Vasodilation

Vasodilation is the widening of blood vessels.[1] It results from relaxation

of smooth muscle cells within the vessel walls, in particular in the large
veins, large arteries, and smaller arterioles. The process is the opposite of
vasoconstriction, which is the narrowing of blood vessels.

When blood vessels dilate, the flow of blood is increased due to a

decrease in vascular resistance and increase in cardiac output. Therefore,
dilation of arterial blood vessels (mainly the arterioles) decreases blood
pressure. The response may be intrinsic (due to local processes in the 3D Medical animation still showing Normal
surrounding tissue) or extrinsic (due to hormones or the nervous system). blood vessel(L) Vs. Vasodilation(R)

In addition, the response may be localized to a specific organ (depending

on the metabolic needs of a particular tissue, as during strenuous
exercise), or it may be systemic (seen throughout the entire systemic circulation).

Endogenous substances and drugs that cause vasodilation are termed vasodilators. Such vasoactivity is necessary for
homeostasis (keeping the body running normally).

Contents
Function
Vasodilation and arterial resistance
Examples and individual mechanisms
Endogenous
Sympathetic nervous system vasodilation
Cold-induced vasodilation
Other mechanisms of vasodilation
Therapeutic uses
Antihypertensives that work by opening blood vessels
See also
References

Function
The primary function of vasodilation is to increase blood flow in the body to tissues that need it most. This is often in response to
a localized need for oxygen but can occur when the tissue in question is not receiving enough glucose, lipids, or other nutrients.
Localized tissues have multiple ways to increase blood flow, including releasing vasodilators, primarily adenosine, into the local
interstitial fluid, which diffuses to capillary beds, provoking local vasodilation.[2][3] Some physiologists have suggested that it is
the lack of oxygen itself that causes capillary beds to vasodilate by the smooth muscle hypoxia of the vessels in the region. This
latter hypothesis is posited due to the presence of precapillary sphincters in capillary beds. These approaches to the mechanism of
vasodilation are not mutually exclusive.[4]

Vasodilation and arterial resistance

Vasodilation directly affects the relationship between mean arterial pressure, cardiac output, and total peripheral resistance (TPR).
Vasodilation occurs in the time phase of cardiac systole, whereas vasoconstriction follows in the opposite time phase of cardiac
diastole. Cardiac output (blood flow measured in volume per unit time) is computed by multiplying the heart rate (in beats per
minute) and the stroke volume (the volume of blood ejected during ventricular systole). TPR depends on several factors,
including the length of the vessel, the viscosity of blood (determined by hematocrit) and the diameter of the blood vessel. The
latter is the most important variable in determining resistance, with the TPR changing by the fourth power of the radius. An
increase in either of these physiological components (cardiac output or TPR) causes a rise in the mean arterial pressure.
Vasodilation works to decrease TPR and blood pressure through relaxation of smooth muscle cells in the tunica media layer of
large arteries and smaller arterioles.[5]

Vasodilation occurs in superficial blood vessels of warm-blooded animals when their ambient environment is hot; this process
diverts the flow of heated blood to the skin of the animal, where heat can be more easily released to the atmosphere. The opposite
physiological process is vasoconstriction. These processes are naturally modulated by local paracrine agents from endothelial
cells (e.g., nitric oxide, bradykinin, potassium ions, and adenosine), as well as an organism's autonomic nervous system and
adrenal glands, both of which secrete catecholamines such as norepinephrine and epinephrine, respectively.[6][7]

Examples and individual mechanisms

Vasodilation is the result of relaxation in smooth muscle surrounding the blood vessels. This relaxation, in turn, relies on
removing the stimulus for contraction, which depends on intracellular calcium ion concentrations and is tightly linked with
phosphorylation of the light chain of the contractile protein myosin. Thus, vasodilation works mainly either by lowering
intracellular calcium concentration or by dephosphorylation (really substitution of ATP for ADP) of myosin. Dephosphorylation
by myosin light-chain phosphatase and induction of calcium symporters and antiporters that pump calcium ions out of the
intracellular compartment both contribute to smooth muscle cell relaxation and therefore vasodilation. This is accomplished
through reuptake of ions into the sarcoplasmic reticulum via exchangers and expulsion across the plasma membrane.[8] There are
three main intracellular stimuli that can result in the vasodilation of blood vessels. The specific mechanisms to accomplish these
effects vary from vasodilator to vasodilator.

Class Description Example

Hyperpolarization-
mediated (Calcium
channel blocker)
cAMP-mediated
cGMP-mediated
(Nitrovasodilator)
Changes in the resting membrane potential of the cell affects the level of
intracellular calcium through modulation of voltage-sensitive calcium adenosine
channels in the plasma membrane.
Adrenergic stimulation results in elevated levels of cAMP and protein
prostacyclin
kinase A, which results in increasing calcium removal from the cytoplasm.
Through stimulation of protein kinase G. nitric oxide

PDE5 inhibitors and potassium channel openers can also have similar results.

Compounds that mediate the above mechanisms may be grouped as endogenous and exogenous.

Endogenous
 Receptor
(↑ = opens. ↓ =
closes) [9] Transduction
Vasodilators [9]
On vascular smooth (↑ = increases. ↓ = decreases) [9]
muscle cells if not
otherwise specified

EDHF ?
PKG activity →

phosphorylation of MLCK
→ ↓MLCK activity →
dephosphorylation of MLC hyperpolarization → ↓VDCC → ↓intracellular Ca2+
↑SERCA → ↓intracellular
Ca2+

↓endothelin synthesis
NO receptor on endothelium [10]

β-2 adrenergic
epinephrine (adrenaline)
receptor
histamine histamine H2 receptor ↑Gs activity → ↑AC activity → ↑cAMP → ↑PKA activity
prostacyclin IP receptor → phosphorylation of MLCK → ↓MLCK activity →
dephosphorylation of MLC
prostaglandin D2 DP receptor

prostaglandin E2 EP receptor

↑Gs activity → ↑AC activity → ↑cAMP → ↑PKA activity

→

phosphorylation of MLCK → ↓MLCK activity →

VIP VIP receptor dephosphorylation of MLC
open Ca2+-activated and voltage-gated
K+channels → hyperpolarization → close VDCC
→ ↓intracellular Ca2+

A1, A2a and A2b ↑ATP-sensitive K+ channel → hyperpolarization →

(extracellular) adenosine
adenosine receptors close VDCC → ↓intracellular Ca2+

(extracellular) ATP activate Gq → ↑PLC activity → ↑intracellular Ca2+ →

↑P2Y receptor
(extracellular) ADP ↑NOS activity → ↑NO → (see nitric oxide)

Gi → ↓cAMP → activation of Na+/K+-ATPase[11] →

imidazoline and α-2
L-arginine
receptor? ↓intracellular Na+ → ↑Na+/Ca2+ exchanger activity →
↓intracellular Ca2+
bradykinin bradykinin receptor
substance P
niacin (as nicotinic acid only)
platelet-activating factor (PAF)
CO2 -
↓interstitial pH → ?[12]
interstitial lactic acid(probably) -
muscle work -
↑vasodilators:

↑ATP consumption → ↑adenosine

↑glucose usage → CO2
 ↑interstitial K+
↑(extracellular) ATP
↑(extracellular) ADP
↑interstitial K+
↓vasoconstrictors:

↑ATP consumption → ↓ ATP (intracellular)

↓oxygen → ↓oxidative phosphorylation → ↓
ATP (intracellular)

natriuretic peptides[10]
prostaglandin I2[10] various receptors on
↓endothelin synthesis [10]
[10] endothelium
prostaglandin E2
heparin [10]

The vasodilating action of activation of beta-2 receptors (such as by adrenaline) appears to be endothelium-independent.[13]

Sympathetic nervous system vasodilation

Although it is recognized that the sympathetic nervous system plays an expendable role in vasodilation, it is only one of the
mechanisms by which vasodilation can be accomplished. The spinal cord has both vasodilation and vasoconstriction nerves. The
neurons that control vascular vasodilation originate in the hypothalamus. Some sympathetic stimulation of arterioles in skeletal
muscle is mediated by epinephrine acting on β-adrenergic receptors of arteriolar smooth muscle, which would be mediated by
cAMP pathways, as discussed above. However, it has been shown that knocking out this sympathetic stimulation plays little or no
role in whether skeletal muscle is able to receive sufficient oxygen even at high levels of exertion, so it is believed that this
particular method of vasodilation is of little importance to human physiology.[14]

In cases of emotional distress, this system may activate, resulting in fainting due to decreased blood pressure from vasodilation,
which is referred to as vasovagal syncope.[15]

Cold-induced vasodilation
Cold-induced vasodilation (CIVD) occurs after cold exposure, possibly to reduce the risk of injury. It can take place in several
locations in the human body but is observed most often in the extremities. The fingers are especially common because they are
exposed most often.

When the fingers are exposed to cold, vasoconstriction occurs first to reduce heat loss, resulting in strong cooling of the fingers.
Approximately five to ten minutes after the start of the cold exposure of the hand, the blood vessels in the finger tips will
suddenly vasodilate. This is probably caused by a sudden decrease in the release of neurotransmitters from the sympathetic nerves
to the muscular coat of the arteriovenous anastomoses due to local cold. The CIVD increases blood flow and subsequently the
temperature of the fingers. This can be painful and is sometimes known as the 'hot aches' which can be painful enough to bring on
vomiting.

A new phase of vasoconstriction follows the vasodilation, after which the process repeats itself. This is called the Hunting
reaction. Experiments have shown that three other vascular responses to immersion of the finger in cold water are possible: a
continuous state of vasoconstriction; slow, steady, and continuous rewarming; and a proportional control form in which the blood
vessel diameter remains constant after an initial phase of vasoconstriction. However, the vast majority of responses can be
classified as the Hunting reaction.[16]
Other mechanisms of vasodilation
Other suggested vasodilators or vasodilating factors include:

absence of high levels of environmental noise

absence of high levels of illumination
adenosine - adenosine agonist, used primarily as an anti-arrhythmic
alpha blockers (block the vasoconstricting effect of adrenaline)
amyl nitrite and other nitrites are often used recreationally as a vasodilator, causing lightheadedness and a
euphoric feeling
atrial natriuretic peptide (ANP) - a weak vasodilator
capsaicin (chili)[17]
ethanol (alcohol)
histamine-inducers

Complement proteins C3a, C4a, and C5a work by triggering histamine release from mast cells and basophil
granulocytes.
nitric oxide inducers

l-arginine (a key amino acid)

glyceryl trinitrate (commonly known as nitroglycerin)
isosorbide mononitrate and isosorbide dinitrate
pentaerythritol tetranitrate (PETN)
sodium nitroprusside
PDE5 inhibitors: these agents indirectly increase the effects of nitric oxide

sildenafil (Viagra)
tadalafil (Cialis)
vardenafil (Levitra)
tetrahydrocannabinol (THC)
theobromine
minoxidil
papaverine an alkaloid found in the opium poppy papaver somniferum
estrogen
apigenin: In rat small mesenteric arteries, apigenin acts on TRPV4 in endothelial cells to induce EDHF-mediated
vascular dilation (Br J Pharmacol 2011 Nov 3)

Therapeutic uses
Vasodilators are used to treat conditions such as hypertension, wherein the patient has an abnormally high blood pressure, as well
as angina, congestive heart failure, and erectile dysfunction, and where maintaining a lower blood pressure reduces the patient's
risk of developing other cardiac problems.[5] Flushing may be a physiological response to vasodilators. Some phosphodiesterase
inhibitors such as sildenafil, vardenafil and tadalafil, work to increase blood flow in the penis through vasodilation. They may
also be used to treat pulmonary arterial hypertension (PAH).

Antihypertensives that work by opening blood vessels

These drugs can keep vessels staying opened or help vessels refrain from being
narrowed.[18]

Angiotensin II receptor blockers

ACE inhibitors
Calcium channel blockers
Drugs that appear to work by activating the α2A receptors in the brain thereby
decreasing sympathetic nervous system activity.[19][18]

methyldopa

According to American Heart Association, Alpha-methyldopa may cause Orthostatic

syncope as it exerts a greater blood pressure lowering effect when one is standing
upright which may lead to feeling weak or fainting if the blood pressure has been
lowered too far. Methyldopa's prominent side effects include drowsiness or
sluggishness, dryness of the mouth, fever or anemia. Additionally to these, male
patients may experience impotence. [18]

clonidine hydrochloride
guanabenz acetate
guanfacine hydrochloride

Clonidine, guanabenz or guanfacine may give rise to severe dryness of the mouth,
constipation or drowsiness. Abrupt cessation taking may raise blood pressure
quickly to dangerously high levels.[18]

Directly relax the muscle in the walls of the blood vessels (especially the arterioles),
allowing the vessel to dilate (widen). [18]

hydralazine
minoxidil

Hydralazine may cause headaches, swelling around the eyes, heart palpitations or
aches and pains in the joints. In clinical setting, hydralazine isn't usually used
alone.[18]
Minoxidil is a potent direct vasodilator used only in resistant severe high blood
pressure or when kidney failure is present. Noted adverse effects comprise fluid
retention (marked weight gain) and excessive hair growth.[18]

See also
Arteriolar vasodilator
Nitrophorin
Vasodilatory shock

References
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