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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.
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
Endothelium –derived vasoconstrictors vs Vasodilators
Contractoion- mediating transmitters
Nitric oxide & cGMP pathway
Prostaglandin E, prostacyclin& cAMP pathway
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
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 .
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.
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
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 - )
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
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.
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
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
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.
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.
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
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
Changes in heart and vessel wall structure
Acceleration of the atherosclerotic process
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.
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
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).
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
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:
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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