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Endothelium vs Erectile dysfunction

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Title: Endothelium vs Erectile dysfunction


1
ENDOTHELIAL DYSFUNCTION(ED) in ERECTILE
DYSFUNCTION(ED)EDED
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 Bucks 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
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
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
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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
16
Tunica intima
LUMEN
Tunica adventitia
Tunica media
17
Vasoconstriction and dilatation
Normal
Vasoconstriction
Vasodilatation
18
Vasoconstriction and dilatation
? Resistance to flow
? Resistance to flow
Vasoconstriction
Vasodilatation
19
Endothelial Apoptosis
Apoptosed
Normal
20
The EndotheliumAs an Endocrine Organ
21
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

22
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).

23
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

24
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

25
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

26
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

29
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
30
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

31
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

32
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.

33
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.

34
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

35
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

36
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 .

37
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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40
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.
45
Risk Factors for Development of Endothelium
Erectile Dysfunction
  • Diabetes Mellitus (DM)
  • Insulin Resistance Syndrome.
  • Cigarette Smoking
  • Hypertension
  • Atherosclerosis Hyperlipidemia

46
Endothelial dysfunction in DM
47
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-)

50
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

51
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.

52
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

53
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

54
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

55
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

56
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.

57
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

58
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

59
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.

60
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

61
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

62
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.

63
Endothelium in Hypertension
64
Endothelial mechanoreceptors changes in
hypertension induced stress
65
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

66
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).

67
Can We MeasureEndothelial Function ??
68
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

71
What is the Treatment. for Endothelial
Dysfunction ??
72
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

73
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).

76
New Horizons in ED Treatment
77
  • 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

84
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

89
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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