Endothelium vs Erectile dysfunction

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ENDOTHELIAL DYSFUNCTION(ED) in ERECTILE
DYSFUNCTION(ED)EDED
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Erectile DysFunction(ED)
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Male Genital Anatomy

• Two paired corpora cavernosa (erectile bodies)
  and a single corpus spongiosum surrounding the
  urethra, all encased within Bucks fascia
• The erectile tissue is comprised of a network of
  vascular sinusoids surrounded by trabecular
  smooth muscle.

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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.

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Mechanism of Erection

• 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

Flaccid penis - arterial pressure 20mm/Hg
Fully erect - arterial pressure 80-100mm/Hg
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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.

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The Whole Picture
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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.

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(L-NMMA) N(G)-mono-methyl-L-arginine
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(L-NMMA) N(G)-mono-methyl-L-arginine
(L-NMMA) N(G)-mono-methyl-L-arginine
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Causes of Erectile Dysfunction(ED)
Hypertension
Depression
Anemia
Drug abuse
Vascular surgery
Endothelial dysfunction ED
Hypogonadism
Smoking
Alcohol abuse
Peyronies disease
Trauma/surgery to pelvis or spine
Endocrine Disorders
Hyperlipidemia
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The Endothelium
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Tunica intima
LUMEN
Tunica adventitia
Tunica media
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Vasoconstriction and dilatation
Normal
Vasoconstriction
Vasodilatation
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Vasoconstriction and dilatation
? Resistance to flow
? Resistance to flow
Vasoconstriction
Vasodilatation
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Endothelial Apoptosis
Apoptosed
Normal
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The EndotheliumAs an Endocrine Organ
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The Vascular Endothelium

• 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

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Vascular Endothelial Mediators

• Nitric oxide (NO)
• Cycloxygenase (CxO)
• Endothelin-1 (ET-1)
• Endothelium Depolarisation Factor (EDF)
• Prostanoids
• Angiotensin
• Rho/Rho-kinase
• Prostaglandin E prostacyclin (cAMP pathway).

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Nitric Oxide (NO)

• 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

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Protective actions of NO

• 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

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Endothelium Dysfunction NO Reduction

• NO deficiency in the vessel wall promotes
• Inflammation
• Oxidation of lipoproteins
• Smooth muscle proliferation
• Accumulation of lipid rich material
• Platelet activation and thrombus formation

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NO induces synthesis of cGMP by stimulation of GC
leading to relaxation of myosin (muscle protein)
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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

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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 ETB receptors
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Endothelin

• ETA receptor mediate the vasoconstrictor effects
  of the peptide, ETB 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

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Endothelin peptides

• Endothelin-1(ET-1)synthesied by lacunar
  endothelium trabecular muscle
• It induces contraction,via ETA receptors in
  penile smooth muscles( corpus cavernosacavernosal
  artery).
• Contraction dependent upon increased
  intracellular calcium via
• Transmembrane calcium flux
• Mobilization of inositol,1,4,5-triphosphate
  (IP3)-dependent calcium stores

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Prostanoids

• Several prostanoidsPGI 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.

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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
  pathwaysignal mediator of endothelial cell
  function. Rho-mediated Ca2sensitization of
  cavernosal smooth muscle maintains the flaccid
  (contracted) state.
• This pathway supppresses eNOS gene expression in
  endothelium.

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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

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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

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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 .

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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 ETB 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.

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ENOTHELIUM DYSFUNCTION(ED)
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The Mechanism of the Assocation Between
EndotheliumErectile Dysfunction
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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 40614066.
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Risk Factors for Development of Endothelium
Erectile Dysfunction

• Diabetes Mellitus (DM)
• Insulin Resistance Syndrome.
• Cigarette Smoking
• Hypertension
• Atherosclerosis Hyperlipidemia

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Endothelial dysfunction in DM
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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 diabetesendothelium-dependent
  vasodilatory responses to brachial artery
  infusions of acetylcholine, methacholine, and
  similar agonists are impaired in the forearm
• In normotensive type 2 diabetesdemonstration 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

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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-)

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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

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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.

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Dyslipidemia in DM (1)

• Elevated TG, low HDL-c, and elevated IDLinsulin
  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

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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

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Increased oxidative stress in diabetes

• Oxidative stressimbalance 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

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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

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Insulin resistance syndrome

• It is hypothesized that compensatory
  hyperinsulinemia maintains the serum glucose
  within the normal range until pancreatic islet
  b-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.

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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

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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, ETA and ETB receptors

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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 ETA
  receptors
• Infusion of ET-1 cause sustained increases in BP
• Nonselective ETA/ETB 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.

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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

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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

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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 vasodilationimpaired.
• Age dependent independent decrease of NO
  synthesis.

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Endothelium in Hypertension
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Endothelial mechanoreceptors changes in
hypertension induced stress
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Cigarette Smoking

• Free radiclesaromatic 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

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ATHEROSCLEOSIS HYPERLIPIDEMIA Effect on penile
endothelium

• Chronic ischaemiareduced 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).

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Can We MeasureEndothelial Function ??
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Clinical Methods for Assessing Endothelium -
Dependent Dilation

• Forearm
• Brachial Artery Diameter ? with Arterial
  Occlusion FMD
• Forearm Blood Flow with ACh

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Penile/Brachial Index (PBI)

• Penile systolic pressure/brachial systolic
  pressure
• 0.7 - 1.0 normal
• 0.6 - 0.7 borderline abnormal
• lt0.6 abnormal

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What is the Treatment. for Endothelial
Dysfunction ??
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What is the Treatment for Endothelial
Dysfunction?

• 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

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Erectile Dysfunction Todays concept

• Penis is the barometer
• of Endothelial Health
• Erectile Dysfunction is a
• mirror of Cardiovascular Risk

ED ED
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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).

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New Horizons in ED Treatment
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• PDE5 inhibitors
• Sildenafil citrate
• Tadalafil
• Vardenafil
• SLX-2101
• Avanafil

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New Horizons in ED Treatment

• 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.

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New Horizons in ED Treatment

• 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).

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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.

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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 .

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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

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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 .

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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

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hMaxi-K

• A single subtherapeutic intracavernous injection
  of the human recombinant Maxi-K ion channel gene
  via a "naked DNA" 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 .

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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

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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

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THANK YOU