Vasodilates
Michael Evans
April 17, 2008
Overview




History
Purposes of
vasodilates
Mechanisms of
different vasodilates
Commonly used
vasodilators, for
therapeutic effects
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"
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 1970’s


More research in the 80’s and 90’s 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, there’s no such thing
as simple “vasodilator research”


When ACE inhibitor therapy first appeared
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
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
Blood Vessels
Homeostatic Mechanisms

Baroreceptors
Constant monitor
 Neck/chest most
important


When there is a change
in blood pressure,
physiologic
mechanisms triggered
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
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
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
Hyperpolarization: Intracellular Ca2+



As you know, muscle contraction occurs when
VDCC’s 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
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 GC’s,
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
cGMP Mechanisms of Action



Second messenger
Activates intracellular
protein kinases [pk’s]
cGMP relaxes
smooth muscles
Renin-Angiotensin-Aldosterone System
as 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
Bradykinin




9-AA Peptide Chain
Released from Venules
Endothelium-dependent vasodilator
Broken down by Angiotensin-converting enzyme (ACE)
Exogenous [from outside the body]
Vasodilators








Quiet, dark
Adenosine antagonists
Alpha-blockers
Amyl nitrite - popper
Alcohol [ethanol]
Histamine-inducers
Nitric Oxide Inducers
THC
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
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
Alpha-Blockers



Alpha-adrenergic
blocking agents
In both arteries and
smooth muscles
The blocked adrenergic
receptors are G proteincoupled receptors



Catecholamines –
adrenaline/noradrenaline[epi/norepi]
If catecholamines bind, increased HR,
vasoconstriction
However, if Badrenergic receptors are
bound by epi or norepi,
vasodilation occurs
More on Alpha Adrenergic Receptors
Nitric Oxide [NO] Inducers



Glyceryl trinitrate (Nitroglycerin)
Prodrug, must be denitrated to produce active
NO
Once active, these nitrates are called
“nitrovasodilators”
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
Other Nitric Oxide [NO] Inducers

Isosorbide mononitrate & Isosorbide dinitrate


Pentaerythritol Tetranitrate (PETN)



Lentonitrat – drug commonly used, pure PETN
So reactive…one of the strongest high explosives known
Sodium nitroprusside



Preventatives of angina, reduced heart workload
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
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.
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
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
Viagra (sildenafil citrate)



More than 65% of men with high blood
pressure also have ED.
PDE5 Inhibitor
Side Effects
Priaprism
 Sudden blindness

OTC Vasodilates



Preworkout
supplements
Taken 30 minutes
before exercise
Stimulate L-Arginine
pathway, along with
NOS
Sources


















http://nobelprize.org/nobel_prizes/medicine/laureates/1998/index.html
http://en.wikipedia.org/wiki/Nitric_oxide
http://www.medicinenet.com/nitroglycerin/article.htm
http://www.medicinenet.com/ace_inhibitors/article.htm
http://www.seloken.com/3430_9816.aspx?l1=&l2=&mid=
^ S. Rosen and P. Olin, Hearing Loss and Coronary Heart Disease, Archives of Otolaryngology, 82:236 (1965)
http://en.wikipedia.org/wiki/Environmental_noise#cite_note-7
http://en.wikipedia.org/wiki/Adrenergic_receptor#Alpha_.CE.B1_receptors
http://health.nytimes.com/health/guides/disease/coronary-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-commons/thumb/4/47/220px-Nitroglycerin-2Dskeletal.png
http://en.wikipedia.org/wiki/Amitriptyline
http://wwwchem.csustan.edu/chem4400/SJBR/Image1.gif
http://fig.cox.miami.edu/~cmallery/150/memb/fig11x12.jpg
http://www.usm.maine.edu/~newton/Chy251_253/Lectures/BiopolymersIII/BradykininPrimary.gif
http://www.mc.uky.edu/pharmacology/images/ped_fin2.gif
http://en.wikipedia.org/wiki/PDE5_inhibitor