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Just Say NO

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Discuss important events leading up to the discovery of endogenous nitric oxide. ... Can potentiate hypotensive effects of other nitrates (e.g nitroglycerin) ... – PowerPoint PPT presentation

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Title: Just Say NO


1
Just Say NO
  • Nitric Oxide and Drug Action

Kevin Perrone 1st year PharmD Student November 1,
2001
2
Objectives
  • Discuss important events leading up to the
    discovery of endogenous nitric oxide.
  • Describe the biochemical pathway of nitric oxide
    in the body.
  • Discuss nitric oxides role in various
    pathologies
  • Demonstrate the importance of nitric oxide in
    select drug therapies.
  • Highlight areas of interest in future drug
    development.

3
What is nitric oxide?
  • Discovered in 1772 by Joseph Priestly
  • Clear, colorless gas
  • Free radical
  • Acid rain offender
  • 6-10 sec lifetime in vivo

4
Finding Nitric Oxide
  • Dr. Ferid Murad
  • Bubbled NO gas through tissue containing guanylyl
    cyclase-gt cGMP levels increased in that tissue.
  • Was well known that nitroglycerin activated the
    same enzyme-gt must release NO.

5
Finding Nitric Oxide
  • Dr. Robert F. Furchgott
  • Furchgott Sandwich
  • endothelial cells produce EDRF in response to
    acetylcholine.

6
Finding Nitric Oxide
  • 1986, Dr. Louis Ignarro
  • Hemoglobin exposed to EDRF from stimulated
    endothelial cells showed identical spectral
    analysis shift as when exposed to nitric oxide.
  • Therefore,

EDRFNO
7
Worthy of Nobel
  • Their collective contributions won them the 1998
    Nobel Prize in Physiology or Medicine for their
    discoveries concerning nitric oxide as a
    signaling molecule in the cardiovascular system
  • Their discoveries have led to an explosion of
    interest in NO and thousands of publications in
    just the last few years.

8
Origin of NO
  • Derived from L-Arginine in two steps catalyzed by
    nitric oxide synthase (NOS). (intermediate
    N-(omega)-Hydroxyarginine
  • Three forms of NOS, neuronal (nNOS), endothelial
    (eNOS), and inducible (iNOS).
  • Despite names, all three isoforms can be found in
    a variety of cell and tissue types.

9
Constitutive NOS
  • eNOS and nNOS are constitutively expressed to
    synthesize NO in response to intracellular Ca
    levels via calmodulin interaction.
  • Increases in intracellular Ca could be due to
    either hemodynamic shear stress (HTN) or
    activation of G-protein-coupled cell surface
    receptors (signal transduction)
  • The ability for both eNOS and nNOS to bind
    calmodulin is directly related to IC Ca levels
    and often results in relatively minute production
    of NOS since Ca levels fluctuate continuously.

10
Inducible NOS
  • iNOS activity is independent of IC Ca (constant
    basal production), yet still dependent on
    calmodulin binding. It binds CaM much tighter and
    subsequently is responsible for producing much
    higher levels of NO.
  • iNOS production of NO is also controlled by
    transcription. Normal cell s of iNOS are
    relatively low yet stimulation of these cells
    with cytokines or bacterial endotoxins can lead
    to increased transcription of these proteins --gt
    PRODUCES LOTS O NO!!!!!!

11
Selected Roles of NO
  • Cardiovascular
  • induces vasodilation in vascular smooth muscle
    via cGMP
  • Essential hypertension often displays aberrant NO
    production.

12
  • Cardiovascular(contd)
  • Endothelial dysfunction (cholesterol mediated
    impairment of endothelium-dependent relaxations)
    promotes NO deficiency and incapacity-gt HTN and
    atherosclerosis
  • High IC levels inhibit platelet aggregation via a
    cGMP-dependent mechanism-gt obvious importance to
    thromboembolic disorders.
  • Hemoglobin transport and targeted
    oxygenation-gt endothelial repair in CV diseases,
    hypoxia, SC anemia, blood substitutes
  • Role in chronic pulmonary hypertension

13
  • Immune System and Inflammation
  • cytokine activated macrophages produce large
    quantities of NO to kill bacteria and cancer
    cells. This NO has been associated with
    disrupting enzymes involved in mitochondrial
    function, Krebs cycle, and DNA synthesis-gt
    non-discriminatory, possible host damage
  • Enhances effect of cyclooxygenases and stimulates
    the production of pro-inflammatory eicosonoids.
  • iNOS relationship

14
Neurotransmission
  • Not regulated by storage, release or targeted
    degradation.
  • NO has no conventional receptor, activates
    guanylate cyclase directly.
  • Reinforcement of glutaminergic signaling at NMDA
    receptors and proposed player in long-term
    potentiation.

Sepsis
  • Duality of NO
  • Severe shock due to bacterial endotoxin iNOS
    activation
  • prevention of microvascular thrombosis often seen
    in organ hypoperfusion (platelet role),
    superoxide scavenger

15
NO Drug Therapy
  • Nitroglycerin and related nitrates
  • Nitroglycerin, sodium nitroprusside
    (Nitropress), isosorbide dinitrate (Isorbid).
  • Action mediated via NO release and subsequent
    smooth muscle vasodilation.

16
  • Viagra (Sildenafil)
  • nitric oxide is released into the corpus
    cavernosum during sexual stimulation- gtcGMP
    mediated vasodilation and penis engorgement.
  • Sildenafil inhibits phosphodiesterase type 5,
    which degrades cGMP and leads to enhanced
    vasodilation in erectile dysfunction.
  • Can potentiate hypotensive effects of other
    nitrates (e.g nitroglycerin)
  • Loose application of NO

17
INOmax(NO inhalation)
  • indicated for full-term and near-term infants
    with hypoxic respiratory failure.
  • Reduces need for invasive surgical extracoporeal
    membrane oxygenation(ECMO)
  • Takes advantage of direct vasodilation effects of
    NO and drug targeting via short life of NO
    molecule.
  • Approved Dec. 29, 1999

18
Possible ACE inhibitor involvement
  • Some studies indicate that tissue-ACE plays
    important role in balancing vasoconstriction
    (AII) and vasodilation (NO)
  • Linkage between quinapril therapy and improvement
    in endothelial function may lead to preservation
    of NO system-gt beneficial in cardiovascular
    disease.

19
Future Candidates
  • Nitronaproxen nirofenac-gtNO-releasing NSAIDs
    capable of accelerating gastric tissue repair in
    animal models
  • BN-80933-gtinhibits NOS and removes reactive
    oxygen species in acute stroke.
  • High NO in depression-gtNOS inhibitors show
    preclinical antidepressant -like properties.
  • MAO-B inhibitors in Alzheimers-gt Selegiline
    stimulates NO production-gtprotects vascular and
    neuronal tissue-gtnew MAO-B inhibitors? NMDA
    related?
  • NOS structure elucidated-gt NOS inhibitors
  • Further understanding of NO action and
    biochemistry leading to drug development in
    cardiovascular, autoimmune, and inflammatory
    diseases.

20
The Gist of It
  • NO is involved in a broad range of normal and
    pathophysiological conditions.
  • It is a growing interest amongst the scientific
    community and likely to stimulate the development
    of many novel drugs in the near future.
  • Its small yet dont underestimate it.

21
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