Vasodilates

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Vasodilates

• Michael Evans
• April 17, 2008

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Overview

• History
• Purposes of vasodilates
• Mechanisms of different vasodilates
• Commonly used vasodilators, for therapeutic
  effects

3
History

• Nobel Prize in Medicine awarded in 1998 to 3
  physicians "for their discoveries concerning
  nitric oxide as a signalling molecule in the
  cardiovascular system"

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History, continued

• Synthesized in 1846, nitroglycerin was first used
  to treat anginal attacks in 1879. It was granted
  FDA approval in 1938.
• Explosion of vasodilator therapy research in the
  1970s
• When ACE inhibitor therapy first appeared
• More research in the 80s and 90s to determine
  long-term effects, as usage to garner acute
  effects has already been proven to work
• One can build up a tolerance to vasodilators, so
  dosages must be increased or there must be a
  nitrate-free interval
• Since all methods work via different mechanisms
  and pathways, theres no such thing as simple
  vasodilator research
• Nitroprusside
• Nitrates
• ACE inhibitors
• Angiotensin II antagonists
• Calcium Channel Blockers
• Nitroprusside, nitrates, hydralazine are direct
  vasodilators
• AII antagonists and ACE inhibitors also have
  indirect components

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History, continued

• VHeFTI trial (1986) first to prove increased
  survival rates with vasodilator treatment for
  patients with Class II and Class III heart
  failure
• Known as a mortality study
• Vasodilation affects the relationship between
  mean arterial pressure, cardiac output, and total
  peripheral resistance
• Your heart pumps against a constant pressure, and
  you can damage your heart if TPR is too high
  hypertension/high blood pressure
• Although blood viscosity hematocrit-determined
  and length of blood vessels contribute to TPR,
  the most important variable is vessel diameter,
  which relates directly to surrounding smooth
  muscle

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Blood Vessels
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Homeostatic Mechanisms

• Baroreceptors
• Constant monitor
• Neck/chest most important
• When there is a change in blood pressure,
  physiologic mechanisms triggered

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Extreme Dilation of Blood Vessels

• Alcohol
• Some allergic reactions
• Some antidepressants
• amitriptyline
• Antihypertensive drugs that dilate blood vessels
  (such as calcium channel blockers,
  angiotensin-converting enzyme inhibitors, and
  angiotensin II receptor blockers)
• Nitrates
• Bacterial infections
• Heat
• Nerve damage (such as that due to diabetes,
  amyloidosis, or spinal cord injuries)
• In this case, the homeostatic controls lose their
  function

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Endogenous rising from within Vasodilators

• Depolarization, which yields decreased
  intracellular Ca2
• Nitric Oxide Pathway, stimulating cGMP ? MLCK
  pathway, which ends up decreasing intracellular
  Ca2
• Beta-2 Andrenergic Receptor antagonists,
  histamine, prostaglandins, and prostacyclin
• VIP
• Adenosine
• ATP and ADP
• L-Arginine
• Bradykinin
• Muscle use

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Endogenous Vasodilators Hyperpolarization

• Endothelium-derived hyperpolarizing factor EDHF
• Depolarization, which opens Voltage-gated K
  channels
• Increase in Interstitial K
• All of the above hyperpolarize the membrane,
  closing voltage-dependent calcium channels,
  decreasing intracellular Ca2
• Effectively the same as Ca2 channel blockers

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Hyperpolarization Intracellular Ca2

• As you know, muscle contraction occurs when
  VDCCs open, allowing Ca2 to flow into the cell
• A vasodilator needs to inhibit smooth muscle
  contraction around blood vessels
• Thus, membrane hyperpolarization to prevent these
  voltage gated channels from opening works to
  achieve this goal

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Endogenous Vasodilators Nitric Oxide

• Nitric Oxide acts on the lyase enzyme Guanylate
  Cyclase GC
• This enzyme catalyzes the conversion of GTP to
  3,5-cyclic guanosine monophosphate better
  known as cGMP and pyrophosphate
• Because there are multiple GCs, one
  membrane-bound and one soluble, it is important
  to clarify that the NO-receptor is the soluble GC
  receptor
• cGMP then regulates cellular proteins, yielding
  vasodilation

GTP
cGMP
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cGMP Mechanisms of Action

• Second messenger
• Activates intracellular protein kinases pks
• cGMP relaxes smooth muscles

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Renin-Angiotensin-Aldosterone Systemas it
pertains to vasodilation

• RAA system is blocked with ACEI
• Angiotensin II is turned off
• This allows indirect acute vasodilatation through
  withdrawal of angiotensin II and the accumulation
  of bradykinin (as ACEI are kininases) which also
  contributes to the vasodilator effect

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Bradykinin

• 9-AA Peptide Chain
• Released from Venules
• Endothelium-dependent vasodilator
• Broken down by Angiotensin-converting enzyme (ACE)

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Exogenous from outside the body Vasodilators

• Quiet, dark
• Adenosine antagonists
• Alpha-blockers
• Amyl nitrite - popper
• Alcohol ethanol
• Histamine-inducers
• Nitric Oxide Inducers
• THC

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Environmental Factors

• Noise
• Excessive noise, annoying noise
• Raise blood pressure, cause hypertension
• Increased stress shown by study
• 5-10 point rise in blood pressure,
  vasoconstriction
• Light
• Clinically measurable stress found from
  overexposure
• People that work in extremely bright environments
  are more prone to hypertension

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Calcium Channel Blockers

• Calcium channel blockers reduce heart rate
• Dilate the blood vessels of the heart
• Decrease oxygen demand
• Increase oxygen supply
• Net drop in BP

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Alpha-Blockers

• Alpha-adrenergic blocking agents
• In both arteries and smooth muscles
• The blocked adrenergic receptors are G
  protein-coupled receptors
• Catecholamines adrenaline/noradrenalineepi/nore
  pi
• If catecholamines bind, increased HR,
  vasoconstriction
• However, if B-adrenergic receptors are bound by
  epi or norepi, vasodilation occurs

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More on Alpha Adrenergic Receptors
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Nitric Oxide NO Inducers

• Glyceryl trinitrate (Nitroglycerin)
• Prodrug, must be denitrated to produce active NO
• Once active, these nitrates are called
  nitrovasodilators

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Mechanisms for Denitration

• Nitroglycerin can be denitrated in many ways
• There are many hypotheses as to the mechanism of
  bioactivation
• Nitrates react with sulfhydryl groups
• Enzymatic breakdown
• Glutathione S-transferase, Cytochrome P450,
  Xanthine oxidoreductase
• Catalyzed denitration by mitochondrial aldehyde
  dehydrogenase
• Ultimately, GTN is broken down into 1,2-glyceryl
  dinitrate Free NO

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Other Nitric Oxide NO Inducers

• Isosorbide mononitrate Isosorbide dinitrate
• Preventatives of angina, reduced heart workload
• Pentaerythritol Tetranitrate (PETN)
• Lentonitrat drug commonly used, pure PETN
• So reactiveone of the strongest high explosives
  known
• Sodium nitroprusside
• Salt that is a source of NO, often administered
  via IV
• For patients with extreme hypertension
• PDE5 inhibitors these agents indirectly increase
  the effects of nitric oxide
• Sildenafil (Viagra)
• Tadalafil
• Vardenafil

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Now what? Free NO

• NO is a potent activator of guanylyl cyclase (GC)
  by heme-dependent mechanisms
• Activation results in cGMP formation from
  guanosine triphosphate (GTP)
• Thus, NO increases the level of cGMP within the
  cell.

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Nitroglycerin

• GENERIC NAME nitroglycerin
• BRAND NAME Nitro-Bid Nitro-Dur Nitrostat
  Transderm-Nitro Minitran Deponit Nitrol
• USES frequently used to lower blood pressure
  when treating angina pectoris, and also used
  during anginal attacks both as a prevention
  method, and as an acute treatment
• Extended release tablets, translingual spray, and
  transdermal patches
• Literature recommends not to stack with other
  high blood pressure medications, because of
  additive effects

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ACE inhibitors

• Class of Drugs ACE (angiotensin converting
  enzyme) inhibitors
• Generic (Brand Name)
• captopril (Capoten)
• benazepril (Lotensin)
• enalapril (Vasotec)
• lisinopril (Prinivil, Zestril)
• fosinopril (Monopril)
• ramipril (Altace)
• perindopril (Aceon)
• quinapril (Accupril)
• moexipril (Univasc)
• trandolapril (Mavik)
• USES
• Hypertension treatment
• Heart failure

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Viagra (sildenafil citrate)

• More than 65 of men with high blood pressure
  also have ED.
• PDE5 Inhibitor
• Side Effects
• Priaprism
• Sudden blindness

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OTC Vasodilates

• Preworkout supplements
• Taken 30 minutes before exercise
• Stimulate L-Arginine pathway, along with NOS

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Sources

• http//nobelprize.org/nobel_prizes/medicine/laurea
  tes/1998/index.html
• http//en.wikipedia.org/wiki/Nitric_oxide
• http//www.medicinenet.com/nitroglycerin/article.h
  tm
• http//www.medicinenet.com/ace_inhibitors/article.
  htm
• http//www.seloken.com/3430_9816.aspx?l1l2mid
  
• S. Rosen and P. Olin, Hearing Loss and Coronary
  Heart Disease, Archives of Otolaryngology, 82236
  (1965)
• http//en.wikipedia.org/wiki/Environmental_noisec
  ite_note-7
• http//en.wikipedia.org/wiki/Adrenergic_receptorA
  lpha_.CE.B1_receptors
• http//health.nytimes.com/health/guides/disease/co
  ronary-heart-disease/other-medications.html
• http//www.merck.com/mmhe/print/sec03/ch023/ch023a
  .html
• http//en.wikipedia.org/wiki/Bradykinin
• http//content.answers.com/main/content/wp/en-comm
  ons/thumb/4/47/220px-Nitroglycerin-2D-skeletal.png
  
• http//en.wikipedia.org/wiki/Amitriptyline
• http//wwwchem.csustan.edu/chem4400/SJBR/Image1.gi
  f
• http//fig.cox.miami.edu/cmallery/150/memb/fig11x
  12.jpg
• http//www.usm.maine.edu/newton/Chy251_253/Lectur
  es/BiopolymersIII/BradykininPrimary.gif
• http//www.mc.uky.edu/pharmacology/images/ped_fin2
  .gif
• http//en.wikipedia.org/wiki/PDE5_inhibitor