood pressure
    • Reduces proliferation of vascular smooth muscle
    • Protects blood vessel intima from injurious consequences of platelet aggregation
    Protective actions of NO
  • 24.
    • NO deficiency in the vessel wall promotes
    • Inflammation
    • Oxidation of lipoproteins
    • Smooth muscle proliferation
    • Accumulation of lipid rich material
    • Platelet activation and thrombus formation
    Endothelium Dysfunction & NO Reduction
  • 25. NO induces synthesis of cGMP by stimulation of GC leading to relaxation of myosin (muscle protein)                                                                                                                                             
  • 26.                                                                                         
  • 27. Endothelium –derived vasoconstrictors vs Vasodilators
    • Contractoion- mediating transmitters
    • Endothelin
    • Prostanoids
    • Angiotensin
    • Rho A/Rho-kinase
    • Relaxation-mediating transmitters
    • Nitric oxide & cGMP pathway
    • Prostaglandin E, prostacyclin& cAMP pathway
  • 28. Endothelin peptides Endothelin-1, a 21-amino-acid peptide, is the predominant isoform of the endothelin peptide family that includes ET-2, ET-3, and ET-4 Endothelin-1 is produced primarily by endothelial cells but can also be synthesized by vascular smooth muscle cells (VSMCs) and by macrophages The action of ET-1 are mediated by 2 receptor subtypes, ETA and E TB receptors
  • 29. Endothelin
    • ET A receptor mediate the vasoconstrictor effects of the peptide, ET B receptors on the endothelium stimulates synthesis of NO
    • Increased ET-1 associated with decreased endothelium-dependent vasodilation, a reduction in the biologic actions of NO, and an increased production of oxygen-derived free radicals
    • These effects are thought to contribute to
    • heightened vasoconstriction and increased blood pressure
    • increased monocyte adhesion to the vascular wall
    • increased thrombosis
    • a vascular inflammatory response
    • augmented proliferation of VSMCs
  • 30. Endothelin peptides
    • Endothelin-1(ET-1):synthesied by lacunar endothelium & trabecular muscle
    • It induces contraction,via ETA receptors in penile smooth muscles( corpus cavernosa&cavernosal artery).
    • Contraction : dependent upon increased intracellular calcium via:
    • Transmembrane calcium flux
    • Mobilization of inositol,1,4,5-triphosphate (IP3)-dependent calcium stores
  • 31. Prostanoids
    • Several prostanoids:PGI &thromboxane
    • Synthesized from arachidonic acid via activity of cycloxygenase in human corpus cavernosa.
    • Synthesis :modulated by oxygen tension &hypoxia.
    • They are responsible for tone & spontaneous activity of trabecular muscle.
  • 32. Rho A/Rho-kinase
    • Rho A: a member of Ras low molecular weight of GTP-binding protein.
    • Both Rho A &Rho –kinase :in different cellular functions including smooth muscle contraction.
    • Human endothelial &corpus cavernosa smooth muscle cells express these proteins.
    • RhoA/Rho-kinase signal transduction pathway:signal mediator of endothelial cell function. Rho-mediated Ca2+sensitization of cavernosal smooth muscle maintains the flaccid (contracted) state.
    • This pathway supppresses eNOS gene expression in endothelium.
  • 33. Angiotesin
    • Renin-angiotensinsystem maintains penile smooth muscle tone.
    • Angiotensin 11 evokes smoth muscle contraction of human corpus cavernosa muscle via relevent receptor & increased IP3 &increased intracellular calcium
  • 34. Endothelium-derived vasodilators Functions
    • relax vascular smooth muscle in both arteries and veins
    • NO and PGI2 also inhibit platelet aggregation
    • NO also interferes with the vascular inflammatory process by decreasing the adhesive interactions between the endothelium and circulating leukocytes, thus interfering with the atherosclerotic process
  • 35. Nitric Oxide(NO)/cGMP PATHWAY
    • Severe erectile dysfunction( ED ) in cGMP-dependent kinase 1-deficient mice, with normal cAMP signaling, also demonstrated the importance of PKG and the inability of the cAMP pathway to compensate for the absence of the cGMP signaling cascade  in vivo  .
  • 36. Endothelium-derived NO & vascular tone
    • NO-a potent mediator of vascular relaxation through action on soluble cGMP in VSMC to inhibit ca-dependent contraction
    • NO synthesis & release occurs continuously under basal conditions & can be increased through activation of muscarinic, thrombin, purinergic, and ET B receptors in the endothelial-cell plasma membrane that mediate the actions of acetylcholine, thrombin, ADP, and ET-1 respectively
    • Changes in vascular wall shear forces associated with increased flow also increase NO release
    • Sustained increase in BP-by continuous administration of stereoselective inhibitors of NO synthase further indicates-NO is important in maintenance a vasodilated state.
  • 37.  
  • 38.  
  • 39. ENOTHELIUM DYSFUNCTION( ED )
  • 40.  
  • 41. The Mechanism of the Assocation Between Endothelium&Erectile Dysfunction
  • 42.  
  • 43. The roles of two forms of nitric oxide synthase in cavernosal smooth muscle relaxation and the initiation and maintenance of penile erection Watts Permission obtained from National Academy of Sciences © Hurt KJ et al . (2002) Proc Natl Acad Sci USA 99: 4061–4066.
  • 44. Risk Factors for Development of Endothelium& Erectile Dysfunction
    • Diabetes Mellitus (DM)
    • Insulin Resistance Syndrome.
    • Cigarette Smoking
    • Hypertension
    • Atherosclerosis &Hyperlipidemia
  • 45. Endothelial dysfunction in DM
  • 46. NO and endothelial dysfunction in diabetes
    • Type 1 diabetes- -impaired endothelium-dependent vasodilation in response to acetylcholine and similar agonists that stimulate the release of NO
    • Type 1 and 2 diabetes—endothelium-dependent vasodilatory responses to brachial artery infusions of acetylcholine, methacholine, and similar agonists are impaired in the forearm
    • In normotensive type 2 diabetes—demonstration of blunted endothelium-dependent vasodilation suggests that the endothelial abnormalities cannot be ascribed solely to the impaired endothelium-dependent vasodilation
    • Contribution of prostaglandins to abnormalities in endothelial function is minimal
  • 47.  
  • 48. Mechanisms of impaired endothelium-derived vasodilation in diabetes
    • Biologic actions of NO are diminished in diabetes, but production of NO is actually increased
    • Increase in the production of ROS by several vascular components in diabetics
    • Interactions of NO & superoxide anion within the microenvironment of the vessel wall-- inactivation of NO & formation of the potent oxidant radical, peroxynitrite (OONO - )
  • 49. Mechanisms of impaired endothelium-derived vasodilation in diabetes
    • The ratio of NADH/NAD+ :increased in diabetes reducing the levels of NADPH which is an essential cofactor for NO synthesase & increase levels of calcium elevating messengers, thus increasing smooth muscle contractility.
    • Decreased endothelium –derived hyperpolarization factor( EDHF ) in human penile arteries,hence reduction of endothelium-dependent relaxation
  • 50. Hyperglycemia in DM
    • Associated with diminished biologic actions of NO
    • Tesfamariam: impaired vasodilatory responses to high glucose levels- -caused by increased oxygen-derived free radicals through a protein kinase C-mediated mechanism that stimulates the formation of vasoconstrictor prostanoids
    • The vasoconstrictor effect can be abolished by aldose reductase inhibitors
    • High glucose increase both NO synthase expression & superoxide anion generation by aortic endothelial cells.
  • 51. Dyslipidemia in DM (1)
    • Elevated TG, low HDL-c, and elevated IDL—insulin resistance syndrome
    • Hypercholesterolemia is associated with impaired endothelium-dependent vasodilation in human forearm & pig coronary arteries & rabbit aorta
    • These functional vascular changes associated with
    • Increase generation of ROS
    • Persistence of endothelial NO release
    • Increased generation of OONO-
    • Oxidative modification of LDL
  • 52. Dyslipidemia in DM (2)
    • The extent of ROS formation-also be a determinant of endothelial NO release-it may affect the proportion of circulating and tissue cholesterol that has been oxidized
    • Oxidatively modified LDL- -impair endothelium-dependent vasodialtion more than native LDL in vascular ring
    • Hypertriglyceridemia -independent risk factor for CAD
    • Postprandial hypertriglyceridemia--cause a transient impairment of endothelium-dependent vasodilation in normal volunteers
    • Postprandial hypertriglyceridemia is more exaggerated in type 2 diabetics & associated with higher forearm venous free radical & greater impairment of flow-dependent vasodilation
  • 53. Increased oxidative stress in diabetes
    • Oxidative stress—imbalance between the production of ROS and the numerous antioxidant defense mechanisms present in biologic systems
    • Reactive oxygen species (ROS) include superoxide anion that is converted to hydrogen peroxide both enzymatically and by several isoforms of the enzyme superoxide dismutase
    • In diabetes, overproduction of ROS overwhelms normal antioxidant defenses with consequent alterations in both the function and the structure of the CV system
  • 54. Insulin resistance syndrome and endothelial dysfunction
    • Syndrome of insulin resistance may precede the onset of overt type 2 diabetes
    • The clinical features include hyperinsulinemia, truncal obesity, hypertension, and dyslipidemia characterized by elevated serum TG, low HDL-C, and increased IDL( Fasting blood sugar more than 140 mg/dl)
    • These hallmarks are thought to result from relative insensitivity of selected tissues, particularly skeletal muscle, to the action of insulin
  • 55. Insulin resistance syndrome
    • It is hypothesized that compensatory hyperinsulinemia maintains the serum glucose within the normal range until pancreatic islet  -cells can no longer produce sufficient insulin, and overt type 2 diabetes occur
    • Insulin resistance is associated with a clustering of CV risk factors that predispose patients with this metabolic syndrome to later CV events
    • There is evidence of sympathetic nervous system activation that may contribute to the hypertension that develops.
  • 56. Insulin resistance syndrome
    • Insulin itself promotes vasodilation, in part through stimulation of endothelial NO release
    • This vasodilatory action may be counterbalanced in the insulin resistance syndrome by the development of hypertension, which independently impairs endothelium-dependent vasodilation
  • 57. Endothelin and endothelial dysfunction in diabetes
    • Endothelin-1, a 21-amino-acid peptide, is the predominant isoform of the endothelin peptide family that includes ET-2, ET-3, and ET-4
    • Endothelin-1 is produced primarily by endothelial cells but can also be synthesized by vascular smooth muscle cells (VSMCs) and by macrophages
    • The action of ET-1 are mediated by 2 receptor subtypes, ET A and E T B receptors
  • 58. Endothelin in DM
    • Plasma ET-1 are increased in type 2 diabetes
    • Most of the ET-1 cause vasoconstriction of VSMCs through a paracrine effect mediated by ET A receptors
    • Infusion of ET-1 cause sustained increases in BP
    • Nonselective ET A /ET B antagonist, bosentan, lowers BP in patients with essential hypertension
    • Plasma ET-1-may be a marker for atherosclerotic disease in type 2 diabetic patients
    • ET-1 participate in the fibrotic process--an essential component of the glomerulosclerosis, cardiac and vascular remodling, and atherosclerosis that occur at an accelerated rate in hypertensive type 2 diabetics.
  • 59. Advanced glycation end products (AGEs)in Diabetes
    • AGEs formed by the nonenzymatic binding of glucose to lipids or to free amino groups on proteins
    • The formation of AGEs is inhibited by NO, whose biologic actions are blunted in diabetics
    • The increased stiffness of the arterial wall contributes to isolated hypertension
    • The increased systolic pressure in turn produces an increased workload on the left ventricle, resulting in increased left ventricular mass
    • Reduction arterial wall compliance linked to increased CV risk in type 1 & 2 diabetics and occur early in the course of DM before vascular disease is clinically apparent
  • 60. Adverse consequences associated with endothelial dysfunction in diabetes mellitus
    • Decreased NO formation, release, and action
    • Increased formation of reactive oxygen species
    • Decreased prostacyclin formation and release
    • Increased formation of vasoconstrictor prostanoid
    • Increased formation and release of ET-1
    • Increased lipid oxidation
    • Increased cytokine and growth factor production
    • Increased adhesion molecule expression
    • Hypertension
    • Changes in heart and vessel wall structure
    • Acceleration of the atherosclerotic process
  • 61. HYPERTENSION and Risk of Endothelium & Erectile Dysfuction
    • CVS complications of hypertension is associated wit ED.
    • In ED due to arterial insufficiency: low oxygen tensionin corporal blood,reduced PGE1 &PGE2, Increased tranformation of transforming growth factor(TGF)-B-induced fibrillar collagen synthesis in corpus cavernosa.
    • Diffused venous leakage & failure of veno-occlusive mechanisms.
    • Endothelial –dependent vasodilation:impaired.
    • Age dependent &independent decrease of NO synthesis.
  • 62. Endothelium in Hypertension
  • 63. Endothelial mechanoreceptors changes in hypertension –induced stress
  • 64. Cigarette Smoking
    • Free radicles&aromatic compounds released from cigarette smoke: decrease endothelial NO Synthesae activity and elicit superoxide –mediated NO degradation ,tending to increased penilemisculature & promoting ED.
    • Direct toxic effects of nicotine & CO2 on penile vasculature.
    • Increased hyper- coaglulability agents
  • 65. ATHEROSCLEOSIS & HYPERLIPIDEMIA :Effect on penile endothelium
    • Chronic ischaemia:reduced NOS activity,reduced enothelium-dependent & neurogenic NO-mediated relaxation of cavernosal tissue together with elevated thromboxane-mediated contractions.
    • High LDL : elevated contraction due to increased intracellular inositol & calcium.
    • Chronic hypercholestraemia :
    • Reduced endothelium dependent relaxation in cavernous tissue.
    • 2.Impaired NO/cGMP pathway due to elevated superoxides & NOS inhibitors (eg.nitromonomethyl l arginine L_NMMA).
  • 66. Can We Measure Endothelial Function ??
  • 67. Clinical Methods for Assessing Endothelium - Dependent Dilation
    • Forearm
    • Brachial Artery Diameter  with Arterial Occlusion FMD
    • Forearm Blood Flow with ACh
  • 68.  
  • 69. Penile/Brachial Index (PBI)
        • 0.7 - 1.0 = normal
        • 0.6 - 0.7 = borderline abnormal
        • <0.6 = abnormal
  • 70. What is the Treatment. for Endothelial Dysfunction ??
  • 71.
    • Control of all the known CV risk factors
    • Main focus on the big six – DM, HTN, Lipids, Obesity, Smoking, Sedentary life style
    • Diet and physical activity are vital in Rx of ED
    • Statins are the first line treatment for ED
    • Insulin and Rx. Insulin resistance improves ED
    What is the Treatment for Endothelial Dysfunction?
  • 72. Erectile Dysfunction – Today’s concept
    • Penis is the barometer
    • of Endothelial Health
    • Erectile Dysfunction is a
    • mirror of Cardiovascular Risk
    ED = ED
  • 73.  
  • 74. Targeting Endothelium Dysfunction in Erectile Dysfunction
    • Treating risk factors &disorders.
    • Cessation of smoking.
    • Long term phosohodiesterase-5 inhibitors therapy
    • Antioxidant therapy
    • Future directions
    • Corporal tissue engeneering
    • Gene therapy(eg Rho A/Rho A-kinase antisense gene therapy) .
  • 75. New Horizons in ED Treatment
  • 76.
    • PDE5 inhibitors
      • Sildenafil citrate
      • Tadalafil
      • Vardenafil
      • SLX-2101
      • Avanafil
  • 77.
    • SLX-2101 (2-in-1 Erection Drug)
      • A long and fast acting drug that acts well beyond 48 hours.
      • An oral PDE-5 inhibitor developed to treat endothelial dysfunction leading to smooth muscle relaxation
      • SLX-2101 improves erections not only in men with erectile dysfunction, but also in men already able to have erections .
    New Horizons in ED Treatment
  • 78.
    • Avanafil
      • Faster, Shorter-Acting Erection Drug
      • Highly selective PDE5 inhibitor
      • Reaches its maximum blood concentrations 35 minutes after it is taken, it has a half-life of 90 minutes (compared with four hours for Levitra and viagra and 17.5 hours for Cialis).
      • Due to its shorter acting time, it could be used in men who take nitrate-based heart drugs (such as Nitrostat, Isordil, and Imdur).
    New Horizons in ED Treatment
  • 79.  
  • 80. Type 5 Phosphodiesterase (PDE5) Inhibitors
    • Viagra (Sildenafil) Tabs: 25, 50, 100 mg.
    • Levitra (Vardenafil) Tabs: 2.5, 5, 10, 20 mg.
    • Cialis (Tadalafil) Tabs: 5, 10, 20 mg.
  • 81. New Horizons in ED Treatment
    • GENE THERAPY
    • The penile nNOS ( PnNOS ) is a potential candidate for gene transfer because it is considered one of the NOS isoforms responsible for penile erection . It is present in the nerve terminals in:
    • corpora cavernosa ,
    • pelvic ganglion ,
    • hypothalamus & spinal cord regions involved in the control of reproductive function .
  • 82. GENE THERAPY
    • One of the most promising approaches is gene transfer of NOS cDNA constructs to the corpora cavernosa to increase NOS concentration in the penis.
    • a single injection of a plasmid construct of the inducible NOS (iNOS; NOS II) cDNA corrects for at least 10 days the defective erectile response of the cavernosal nerve in the aging rat without any detectable side effects
  • 83. GENE THERAPY
    • Erectile response has been obtained with an adenoviral (AdV) construct of endothelial NOS ( eNOS; NOS III ), which is not normally involved in the nitrergic neurotransmission necessary for penile erection .
    • The efficacy of gene therapy to ameliorate erectile dysfunction has been extended to other genes related to either cavernosal relaxation, such as:
    • Maxi K+ channels (hSlo) .
    • Vascular endothelial growth factor .
  • 84. hMaxi-K
      • It is a form of gene therapy called naked DNA, which forces the cells to make a protein that tells smooth muscles to relax.
      • Its effects remain for as long as 6 months.
      • The drug lets individuals get normal erections whenever they are aroused
  • 85. hMaxi-K
      • A single subtherapeutic intracavernous injection of the human recombinant Maxi-K ion channel gene via a &quot;naked DNA&quot; plasmid vector
      • (hMaxi-K) is safe in men with moderate to severe erectile dysfunction (ED).
      • The hMaxi-K injection increases the expression of the Maxi-K channel in a small percentage of penile smooth muscle cells, whose signal for smooth muscle relaxation upon neural stimulation is amplified by gap junctions.
      • The primary function of K channels : to modulate Ca++ influx through Ca-channels.
      • The amount of Ca++ that enters the cell through these channels is a major determinant of the free intracellular calcium levels inside the smooth muscle cell, which in turn determines the degree of smooth muscle cell contraction.
      • Increased Maxi-K channel activity is associated with smooth muscle cell relaxation, resulting in penile erection .
  • 86.  
  • 87. hMaxi-K
    • It isn't just for getting erections; it may also be effective in other ailments including overactive bladder, asthma, irritable bowel syndrome, benign prostatic hyperplasia, premature labor, and premenstrual syndrome
  • 88. Take Home Messages
    • Common under laying pathology is ED & ED .
    • Endothelial Dysfunction can be measured
    • Endothelium is the largest endocrine gland
    • ED is diagnostic and prognostic
    • ED can be treated and monitored
    • ED = ED – So careful evaluation is needed
    • Penis is the barometer of CV Risk
  • 89. THANK YOU