Intro to ANS pharm

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What are the two categopries of the efferent portion of the NS?

1. autonomic
2. somatic

What does the somatic NS control?

consciously controlled actions

What does the ANS control?

actions not under direct conscious control (visceral fxns like CO, blood flow to various organs and digestion)

What are the 2 divisions of the ANS?

1. sympathetic (thorocolumbar)
2. parasympathetic (craniosacral)

What are the 5 NTs of the ANS?

1. Acetylcholine (ACh)
2. Norepiphrine (NE)
3. Epinephrine (Epi)
4. Dopamine (DA)
5. Co transmitters

What is the major NT of the parasympathetic NS?

ACh

What are the three places where ACh is found?

1. All preganglionic autonomic fibers (almost all efferent fibers leaving the CNS in both parasympathetic and sympathetic NS)
2. All postganglionic parasympathtic fibers
3. A few postganglionic sympathetic fibers (sweat glands)

What receptors does ACh bind to and activate?

Both nicotinic and muscarinic ACh receptors (nAChR and mAChR)

What is the major NT of the sympathetic NS?

NE

Where is NE found?

At the vast majority of postganglionic sympathetic fibers

What are NE, Epi and DA categorized as?

catecholamines

Where is Epi synthesized?

Only at the adrenal medulla and in a few Epi containining neuronal pathways in the brainstem

How do Epi and NE get released into general circulation?

Upon depolarization of the preganglionic sympathetic neuron (cholingergic), ACh is released and binds to the nAChRs on the adrenal medulla releasing catecholamines (80% Epi, 20% NE) into general circulation

What is dopamine (DA) and where is it synthesized?

Precursor to NE and Epi, synthesized in cytoplasm of neurons from tyrosine. (tyrosine --> DOPA --> DA)

Where does DA act?

Has actions in the CNS and renal vascular smooth muscle

Name 4 co-transmitters

1. ATP
2. Neuropeptide Y
3. Vasoactive Intestinal Peptide (VIP)
4. Substance P

What is cholinergic transmission

Any neurotransmission in which ACh is released in vesicles

What are cholingeric neurons?

Neurons that release ACh

What enzyme synthesizes ACh and from what precursors?

Choline acetyltransferase (ChAT) catalyzes the final step in the synthesis of ACh by combining the acetyl moiety of acetyl co-A with choline.

What happens to ACh after it is synthesized?

It is immediately sequestered within synpatic vesicles

How does the choline used to make ACh get into the neuron?

The choline transporter transports choline from the extracellular space into neurons and is dependent of extracelllular Na+ concs (both choline and Na+ are cotransported)

How is ACh stored in the neuron?

The ATPase-dependent ACh vescicular transporter transports ACh into neuronal vesicles.

How is ACh released from the neuron when an action potential is received?

1. When the AP reaches the axonal terminal of the preganglionic fiber, depolarization causes the opening of voltage gated calcium channels and calcium enters the neuron.
2. Ca++ influx promotes the fusion of the vesicular membrane with the cell membrane and ACh is released.

What is responsible for the fusion of the vesicle membrane and the synaptic membrane?

The SNARE protein complex (VAMP on the vesicle membrane and SNAP on the synaptic membrane)

What happens when ACh binds to and activated nAChRs of the neuronal subtype?

1. It facilitates entry of sodium into the postganglionic fiber or adrenal medulla.
2. sodium entry causes depolarization and subsequent AP of the postganglionic fiber or release of Epi and NE from the adrenal medulla.

What happens when ACh binds to the postsynaptic mAChRs in organs and tissues innervated by parasympathetic nerves?

It causes SM contraction, a decrease in heart rate, glandular secretion etc depending on the organ

How does ACh modify its own release?

ACh can bind to and activate both nAChRs and mAChRs on presynaptic membrances, thereby modifying its own release.
1. Activation of prejunctional nAChRs mobilized additional transmitter for subsequent release
2. Activation of prejunctional mAChRs inhibits further release of ACh

How is ACh signaling terminated?

Acetylcholinesterase (AChE) cleaves ACh into acetate and choline

What happens to the breakdown products of ACh?

Acetate diffuses out of the synapse while most of the choline is recycled back into the nerve terminal by the choline transporter

Where are NnACHRs found in the ANS?

All ganglia (sympathetic and parasympathetic) and the adrenal medulla (sympathetic)

What are nAChRs?

Ligand gated ion channels that allow Na+ to pass through the ion channel pore when activated (ionotropic receptor)

What can activate a nAChR?

both ACh and nicotine

Where are the subtypes of nAChR found?

Distinct subtypes exist at:
1. NMJ
2. Ganglia
3. CNS

Where are nAChRs found in the ANS

Peripherial neuronal nAChRs (Nn) exist at autonomic ganglia and the adrenal medulla.

How many subtypes of mAChRs are there

5 (M1-M5)

What is the structure of mAChRs?

7-transmembrane spanning G-protein coupled receptors (GPCRs - metabotropic receptors)

What are the predominant smooth muscle mAChRs?

M2 and M3

What is the predominant cardiac muscle mAChR?

M2

What happens when mAChRs are activated?

Leads to a series of intracellular events triggered by second messengers

What determines agonist slectivity and intracellular response of mAChRs?

The subtype of mAChRs and G proteins that are present in a given cell

What is adrenergic neurotransmission?

Neurotransmission in which catecholamines (NE, Epi, DA) are released upon stimulation by an AP

What are adrengeric neurons?

Neurons that release catecholamines

What is the principal NT of most sympathetic postganglionic fibers?

NE

What is the major hormone/NT released by the adrenal medulla?

Epi

What is DA the predominant transmitter of?

The mammalian extrapyramidal system and several mesocortical and mesolimbic neuronal paths

What are the steps in the synthesis of catecholamines?

tyrosine -> DOPA --> DA --> N--> Epi

Where does the final step (synethesis of Epi) occur?

Only in the adrenal medulla and in a few Epi containing neuronal pathways in the brainstem

What is the precursor to all catecholamines and how does it get into the nerve terminal?

Tyrosine. It is transported into the nerve terminal by a sodium dependent transporter

What is VMAT-2 and what does it doi?

Vesicular monoamine transporter that transports DA into the vescicle during de-novo catecholamine synthesis

Where is DA synthesized?

Enzymatic conversion of tyrosine to DOPA and DOPA to DA occurs in the nerve cytoplasm

Why is VMAT-2 promiscuous?

It transports DA. NE, EPi and 5-HT across the vesicle membrane

What does the drug reserpine do?

Inhibits VMAT-2 and leads to depletion of catecholamines from sympathetic nerve endings

How are catecholamines released from adrenergic neurons?

similar to the release of ACh by cholinergic neurons after depolarization from and AP and influx of calcium

What is the triggering event for the adrenal medulla to release catecholamines?

The release of ACh by preganglionic fibers and its interaction with nAChRs on chromaffin cells to produce a localized depolarization

What are 2 types of receptors catecholamines bind to? What effect does this have?

Adrengergic alpha and beta receptors (GPCRs) activating stimulatory and inhibitory G-proteins depending on the receptor subtype

What are some examples of effector organ responses from the binding of catecholamines?

1. Contraction
2. Glycogenolysis
3. Gluconeogenesis
4. Relaxation
5. Increased force and rate of cardiac muscle contraction

What are 3 ways catecholamine signaling can be terminated?

1. Reuptake into nerve terminals
2. Dilution by diffusion out of the junctional cleft and uptake at extraneural sites
3. Metabolic transformation

Can catecholamine action be terminated by degradtive enzymes?

No, this does not happen in adrenergic signaling

What is the major mechanism that terminates the actions of catecholamines?

Reuptake into the nerve terminals

What are the 2 neuronal membrane transporters that are responsible for the reuptake of catecholamines?

1. NET (norepi transporter)
2. DAT (dopamine transporter)

What happens to catecholamines after reuptake?

They are stored in vesicles by VMAT-2

What is repsonsibnle for the uptake of catecholamines at extraneuronal sites?

ENT, OCT1 and OCT2 (nonneuronal catecholamine transporters found at various sites, such as the liver, intestine, kidney and blood vessels)

What are the two enzymes that are responsible for metabolic transformation of catecholamines?

1. MAO (monoamine oxidase)
2. COMT (catechol-O-methytransferase)

What is MAO and where is it found?

Metabolized catecholamines that have been released and undergone reuptake within nerve terminals. Associated with the outer surface of mitochondria.

What is COMT and where is it found?

Plays a major role in the metabolism of endogenous circulating and administered catecholamines (particulary in the liver). In contrast to MAO, COMT is largely cytoplasmic.

What are cotransmitters?

multiple NTs can exist within one vesicle

What are the common cotransporters within adrenergic vesicles?

NE, ATP and NPY

How can the release of the three sympathetic cotransmitters be modulated?

The release of the 3 sympathetic cotransmitters can be modulated by prejunctional receptors. NE, NPY and ATP can feedback on prejunctional receptors to inhibit the release of each other.

What are some examples if receptors on sympathetic nerve varicosities that also inhibit the release of sympathetic NTs?

1. M2 and M4 mAChRs
2. 5-HT
3. PGE2 (prostaglandin E2)
4. Histamine
5. Enkephalin
6. DA
7. Alpha 2 receptors

What are some examples of receptors on sympathetic nerve varicosities that enhance sympathetic NT release?

1. Beta 2 adrenergeic receptors
2. Angiotension II receptors
3. nAChRs

What are the 2 types of alpha adrenergeic receptors?

alpha 1 and alpha 2

What is the end result of alpha 1 receptor activation?

muscle contraction

What is the effect of alpha 1 receptor activation on smooth and cardiac muscle?

smooth = vasoconstriction
cardiac = increase in contractile force of the heart

What is the effect of alpha 1 receptor activation in the gut?

This is the exception - activation of alpha 1 receptors and the subsequent increase in calcium causes hyperpolarization and muscle relaxation by activation of calcium dependent potassium channels (potassium is released out of the cell causing hyperpolarization)

What results from the activation of alpha 2 receptors?

Vascular SM contraction, decreased insulin secretion, and a decreased release of NE (presynaptic alpha 2 receptors)

What are alpha 1 receptors prefernetially activated by? alpha 2 receptors?

alpha 1 receptors are preferentially activated by the agonist phenylephrine while alpha 2 receptors are preferentially actived by the agonist clonidine

What are the three subtypes of beta adrenergic receptors?

Beta 1,2, & 3

What results in the activation of all the beta receptors?

activation of adenylyl cyclase and increased concentrations of cAMP through stimulatory Gs protein

Where are beta-1 receptors found, what happens when they are activated?

Mainly in the myocardium. Activation results in an increased force and rate of heart contraction and AV nodal conduction velocity.

Where are the beta 2 receptors found and what happens when they are activated?

Smooth muscle and most other sites. Activation causes vascular, broncial, genitournary and GI SM to relax

What do Beta1 and Beta2 receptors preferentially respond to?

Beta1 receptors preferentially respond to the agonist dobutamine
Beta2 receptors preferntially respond to agonist terbutaline

Where are Beta3 receptors found and what does they activation result in?

Found only in adipose tissue, activation results in lipolysis

Alpha1: G protein and effectors

Gq = increased phospholipase C, IP3 and DAG, intracellular calcium

Alpha 2: G protein and effectors

Gi, Go, decreased adenyly cyclase, decreaed cAMP

Beta1 - G protein and effectors

Gs - increase adenylyl cyclase, cAMP, L-type Ca channel opening

Beta2 - G protein and effectors

Gs, increase in adenylyl cyclase

Beta 3: G protein and effectors

Gs, increased adneyly cyclase

What are the responses of alpha 1 receptor activation?

Vascular SM = contraction
GU SM = contraction
Liver = glycogenolysis, gluconeogenesis
Intestinal SM = hyperpolarization and relaxation
Heart = increased contractile force, arrhythmias

What are the responses of alpha2 receptor activation?

Pancreatic Islet (beta cells) = decreased insulin
Platelets = aggregation
Nerve terminals = decreased release of NE
Vascular SM = contraction

What are the responses of beta 1 receptor activation

Juxtaglomerular cells = increased renin secretion
Heart = increased force and rate of contraction and AV nodal conduction velocity

What are the responses of beta2 receptor activation?

smooth muscle (vascular, bronchial, GI, GU) relaxation
Skeletal muscle - glycogenolysis, uptake of potassium

What are the responses of beta 3 receptor activation?

Adipose tissue - lipolysis

How many types of DA receptors are there? What type of receptors are there?

5 distinct types (D1-D5) they are GPCRs

What happens when DA activates D1 receptors in renal smooth muscle?

increases cAMP and causes dilation

What happens when DA activates D1 receptors in renal vascular SM?

Vasodilation, naturiesis and diuresis

What does DA activate at higher concentrations?

Alpha 1 and Beta 1 recptors to cause an increase in heart rate and geneal vascular vasoconstriction

What is the innervation of the SM of blood vessels?

NOT innervated by parasympathetic neurons but IS innervated by sympathetic neurons

What is necessary to acheive vascular relaxation in response to ACh?

An intact epithelium.

What is the inner cellular layer of the blood vessel (endothelium) responsible for?

Modulates autonomic and hormonal effects on the contractility of blood vessels

What is EDRF?

In response to a variety of stimuli, blood vessel endothelial cells release a short lived vasodilator called endothelium derived relaxing factor (EDRF) which is now known as NO

What are three stimulli that would cause the endothelial cells to release NO?

1. ACh
2. Vasoactive products of inflammation and platelet aggregation (bradykinin, histamine, 5-HT, purines, thrombin)
3. Physical stimuli

Release of EDRF

1. In response to and AP, parasympathetic neurons release ACh
2. The exact mechanism of how ACh acts as an endocrine molecule in the regualtion of blood vessel diameter is unclear, but circulating ACh ultimately activates mAChRs on endothelial cells
3. NO is produced by the endothelial cells and diffuses back to the SM cells surrounding the blood vessels, where it causes relaxation

What is the primary controlled variable in cardiovascular fxn?

Mean arterilal pressure

How is mean arterial pressure maintained?

Changes in any variable contributing to mean arterial pressure evokes homeostatic secondary responses that tend to compensate for the directly evoked change.

How does the alpha receptor agonist phenylephrine help maintain MAP?

It increases peripherial vascular resisitance, which initiates events to compensate for the increase in BP by decreasing peripherial vascular resistance

What is NE effects on vascular and cardiac muscle? What happens if you do not have baroreceptor response?

NE produces direct effects on both vascular (smooth) and cardiac muslce. A slow infusion increases peripheral vascular resistance and increases MAP. In the absence of a reflex control (such as heart transplant) NE inceases HR and contractile force.

In regards to NE effects on vascular and cardiac muscle, what happens with an intact baroreceptor reponse?>

The negative feedback response to increased MAP is decreased sympathetic outflow and increase parasymp discharge @ cardiac pacemaker. This is due to the barorecptor reponse.

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