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Pharmacology of Smooth

Muscle
Tina K. Machu, Ph.D.

Objectives
1. Describe the basic peripheral neural pathways of the parasympathetic
and sympathetic autonomic nervous systems, listing:
the neurotransmitter released at ganglia and neuroeffector junctions
the receptor type mediating the effects on postganglionic neurons or
effector organ function.
2. Describe the basic structural features and signal transduction
mechanisms of nicotinic and muscarinic cholinergic receptors and
alpha and beta adrenergic receptors.
3. Describe the major steps in cholinergic and adrenergic
neurotransmission.
4. List the major physiological effects regulated by the parasympathetic
and sympathetic nervous systems with particular attention to smooth
muscle responses.

Objectives
5. Describe the effects of the following drug prototypes on smooth muscle
function:
Muscarinic agonists acetylcholine, muscarine, bethanechol
Muscarinic antagonists atropine, ipratropium bromide
Alpha adrenergic agonists norepinephrine, epinephrine, phenylephrine
Alpha adrenergic antagonists phentolamine
Beta adrenergic agonists norepinephrine, epinephrine, albuterol
Beta adrenergic antagonists propranolol

Drug List
Muscarinic Receptor Agonists:
Acetylcholine, Muscarine, Bethanechol

Muscarinic Receptor Antagonists


Atropine, Ipratropium

Alpha () Adrenergic Receptor Agonists


Norepinephrine, Epinephrine

Alpha () Adrenergic Receptor Antagonist


Phentolamine

Beta () Adrenergic Receptor Agonists


Norepinephrine, Epinephrine
Albuterol (2-selective

Beta () Adrenergic Receptor Antagonist


Propranolol

Motor: Somatic versus Autonomic


Somatic: voluntary movement: alpha motor
neuron synapses at skeletal muscle
Autonomic Nervous System: involuntary
responses- visceral functions necessary for life
Sympathetic: stress, exercise, and fight or flight
response
Parasympathetic: rest and digest

Balance of SNS and PNS sets tone of body


Pages 78 and 79 of Katzung

Key Terms
Cholinergic refers to acetylcholine (ACh)
Nerves that release ACh are cholinergic
Receptors activated by ACh are cholinergic
Nicotinic and muscarinic

Drugs that effect neurotransmission by Ach


terms such as cholinergic drugs, anticholinergics, cholinomimetic are
used.

Adrenergic refers to norepinephrine (NE) from neurons


and epinephrine from adrenal medulla
Epinephrine = adrenaline

adrenergic

Nerves that release NE (noradrenalin) are adrenergic


Receptors activated by NE are adrenergic
Alpha () and Beta ()

Drugs that affect neurotransmission by NE


Another key term is sympathomimetic (mimic sympathetic)

Autonomic
Nervous
System

Autonomic Nervous System

Steps in
Acetylcholine
Neurotransmission

Muscarinic Cholinergic Receptors

Brody et al., (1998). Human Pharmacology: Molecular to Clinical,


Mosby-Year Book, Inc., pp.120.

Adrenergic receptors
Alpha adrenergic receptors

Beta adrenergic receptors


Knowledge of tissue locations of receptors is


important for predicting drug responses.

or M2, M4
Muscarinic
receptor

Parasympathetic System
Discrete, localized discharge
Rest & Digest

Slows heart rate, lowers blood pressure


Stimulate GI movements and secretions
Aids absorption of nutrients
Protects retina from excessive light
Empties the bladder and rectum

Cholinergic neurons both preganglionic &


postganglionic
Responses on end organs mediated via
muscarinic cholinergic receptors

Sympathetic System
Preganglionic sympathetic neurons are cholinergic
(ACh)
Postganglionic sympathetic neurons are adrenergic
(NE)
Exception is sympathetic neurons to sweat glands these
sympathetic neurons are cholinergic, i.e., release Ach
Exception is specialized neurons innervating afferent arterioles of
kidney these neurons release dopamine which causes relaxation
of the vascular smooth muscle & vasodilation by activating D1
dopamine receptors

Adrenal medulla is like a modified ganglia no axons,


instead releases Epi into blood
Preganglionic fibers to adrenal medulla are cholinergic

Sympathetic System
Fight or Flight (NE & Epi)
Heart rate increases, blood pressure rises
RBCs poured into blood from spleen to carry more
O2
Blood flow shifted from skin and splanchnic region
to skeletal muscles
Blood glucose rises
Bronchioles and pupils dilate
Brain receives signals to facilitate purposeful
responses & to imprint the event in memory

Effects resulting from stimulation


muscarinic receptors
Heart: bradycardia (slowing of the heart rate)
Bronchial: smooth muscle contraction
Gastrointestinal: increased smooth muscle tone,
motility
Urinary bladder: contraction of walls and relaxation of
sphincter (opening)
Eye muscle: miosis (constriction of pupils) via
contraction of iris circular muscle and accommodation
via ciliary muscle contraction
Stimulation of secretion from glands: bronchial, GI,
salivary, lacrimal, sweat glands

Therapeutic uses of
cholinoceptor activating drugs
Bethanechol: (prototype)
Postoperative or neurogenic urinary
retention
Postoperative atonic bowel without
obstruction

Muscarinic Antagonists: Atropine


Atropine is the prototype, many others
available
Binds to all subtypes of muscarinic
receptors
Prevents binding by acetylcholine and any
other muscarinic agonist
Blocks the effects of ACh and muscarinic
agonists

Atropine Effects
Heart:
Eye:

tachycardia

Bronchial:

smooth muscle relaxation,


decrease secretions

mydriasis (dilation of iris circular muscle)


cycloplegia (relaxation of ciliary muscle)

GI Tract:
Urinary:
Glands

decreased tone, motility


relaxation smooth muscle
decrease in all secretions

Bronchodilators:
Ipratropium bromide
A muscarinic receptor antagonist
If given parenterally, effects are like atropine
But, only given as inhaled aerosol
few side effects, even when swallowed because is poorly
absorbed from GI and does not cross into brain
poor diffusion across membranes

Parasympathetic - mediated bronchospasm is a


significant component of airway resistance in some
asthmatics and COPD patients, especially
psychogenic exacerbations

Responses

Responses
Responses to Adrenergic and Cholinergic Nerve Stimulation
Organ or tissue
function

Predominant
adrenoceptor
type
Bronchial smooth 2
muscle
Blood vessels
Cutaneous
1
Visceral
1
Pulmonary
1
Skeletal muscle 1, 2
-Coronary
1,
Cerebral
Veins

1
1

Sympathetic/
Adrenergic
response
Relaxation

Parasympathetic/
Muscarinic Receptors
a
Cholinergic response
Contraction

Constriction
Constriction
Constriction
d
Constriction
Constriction,
f
dilation
Constriction
Constriction

No innervation
e
No innervation
e
No innervation
Dilation
e
No innervation

No innervation

Responses

Responses

Rules of Thumb - Smooth muscle


Alpha1 ( 1) Receptors
Stimulate contraction of all smooth muscle
Vascular smooth muscle Vasoconstriction
Glandular smooth muscle contracted

Beta2 ( 2) Receptors
Relax smooth muscle

Muscarinic Cholinergic Receptors


Contract smooth muscle (but not in all cases)
Different intracellular signal than 1 receptors (M2 and M4)
Same intracellular signal as 1 receptors (M1, M3, and M5)

Adrenergic Effects
1 Heart
stimulation of heart rate
chronotropic effect
stimulation of force of contraction
inotropic effect

Adrenergic Effects
Smooth Muscle Relaxation 2

relaxation of bronchioles 2

relaxation of uterus 2

relaxation of vascular smooth muscle 2


(vasodilation, certain vascular beds only)
relaxation of detrusor (bladder) 2

relaxation of intestinal smooth muscle 2

Skeletal Muscle

2 stimulates potassium uptake

2nd Messenger

Effect on Smooth Muscle

Receptors

Increased Ca2+

Contract

1, M1, M3, M5

Increased cAMP

Relax

Decreased cAMP

Contract

M2, M4

Decreased cAMP

Relaxation

2 (see last bullet below)

Note that 1, 2, and 3 receptors INCREASE cAMP, but in smooth muscle 2 receptors
are the predominant type

Note that 1 receptors cause increased heart rate and increased strength of contractionHeart muscle is different than smooth muscle: increased cAMP enhances cardiac function.

Note that muscarinic receptors on smooth muscle cause relaxation of vasculature, if


exposed to muscarinic agonists (via release of NO). There is no innervation of the
vasculature by the PNS.

Note that muscarinic receptors cause relaxation of sphincters- promote urination and
defecation. Muscarinic receptor mediated release of NO is likely the cause.

Note that 2 receptors cause smooth muscle relaxation. 2 receptors are located presynaptically on norepinephrine (NE) containing neurons. Activation of 2 receptors
reduces NE release. Less NE release means less NE to stimulate smooth muscle of the
blood vessels.

Adrenergic Effects
Metabolic and Hormonal
glycogenolysis 2 (liver)
gluconeogenesis (liver)
lipolysis 3(fat cells)
stimulation of insulin release
stimulation of renin release

Albuterol (Proventil, Ventolin)


relatively selective 2 (10x) agonist
bronchodilation
used for treatment of bronchospasm in asthma
aerosol delivery - restricts to lungs, decreases
systemic absorption and side effects
p.o. - sometimes used, more side effects when oral

Side effects:
muscle tremors, tachycardia (1 and reflex), anxiety,
restlessness, headache, hyperglycemia, hypokalemia

Beta Adrenergic Receptor Blockers


A. Propranolol (Inderal) is the prototype
Mechanism: Non-selective competitive antagonist
at -1 and -2 receptors (& -3).

Alpha 1 Agonist
Phenylephrine

1 > 2 activity
Decongestant (oral or spray)
Mydriatic (causes mydriasis)
Increases blood pressure (vasoconstriction)

Alpha 2 Agonist
2 receptors- presynaptic location on
noradrenergic neurons
Decrease the release of NE

Clonidine
2 receptor agonist
Decreases release of NE
Decreases blood pressure, anti-hypertensive

Alpha Blocker
Phentolamine Non-selective competitive
antagonist for alpha-1 and alpha-2 receptors.
Duration of several hours.
Competitive blocker Rapid onset of
blockade. Surmountable by high
concentrations of alpha-1 agonists or alpha-2
agonists.

Other chemical modulators of


smooth muscle contraction/relaxation
Nitric oxide (NO) - relaxation
Histamine contraction of smooth muscle in lungs
and GI tract
Histamine relaxation of smooth muscle in
vasculature
Vasopressin - contraction
ATP - contraction
Adenosine - relaxation
Angiotensin II - contraction