Download Pharm Chapter 21 [4-20

Pharm Chapter 21: Pharmacology of Vascular Tone
Vascular tone – the degree of contraction of vascular smooth muscle
In combo with cardiac output, vascular tone determines the amount of perfusion of body tissues
The vascular tone of the arteries and veins are important in controlling the balance of how much O2 the
heart needs
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The major things determining how much O2 the heart needs are heart rate, contractility, and
ventricular walls stress
o Wall stress = (ventricular pressure x ventricle radius) / (2 x ventricle wall thickness)
Ventricular wall stresses are affected by systemic arteriolar and venous tone
o Arteriolar tone directly controls systemic vascular resistance, and therefore arterial
blood pressure
 Mean arterial blood pressure = systemic resistance x cardiac output
o During systole, the pressure in the ventricles must be more than the arterial pressure for
blood to be ejected
o Afterload – systolic ventricular wall stress; It’s the resistance that the ventricle must
overcome to eject its blood (so it’s aorta pressure, how hard the heart has to work to
pump)
o Systolic arterial blood pressure is about equal to afterload (systolic ventricular walls
stress)
o So resistance is the most important thing controlled by arterial tone
The most important thing determined by vein tone is capacitance
o Venous capacitance regulates the volume of blood returning to the heart, which helps
determine the end-diastolic volume of the heart
o Preload- end diastolic ventricular wall stress; it’s the stretch on the ventricle just before
contraction (how much blood has filled the heart before pumping)
 About equal to the end diastolic volume or pressure
o So venous tone determines the end-diastolic ventricular wall stress (aka preload)
Remember: preload = EDV, and afterload = aortic pressure
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Most causes of MI involve some sort of abnormal vascular tone
Angina pectoris – chest pain
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Common, but not always present in an MI
Nitroglycerin is common given for angina pectoris, cause it’s a vasodilator that decreases
vascular tone
Things that regulate vascular tone work by influencing the actin-myosin contraction of vascular smooth
muscle cells
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Actin-myosin interaction causes contraction, and is regulated by intracellular [Ca2+]
Stimulation of vascular smooth muscle cells can increase the cytoplasmic [Ca2+] by voltage gated
calcium channels in the sarcolemma, or by release of intracellular calcium from the SR
Vasoconstriction is contraction of vascular smooth muscle, so it’s triggered by opening of
calcium channels during depolarization
o The calcium moves into the cell and activates cytoplasmic calmodulin
o The calcium-calmodulin complex then binds to and activates myosin light chain kinase,
which phosphorylates myosin light chains, causing the myosin head to interact with the
actin, and cause smooth muscle contraction
Vasodilation is relaxation of vascular smooth muscle, and happens when there’s
dephosphorylation of the myosin light chain
o Dephosphorylation happens when guanylyl cyclase is activated in smooth muscle
o Activated guanylyl cyclase increases the making of cGMP, which stimulates cGMPdependent kinase, which then activates myosin light chain phosphatase
o Dephosphorylation of the myosin light chain inhibits the interaction of the myosin head
with actin, causing smooth muscle relaxation
Regulation of vascular tone:
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Vascular endothelium:
o Nitric oxide (NO)
 Acetylcholine stimulates the endothelium to make nitric oxide, which goes to
vascular smooth muscle and activates its guanylyl cyclase
 Other things that tell the endothelium to make NO are shearing stress,
histamine, bradykinin, sphingosine-1-phosphate, serotonin, substance
P, and ATP
 NO is made by calcium-calmodulin activated NO synthases
 Endothelial NO synthase makes NO in the endothelium, and is critical in
controlling vascular tone and platelet aggregation
 NO can also cause vasodilation by activating Ca2+-K+ channels in vascular smooth
muscle cells, which hyperpolarizes the cell, causing vasodilation
o Endothelin – a vasoconstrictor peptide
 Most potent vasoconstrictor in the body
 Endothelin is made by the endothelium
 Endothelin is also involved in vascular remodeling
 ET-1 is the form of endothelin made by the endothelium and involved in
cardiovascular actions
 ET-1 works in a paracrine or autocrine way
 To make endothelin:
 First, preproendothelin is cleaved into big endothelin
 Then big endothelin is cleaved by endothelin-converting enzyme into
endothelin
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The endothelin receptor is a G protein-coupled receptor that uses
phospholipase C
 When endothelin binds to an endothelin receptor on vascular smooth muscle
(ETA), it causes vasoconstriction
Autonomic nervous system
o Sympathetics are very involved in vascular tone
 Symp postganglionic neurons release norepinephrine to vascular smooth muscle
to activate α1-adrenergic receptors, or β2-adrenergic receptors
 α1-adrenergic receptors cause vasoconstriction
 β2-adrenergic receptors cause vasodilation
 usually, norepinephrine has a much great effect on the α1-adrenergic
receptors, causing vasconstriction
o blood vessels are not innervated by parasympathetics, so they aren’t involved
Hormones
o Catecholamines from the adrenal gland, can act on α1-adrenergic receptors, or β2adrenergic receptors
 Ex: epinephrine
o Angiotensin 2 – vasoconstricts arterioles and increases intravascular volume
o Aldosterone – mineralocorticoid that increases intravascular volume
o Natriuretic peptide- promotes renal natriueresis (Na+ excretion) during volume
overload, and cause vasodilation by stimulating guanylyl cyclase
o Antidiuretic hormone/arginine vasopressin – stimulates constriction of arterioles, and
activates renal receptors to increase intravascular volume
Local mechanisms
o The vascular smooth muscle repsonds to changes in perfusion pressure with
vasoconstriction or vasodilation, to keep blood flow at a constant level
 Blood flow = perfusion pressure / resistance
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o H , CO2, O2, adenosine, lactate, and K+ are all part of local control of blood flow
Vasodilators decrease vascular tone
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Most act by decreasing the contractility of actin-myosin complexes in vascular smooth muscle
Pharmacologic donors of NO, like nitrates and sodium nitroprusside, cause vasodilation by
activating guanylyl cyclase to increase dephosphorylation of myosin light chains
cGMP phosphodiesterase type 5 (PDE5) inhibitors prevent cGMP hydrolysis, and therby
promote myosin light chain dephosphorylation
Calcium channel blockers decrease intracellular [Ca2+] to cause vasodilation
Potassium channel openers open K+ channels, causing hyperpolarization of the cell to make it
harder for calcium influx to cause vasoconstriction, therefore promoting vasodilation
Endothelin receptor antagonists block endothelin from causing vasoconstriction
α1-adrenergic antagonists inhibit epinephrine and norepinephrine from causing
vasoconstriction, therefore promoting vasodilation
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ACE inhibitors inhibit the making of angiotensin 2, so then it can’t cause vasoconstriction
Angiotensin 2 receptor subtype 1 (AT1) antagonists inhibit the angiotensin 2
Nitrates, NO, and sodium nitroprusside:
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Indications for nitroglycerin (NTG) are angina pectoris, acute MI, hypertension, and heart failure
In the body, organic nitrates are chemically reduced to release NO
Mitochondrial aldehyde dehydrogenase can catalyze making of NO
Although NO can dilate both an artery or vein, venous dilation is what the therapeutic doses
cause
o NO induced venous dilation increases venous capacitance, leading to a decrease in the
return of blood to the right side of the heart, causing decreased right and left ventricle
end diastolic pressure and volume
o This decrease in preload decrease heart O2 demand
Higher concentrations of nitrates can cause arterial vasodilation
o Arterial vasodilation leads to a decrease in systemic vascular resistance, causing a
decrease in systolic wall stress (aka afterload), and a decrease in heart O2 demand
In coronary vessels, nitroglycerin dilates the large epicardial arteries, and his only minimal
effects on coronary arterioles
o This favoring the big vessels over the small prevents the coronary steal syndrome, that
cause intense dilation of the small arterioles
Vasodilators won’t do anything if either the vessel is already vasodilated to its max, or the vessel
has lots of calcified atherosclerotic plaques
The doses used to vasodilate the large epicardial arteries can be dangerous, due to how much
vasodilation they cause in the system arteries, possibly causing hypotension
o These symptoms would be dizziness, lightheadedness, syncope, or even MI
o Systemic hypotension can cause reflex tachycardia, which would decrease heart O2
supply by decreasing the time of diastole
 Tachycardia can also increase the demand for oxygen
 Reflex tachycardia usually happens when baroreceptors in the aortic arch and
carotid sinuses sense a decrease in blood pressure
 In patients with heart failure, tachycardia is rare, so nitrates can be used to
decrease pulmonary congestion in patients with heart failure, without causing
tachycardia
Adverse effects of nitrates are effects of excessive vasodilation:
o Flushing from vasodilation of cutaneous vessels, and headache, caused by vasodilation
of cerebral arteries
The most commonly used nitrates are nitroglycerine, isosorbide dinitrate, and isosorbide 5mononitrate
Inhaled nitric oxide gas can be used to target and dilate pulmonary vessels
o Since NO is rapidly inactivated by binding to Hgb in blood, NO gas has little effect on
systemic blood pressure when it’s inhaled
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Sodium nitroprusside is a nitrate that’s made of nitro, cyanide, and iron groups
o Causes vasodilation by release of NO
o Unlike organic nitrates, sodium nitroprusside doesn’t use any enzymes to release NO
 Because of this it’s not selective, and dilates both arteries and veins
o Sodium nitroprusside can be used intravenously for hypertensive emergencies and
severe heart failure
o Sodium nitroprusside works rapidly, doesn’t last long, and is very powerful, so it has to
be monitored
o Sodium nitroprusside gets decomposed into NO and cyanide
 The cyanide then gets converted into thiocyanate in the liver, which gets
excreted by the kidneys
 Excessive cyanide can cause death
Sublingual nitrates work quickly, and can be used in acute situations
Orally administered nitrates have low bioavailablity because of nitrate reductases in the liver
that metabolize them
o So sublingual is a way to take nitroglycerin or isosorbide dinitrate to bypass the first pass
effect in the liver and get enough NO in the blood
Intravenous nitroglycerin is indicated when you need a continuous titration of the drug
Isosorbide dinitrate has a longer half-life than nitroglycerin, and can therefore be more effective
o A breakdown product of isosorbide dinitrate called isosorbide-5-mononitrate has an
even longer half-life, and can be absorbed from the GI tract without going through the
first pass effect of the liver
Sympathetic and renal responses can offset the effects of nitrates
o Sympsvasoconstriction
o Kidneyssalt and water retention
Pharmacologic tolerance to organic nitrates can limit their effect
o Ex: “Monday morning sickness” – people exposed to nitrates at work would have a
headache Monday from their effects, then build up a tolerance and be fine all week, go
home for the weekend and lose their tolerance to nitrates, and come back Monday and
get another headache
o Although that is a good tolerance, the body can also become tolerant of NO’s
therapeutic effects, which is bad
 You can minimize the development of tolerance by having their dosing schedule
include “nitrate-free” intervals
 Isosorbide-5-mononitrate is a good one to use to get around this tolerance
Nitrates can also relax other smooth muscle
o Includes the esophagus, which can lead to a misdiagnosis
o Usually, though, this relaxation of nonvascular smooth muscle is of no clinical
significance
NO from nitrates can be an antiplatelet as well
o NO increases platelet cGMP, which inhibits platelet aggregation
Contraindications to nitrates:
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Nitrates are contraindicated in patients with hypotension
Nitrates are also contraindicated in patients with increased intracranial pressure,
because vasodilation could elevate it even more
Nitrates are contraindicated for hypertrophic obstructive cardiomyopathy, because the
obstruction can be worsened by NO caused decrease in preload
Nitrates are also contraindicated in patients with diastolic heart failure, who are
depending on that increased ventricular preload to good cardiac output
Also, don’t take nitrates when you’re taking another vasodilator
Phosphodiesterase inhibitors
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Phosphodiesterase inhibitors prevent the hydrolysis (breakdown) of cAMP and cGMP to their
monophosphate forms
Sildenafil is the prototype phosphodiesterase inhibitor that’s selective for cGMP
phosphodiesterase type 5 (PDE5)
o PDE5 is expressed mainly in the corpus cavernosum of the penis
o Hence PDE5 inhibitors are used for erectile dysfunction
o Other PDE5 inhibitors are vardenafil and tadalafil
 Tadalafill takes longer to work, but then has a longer half-life than the other
PDE5 inhibitors
o Penile nerves release NO that activates guanylyl cyclase in smooth muscle of the corpus
cavernosum, leading to increased intracellular cGMP concentration, smooth muscle
relaxation, inflow of blood, causing penile erection
Although PDE5 is mainly in the penis, there’s some throughout the body, so PDE5 inhibitors can
work a little bit on the body
o Ex: PDE5 inhibitors can help in pulmonary hypertension
Adverse effects of PDE5 inhibitors:
o Result from drug induced systemic vasodilation
o Can cause headache and flushing, but systemic effects are rare because the dose used in
PDE5 inhibitors isn’t really enough to affect systemic blood pressure
o Don’t take PDE5 inhibitors with other vasodilators like nitrates, it will cause
hypotentsion!
o PDE5 inhibitors have also been associated with a risk for vision loss
Calcium channel blockers
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Calcium channel blockers act on both vascular smooth muscle and the myocardium
Calcium channel blockers mainly dilate arteries
Calcium channel blockers are commonly used in treatment of hypertension, heart arrhythmias,
and certain anginas
There are many different subtypes of voltage-gated calcium channels, called L, T, N, and P
channels
o Calcium influx through the L-type channel is the important one for vascular tone
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Calcium channel blockers inhibit calcium entry through the L-type channel
In smooth muscle, decreased calcium going through L-type channels keeps intracellular calcium
low, decreasing calcium-calmodulin mediated activation of myosin light chain kinase, so no
vasoconstriction
Calcium channel blockers can work on all kinds of smooth muscle, but work best on vascular
smooth muscle
o Arterial smooth muscle responds more than venous smooth muscle
Vasodilation of arterioles decreases systemic vascular resistance and lowers arterial blood
pressure, which decreases ventricular systolic wall stress and heart O2 demand
In heart myocytes, less calcium through L-type channels leads to a decrease in heart
contractility, SA node pacemaker rate, and AV node coonductin veolocity
Skeletal muscle isn’t really affected by calcium channel blockers, because skeletal muscle relies
on intracellular calcium
There are 3 classes of calcium channel blockers:
o Dihydropyridines- like nifedipine, amlodipine, and felodipine
o Benzothiazepines- like diltiazem
o Phenylalkylamines- like verapamil
o All 3 classes block the L-type channel, but each has different binding sites on the
channel
 Nifedipine binds to the N binding site
 Diltiazem binds to the D binding site
 Verapamil binds to the V binding site
o The D and V binding sites overlap, while the N site is further away from them
 So diltiazem and verapamil affect each other’s binding and inhibit each other’s
binding
 Niifedipine and diltiazem enhance each other’s binding
o The dihydropyridines cause more arterial vasodilation than other calcium channel
blockers, but don’t really affect the heart much, , so the heat side effects aren’t present
o Clevidipine is only available intravenously, and used for hypertensive emergencies
o Deltiazem and verapamil aren’t as specific as dihydropyridines, and can therefore affect
the heart
 Verapamil suppresses the heart the most
Calcium channel blockers are usually given orally, except for the IV forms of diltiazem and
verapamil
Nifedipine and verapamil are excreted by the kidney, and diltiazem is excreted by the liver
First pass metabolism decreases the bioavailability of oral calcium channel blockers (nifedipine,
diltiazem, and verapamil)
Oral nifedipine works rapidly, and can cause a quick fall in blood pressure, causing hypotension
that activates reflex tachycardia, which can worsen an MI by increasing demand of O2, and
decreasing O2 supply by shortening diastole
o Oral nifedipine also has a short half-life, so you have to take it a lot
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Amlodipine has a high bioavailability that lets it be effective at low doses, because more reaches
systemic blood
Flushing and constipation can be caused by calcium channel blockers, due to excessive smooth
muscle relaxation
Excess calcium channel blockers can cause bradycardia, AV block, and heart failure
Potassium channel openers
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Potassium channel openers cause direct arterial vasodilation by opening ATP-modulated
potassium channels (aka K+ATP channels) in plasma membrane of vascular smooth muscle cells
Work well to treat hypertension
Opening a potassium channel will hyperpolarize a membrane
o So if enough potassium channels are open at one time, excitatory signals can’t cause an
action potential for depolarization as easily
o No depolarization means no calcium channels open, so no calcium in, and no smooth
muscle contraction happens
Potassium channel openers are minoxidil, cromakalim, pinacidil, and nicorandil
Potassium channel openers act mainly on arterial smooth muscle cells to decrease arterial blood
pressure
Adverse effects of potassium channel openers are headache from excessive dilation of cerebral
arteries, and flushing, from excessive dilation of cutaneous arteries
Arterial vasodilators like potassium channel openers, and calcium channel blockers, usually
trigger reflex sympathetics, leading to tachycardia and increased heart work
The use of β blockers with arterial vasodilators can help block the effects of reflex symp activity
Endothelin receptor antagonists
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Bosentan is a competitive antagonist at ETA and ETB receptors
o It’s approved for use for pulmonary hypertension
o Adverse effect is elevation in serum transaminase levels
Ambrisentan is an endothelin receptor antagonist more specific for the ETA receptor
o Used for pulmonary hypertension
o Less toxic than Bosentan
Hydralazine – oral arteriolar vasodilator used for hypertension and heart failure
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Prevents nitrate tolerance
Low bioavailabilty
A rare adverse effect is lupus erythematosus-like syndrome
…α1-adrenergic antagonists
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Epinephrine and norepinephrine stimulate α1-adrenergic receptors on vascular smooth muscle,
causing vasoconstriction
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The α1-adrenergic receptor is a G protein receptor that activates phospholipase C to make
inositol triphosphate (IP3) and diacylglycerol (DAG)
α1-adrenergic antagonists, like prazosin, block α1-adrenergic receptors in arterioles and venules,
causing vasodilation
they have a greater effect on arterioles, and cause a decrease in arterial pressure, so they’re
used for hypertension
like all vasodilators, α1-adrenergic antagonists can cause retention of salt and water
o β-adrenergic blockers and diuretics can be used with α1-adrenergic antagonists to
prevent this
β-adrenergic antagonists
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Activation of β2-adrenergic receptors on vascular smooth muscle cells causes vasodilation
o When activated, they increase intracellular cAMP, which causes smooth muscle
relaxation by accelerating the inactivation of myosin light chain kinase, and by
increasing removal of calcium
o Activation of β2-adrenergic receptors on endothelial cells also causes vasodilation by
activation of eNOS
β-adrenergic antagonists are way more important than the agonists when treating
hypertension, angina, and arrhythmias
β-adrenergic antagonists work on β1-adrenergic receptors
β-adrenergic antagonists work negatively on the heart, by reducing cardiac output
antagonism of β2-adrenergic receptors can let activation of α1-adrenergic receptors go
unopposed and cause vasoconstriction and increase systemic vascular resistance
β-adrenergic antagonists decrease blood pressure
so they’re used to get rid of bad symptoms of heart disease because of their good effects
Renin-Angiotensin system blockers
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Inhibiting this system causes vasodilatioin
The hypotensive effect of Ace inhibitors may be caused by decreased catabolism of bradykinin, a
vasodilator released in response to inflammatory stimuli
Antagonists at the AT1 receptor, which selectively inhibit angiontensin 2 caused
vasoconstriction, act more directly
ACE inhibitors and AT1 receptor antagonists are called “balanced” vasodilators because they
affect both arterial and venous tone
Both treat hypertension and heart failure
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