Pharmacology of Smooth Muscle

Tina K. Machu, Ph.D.

Objectives1. Describe the basic peripheral neural pathways of the parasympathetic

and sympathetic autonomic nervous systems, listing:the neurotransmitter released at ganglia and neuroeffector junctionsthe 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.

Objectives5. Describe the effects of the following drug prototypes on smooth muscle

function:Muscarinic agonists – acetylcholine, muscarine, bethanecholMuscarinic antagonists – atropine, ipratropium bromideAlpha adrenergic agonists – norepinephrine, epinephrine, phenylephrineAlpha adrenergic antagonists – phentolamineBeta adrenergic agonists – norepinephrine, epinephrine, albuterolBeta 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)

AutonomicNervousSystem

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 viamuscarinic 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: tachycardia• Eye:

– mydriasis (dilation of iris circular muscle)– cycloplegia (relaxation of ciliary muscle)

• Bronchial: smooth muscle relaxation, decrease secretions

• GI Tract:decreased tone, motility• Urinary: relaxation smooth muscle• Glands 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

ResponsesResponses to Adrenergic and Cholinergic Nerve Stimulation

Organ or tissue function

Predominant adrenoceptor type

Sympathetic/ Adrenergic response

Parasympathetic/ Muscarinic Receptors Cholinergic responsea

Bronchial smooth muscle

2 Relaxation Contraction

Blood vessels Cutaneous 1 Constriction No innervatione Visceral 1 Constriction No innervatione Pulmonary 1 Constriction No innervatione Skeletal muscle 1, 2 Constrictiond Dilation -Coronary 1, Constriction,

dilationf No innervatione

Cerebral 1 Constriction Veins 1 Constriction 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 contraction- Heart 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 pre-synaptically 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 BlockersA. 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