Effector Organ

eye

4

• Radial muscle
• Iris sphincter muscle
• Iris ciliary muscle
• Ciliary body

Eye

Sympathetic receptors and responses

5

• α1-Contraction (mydriosis)

• β2-Relaxation for far vision

• β1/2- increase production of aqueous humor

• α1- Decrease production of aqueous humor

• α2- Decrease production of aqueous humor and increase outflow
  

Eye

Parasympathetic receptor and responses

• Contraction (miosis) (M2-M3)
• Contraction for near vision (M2-M3)

Effector Organ

Heart

6

• All β1 > β2; M2 > M3
• SA node
• Atria
• AV node
• His-Purkinje System
• Ventricles
  

Preganglionic

ACh 

(5)

• Acetylcholine (Ach; "cholinergic")
• Used by both the sympathetic and parasympathetic neurons
• Acts through nicotinic cholinergic receptors located on the post ganglionic neurons
• Drugs that alter the levels of ACh or affect nicotinic receptors will therefore affect both the sympathetic and parasympathetic nervous system.
• Lower motor neurons innervating skeletal muscle also use acetylcholine acting through nicotinic receptors

Postganglionic

Sympathetic

6

• Sympathetic postganglion neurons use Catecholamines (DA, NE, Epi) as their neurotransmitters
• Most post gang neurons use NE. A clear exception to this rule is the post gang sympathetic innervation of the eccrine (thermoregulatory) sweat glands which is cholinergic
• Some sympathetic postganglionic neurons may also release dopamine (DA)
• The adrenal gland synthesizes both NE and Epi
• NE and epi act on α & β receptors in effector organs
• DA activates D1 and D2 dopamine receptors as well as α & β receptors
  

Postganglionic

Parasympathetic

(2)

• Use Acetylcholine (ACh)
• The ACh acts on muscarinic cholinergic receptors in the effector tissues

ACh

Synthesis

• From Choline to acetyl co-enzyme A
• Enzyme is choline Acetyltransferase (ChAT)
• No clinically useful drugs affecting this step

ACh

inactivation

Released Synaptic

(4)

• Synaptic ACh is RAPIDLY degraded by acetylcholine esterase (AChE)
• Bound to extracellular surface of postganglionic neurons
• Extremely effecient enzyme (1000ACh/sec/AChE)
• Enzymatic inactivation is therefore the primary means by which the action of AE released ACh is terminated

ACh

Inactivation Blockade

(6)

• Blockade of acetylcholinesterase leads to increased synaptic/extracellular levels of ACh
• Will get greater activation of post-synaptic nicotinic and muscarinic receptors
• Affects tissues innervated by postganglionic parasympathetic fibers
• Affects signaling in BOTH the sympathetic and parasympathetic ganglia
• Affects signaling at neuro muscular junction

ACh

Muscarinic Receptors

(8)

• G-protein coupled receptors
• Located Post-synaptically in tissue innervated by postganglionic parasympathetic fibers. Also in CNS
• Mediate effects of parasymp. postganglionic fibers on tissues
• Important effects
• slowing of heart,
• Decreased contractility of heart
• Stimulation of secretion
• Contraction of the circular muscle of the Iris

• Stomach

        Acid Secretion

        Increase IP3/DAG

• CNS

        Undefined

M2

Heart

Heart

• SA node- Decrease HR (hyperpolarization)
• Atria- Decrease AP duration and contractility
• AV node- Decrease conduction, AV block
• Ventricle- Decrease contractility
• Actions-
•          Decrease cAMP
•          Increase K+ conduction
•          Decrease Ca++ conduction

M3

(5)

• Smooth muscle- Contraction, Relaxation
• Secretory glands- Increase Secretions
• Actions-
•         Increase IP3/DAG
•         EDRF (NO)

ACh

Nicotinic Receptors

(6)

• Ligand gated ion channel
• Located on sympathetic and parasympathetic postganglionic neurons in autonomic ganglia
• Mediate effects of preganglionic fibers on postganglionic sympathetic and parasympathetic
• Allow for influx of Na+ and therefore depolarization and excitation of neurons
• Also found in skeletal muscle and CNS
• Nicotinic receptors in neurons and skeletal muscle, to some extent, have diff pharmacologies

Nicotinic m

(4)

• Muscle
• Neuromuscular junction
• Depolarizes end plates
• Ligand-gated Na+ channel

Nicotinic n

(7)

• Neuronal
• Tissue 
• Autonomic ganglia
•  Adrenal medulla
•  CNS
• Responses
•  Depolarizes post-synaptic neurons
• Catecholamine secretion
• Actions - Ligand gated Na+ channel

Catecholamines

(3)

• Dopamine
• Norepinephrine
• Epinephrine

Catecholamine synthesis

(5)

1. Synthesized from Tyrosine via tyrosine hydroxylase (This enzyme is the rate limiting step)
2. Tyrosine is metabolized to L-Dopa, which is then metabolized to dopamine via aromatic aa decarboxylase. This enzyme is ubiquitous in the body, not just catechol synthesis (in some cells synthesis stops here at dopamine)
3. In NE and epi neurons, dopamine is metabolized by dopamine β-hydroxylase to NE.
4. In Epi-synthesizing neurons, such as those of the adrenal gland, NE is then metabolized to Epi by the enzyme phenyl-N-methyl transferase
5. Epi neurons also contain dopamine and NE, & thus neurons that make NE will always have dopamine, but not necessarily epi
   

Catecholamine

Storage

(5)

• Like all neurotransmitters, catecholamines are stored in synaptic vesicles before they are released
• The vesicular monoamine transporter (VMAT) is the protein that transports the catecholamines from cytoplasm into the synaptic vesicles, from which release can occur
• For most physiological neurotransmission, these vesicular stores of neurotransmitters are critical
• Therefore, blocking the storage of catecholamines disrupts normal neurotransmission btwn sympathetic postganglionic fibers & effector tissue
• Serotonin is a monoamine so its storage is regulates the same way.

Catecholamine

Enzymatic inhibition

(4)

• Catecholamines can also be enzymatically degraded
• Monoamine oxidase is a mitochondrial enzyme in the nerve terminal. Therefore, its activity can modulate the amnt of neurotransmitter available in the nerve terminal
• Catechol-O-Methyl transferase (COMT) is located extra-cellularly on membranes throughout the body. it can therefore metabolize released catecholamines into inactive metabolites
• These enzymes are NOT responsible for terminating the action of synaptically released catecholamines; however, their inhibition does alter the level of catecholamine signaling

Catecholamine

Re-uptake inhibition

(3)

• Post synaptic effects are terminated by reuptake back into nerve terminals. Primary means of inactivation of the catecholamines
• Different plasma membrane proteins/transporters are responsible for taking up dopamine and NE (Dopamine transporter (DAT)) (NE transporter (NET))
• Blocking the DAT or NET leads to an accumulation of DA or NE, respectively, in the synapse & extracellular fluid, & thus increased activation of the dopaminergic or adrenergic receptors

α 1

Table

(6)

• Tissues
•         Radial muscle of Iris - Contract
•         Vasculature - Constrict
•         Genitourinary (a1a) and GI sphincters               constrict
• Actions

         increase IP3/DAG

a,b,d

α 2

Table

• Tissues

        Vasculature - Constrict

        NE nerve terminals (auto receptor)-Dec. NE release

        Brain stem (Dec. sympathetic neurons system activity, Inc. parasympathetic neuron system activity)

• Actions (Dec. cAMP, Inc. K+ conductance, Dec. Ca2+ conductance)

a/b/c

α 1

(5)

• Critical α1 distribution is in the;
•  radial muscle of the Iris
•  the vasculature
•  the genito urinary (a-1a) & gastrointestinal sphincter
• Activation of these receptors causes contraction of the muscle
  

α 2

(3)

• Also located in the vasculature, although they play a less of a critical role than the α 1
• Located on NE nerve terminals (So function as inhibitory autoreceptors. That is, activation of these receptor decrease the amnt of NE released)
• Located in the brainstem where activation leads to decreased sympathetic & increased parasympathetic nervous system activation
  

β 1

Table

heart

(7)

• Tissues
• SA node- increase HR
• Atria- increase conduction velocity & contractility
• AV node- increase automaticity & conduction velocity
• His-Purkinje system- increase automaticity & conduction velocity
• Ventricles- increase automaticity, conduction velocity,contractility
• Actions- increase cAMP

β 2

Table

(8)

• Tissue
• Eye
• ciliary muscle-relaxation for far vision
•  ciliary epithelium-increased production of aqueous humor
• Vascular (Relaxation esp. in skeletal muscle)
• Lungs (Tracheal & bronchial smooth muscle:relaxation)
• Urinary bladder detrusor muscle- relaxation
• Uterine wall- relaxation
• Actions- increase cAMP

β adrenergic pharmaco

• A VERY important aspect of beta adrenergic receptor pharmacology is that the affinity of EPI for β2 is greater (~100 fold) than the affinity of NE for β2
• Therefore Epi has more β2 effects a clinically used doses
• This diff in pharmacology underlies the different clinical indications for Epi vs. NE
  

β-2

• Receptors are critical for their localization in several tissues
• β2 receptors in the vasculature of the skeletal muscle beds mediate vasodilation in skeletal muscle
• β2 receptors in bronchial & tracheal smooth muscle mediate bronchodilation

• β2 in the smooth muscle of the bladder & uterine walls mediate relaxation of those muscles.
  

β-1

• β-1 receptors are important because of their localization in cardiac muscle
• Activation leads to increase conduction and contractility in the heart
• therefore, β-1 receptor activation increases cardiac output
  

Dopaminergic

G-protein coupled receptors

synthesis

(5)

• Dopamine is synthesized in sympathetic postganglio neurons as a precursor of NE synthesis
• It may therefore be released from those fibers and act as a neurotransmitter in that system
• Dopamine is also synthesized in cells of kidney (cells of proximal and distal tubules) & is released from those cells to exert effects on renal function             
• D1 receptors localized to intra renal vasculature, proximal & distal convoluted tubules & collecting ducts
• Dopamine is likely to play a critical role in the regulation of cardiovascular & renal function.

Dopamine

D1 and D2

• Dopamine acts on D1 & D2 receptors to exert its effects
• D1 receptors are most imp. right now in terms of autonomic function
• Activation of these receptors increases renal blood flow, glomerular filteration rate, & Na+ excretion
• Activation of D1-like receptors in the kidney inhibits the function of several transporters involved in Na+ transportation, therefore, Na+ excretion is inactivated
• Activation of these receptors also causes vasodilation in renal, cardiac, cerebral, & mesenteric vasculature
• At higher but clinically relevant doses, dopamine also activates β & α receptors
  

• D1, D5

Tissues

• Kidney- increase renal blood flow:(inc. cAMP/PKA), increase glomerular filteration rate:(Inc. PKC),   increase sodium excretion
• Vasculature- vasodilation: (inc. PLC/PLA2)
• Heart
• CNS

• D2, D3, D4

Tissues

• Kidney- decrease cAMP
• Post gangli symp nerve terminals- decrease neurotransmitter release- increase K+ conductance
• Chemoreceptor trigger zone- n/v- decrease Ca2+ conductance
• CNS

• There may be receptors on effector organs that aren't innervated (Muscarinic receptors on vascular smooth-cause vasodilation)
• Effector organs are usually dually innervated. Generally, but not always symp. & parasymp. activation have opposite effects
• Neuronal activity can determine the response to a drug. This is especially true for antagonists
• Both direct & reflex effects of the drugs are important for understanding their clinical usefullness
• A critical reflex often evoked in response to manipulations of the ANS is the baroreceptor reflex

Sympathetic Regulation

of the heart

• β-1 receptors are critically imp. in regulating HR and contractility
• 1.SA node- increase HR
• 2.Atria- increase contractility & conduction velocity
  
• 3.AV node- increase automaticity & conduction velocity
• 4.His-Purkinje system- increase automaticity & conduction velocity
• 5.Ventricles- increase contractility, conduction velocity, & automaticity
• TAKE HOME MESSAGE: β-1 receptor activation increases cardiac output

Parasympathetic regulation of

the Heart

• Muscarinic (M2)
• 1. SA node- decrease HR
• 2. Atria- decrease contractility & AP duration
• 3. AV node- decrease conduction velocity, AV block
• 4. His-Purkinje- not much effect
• 5. Ventricles- decrease contractility (Slightly)
• TAKE HOME MESSAGE: Muscarinic receptor activation decrease cardiac output

Sympathetic Regulation

of the Vasculature (Vascular Smooth Muscle)

• α1 receptor activation causes vasoconstriction. Main autonomic determinant vascular tone/total peripheral resistance
• α2 receptor activation causes vasoconstriction (not as prominent)
• β2 receptor activation causes vasodilation in skeletal muscle vasculature
• TAKE HOME MESSAGE: Effect of sympathetic activation/drugs will depend on relative levels of α1 & β2 activation.
  

Parasympathetic regulation

of teh vasculature (VSM)

• VSM is not innervated by sympathetic nervous system
• there are, however, muscarinic receptors on VSM- Activation of these causes vasodilation
• TAKE HOME MESSAGE: parasympathetic nervous system activation will not alter total peripheral resistance, but direct-acting muscarinic agonists can

Baroreceptor Reflex

General Points

• Mean arterial pressure is a function of cardiac output and total peripheral resistance
• Body attempts to maintain homeostatic set-point w/ respect to blood pressure

• Pressure sensitive cells in aortic arch and carotid sinus
• Increase firing rate when blood pressure increases
• Decrease firing rate when blood pressure decreases
• Provide afferents to cardiovascular centers in the medulla

Baro receptor

Decreasaed blood pressure (eg. hemmorhage)

• Baroreceptor firing decreases
• Inhibition of parasympathetic nervous system: (Decreased stimulation of muscarinic receptors in heart, Increased heart rate & contractility so increased cardiac output)
• Activation of sympathetic nervous system (Increased α1 receptor-mediated vasoconstriction, so vessels constric leading to increased peripheral resistance, Increased β1 receptor activation in heart, so increased heart rate & contractility leading to increased cardiac output)
• Final outcome: Increased cardiac output & increased total peripheral resistance lead to increased mean arterial pressure
  

Baro receptor

Increased Blood Pressure

• Baroreceptor firing increases
• Activation of PNS (Activation of muscarinic receptors in heart, Decrease HR & contractility so decreased cardiac output)
• Inhibition of sympathetic nervous system (Decreased α1 receptor-mediated vasoconstriction, so vessels dilate leading to decreased total peripheral resistance, Decreased β1 receptor activation in the heart, so decreased heart rate & contractility leading to decreased cardiac output)
• FINAL OUTCOME: Decreased cardiac output and decreased total peripheral resistance lead to decreased mean arterial pressure.
  

Pupillary Function

Sympathetic Regulation

• Radial/dilator muscle of the Iris
• α1 receptor activation causes contraction
• Contraction of radially oriented fibers causes pupillary dilation (mydriasis)
  

Pupillary Function

Parasympathetic regulation

• Sphincter muscle of the Iris
• Muscarinic receptor activation causes contraction
• Contraction of this circular muscle around the pupil causes pupillary constriction (miosis)

Sympathetic Regulation

of intra ocular pressure

• α1 receptor activation decreases blood flow to ciliary body & trabecular network. Decreases production & increases outflow of aqueous humor
• α2 receptor activation decreases production of aqueous humor & increases outflow of aqueous humor
• β1 receptor activation increases the production of aqueous humor
• β2 receptor activation increases aqueous humor production & increases outflow of aqueous humor.
  

Parasympathetic regulation of

intraocular pressure

• Muscarinic receptor activation causes contraction of ciliary muscle
• Tension on trabecular network leads to increased outflow of aqueous humor through the network

Drugs &

Intraocular Pressure

• Drugs that decrease production of aqueous humor &/or increase the outflow of aqueous humor will decrease intraocular pressure

Sympathetic regulation of the

Bronchioles

• Mediated by β2 receptors
• Relaxes smooth muscle- bronchodilation
• Decreases vascular permeability
• Inhibits release of inflammatory mediators from mast cells
• Increases cilial beat frequency
  

Parasympathetic Regulation

of the Bronchioles

• Constricts smooth muscle
• Increases mucous secretion

Sympathetic Regulation of the

Urinary Bladder

• α1a (Subtype clinically/pharmacologically relevant) receptor stimulation causes contraction of sphincter muscle/neck of bladder, as well as smooth muscle of prostate and prostate capsule.
• β2 receptor stimulation causes relaxation of bladder wall (detrusor muscle)

Parasympathetic Regulation of the

Urinary Bladder

• Muscarinic receptor activation causes relaxation of sphincter muscle
• Muscarinic receptor activation causes contraction of bladder wall (detrusor muscle)