RCS 02 - Intro to Autonomic Pharmacology

Question 1

From which regions of the spinal cord do the SNS and PSNS neurons usually arise?

Answer 1

SNS (aka - thoracolumbar) originate from T1-L2/L3

PSNS (aka - carniosacral) originate from S2-S4 and the cranial nerves

Question 2

The ANS always consists of a preganglionic and postganglionic neuron except for when?

Answer 2

The adrenal medulla is directly innervated by a single neuron

Question 3

List the primary processes controlled by the ANS

Answer 3

• Smooth muscle control
• All Exocrine Glands
• Some endocrine glands
• The heartbeat
• Certain steps in intermediary metabolism

Question 4

Does the SNS or PSNS predominate in the following tissues:

• Kidney
• Heart
• Sweat Glands
• Pilomotor muscles
• Adrenal Medulla

Answer 4

PSNS predominates in the heart

The rest of the tissues are only innervated by the SNS

Question 5

Is BP primarily controlled by the PSNS or SNS?

Answer 5

SNS

Question 6

What are the two major types of ANS fibers?

Answer 6

Cholinergic - release Ach

Adrenergic - release NE

Question 7

State whether each one of the following are mostly/all cholinergic or adrenergic fibers:

• preganglionic efferent SNS fibers
• preganglionic efferent PSNS fibers
• postganglionic efferent SNS fibers
• postganglionic efferent PSNS fibers
• somatic motor fibers

Answer 7

Cholinergic Fibers:

• All preganglionic efferent ANS fibers
• All PSNS postganglionic fibers
• All somatic motor fibers

Adrenergic Fibers:

• Most SNS postganglionic fibers

Question 8

Which SNS postganglionics are not adrenergic?

Answer 8

• SNS postganglionics supplying the sweat glands are cholinergic
• Certain SNS postganglionics (like those that supply renal vascular smooth muscle) are dopaminergic

Question 9

Describe the basic life cycle of ACh as a neurotransmitter from synthesis to degradation. What is the limiting step to ACh synthesis?

Answer 9

1. Choline Transporter 1 (CHT1), a symporter, transports choline and a Na+ into the neuron from the ECF. This is the limiting step in ACh synthesis
2. Choline Acetyltransferase (ChAT) combines acetylCoA and choline into ACh
3. Vesicular ACh Transporter (VAChT), an antiporter, trasports ACh into and H+ out of a vesicle
4. When AP happens and the Ca++ channels open, the ACh filled vesicles exocytose
5. ACh-esterase on the post-synaptic membrane breaks ACh down into Choline and acetate

Question 10

How is the release of ACh from a cholinergic neuron regulated?

Answer 10

There is an inhibitory M2 (muscarinic) receptor on the presynaptic membrane. Some of the ACh released by the presynaptic neuron will bind to the M2 receptor, thereby inhibiting it’s own release.

Question 11

Describe the basic life cycle of NE in an adrenergic neuron from synthesis to degradation. What is the rate limiting in the synthesis of NE?

Answer 11

1. A tyrosine transporter, System L, brings TYR into the neuron from the ECF
2. Tyrosine Hydroxylase converts tyrosine into L-DOPA. This is the rate limiting step in the synthesis of NE
3. DOPA-decarboxylase converts L-DOPA into Dopamine (DA)
4. The Vesicular Monoamine Transporter (VMAT), an antiporter, will transprot DA into and H+ out of a vesicle.
5. In the vesicle, DA-hydroxylase converts DA into NE
6. Vesicles exocytose when an AP occurs
7. Excess NE and E in the cytosol of the neuron are broken down by MAOs and Catechol-O-methyltransferases (COMTs)

Question 12

How is the effect NE has on its target tissue regulated?

Answer 12

• Typically, the distance between an adrenergic neuron and its target tissue is farther than the distance between a cholinergic neuron and its target tissue. Therefore, more NE diffuses away before reaching its target tissue
• NE transporters (NETs), symporters on the presynaptic neuron, transport NE and Na+ back into the cell for later use
• NE binds to α2-adrenergic receptors on the presynpatic neuron to inhibit the release of NE vesicles

Question 13

Describe how adrenal medulla cells synthesize epinephrine (E).

Answer 13

1. NE is synthesized the same way it is in typical cholinergic neurons
2. NE exits the vesicle and enters the cytosol
3. Phenylethanolamine N-methyltransferase (PNMT) converts NE into E
4. E goes back into the vesicles

Question 14

List the two major types of cholinergic receptors and describe their key difference

Answer 14

• Nicotinic - ion channel linked - 2 ACh molecules bind to a Na+ ion channel and open it.
• Muscarinic - GPCR linked

Question 15

List the nicotinic receptor subtypes, their similarities, and their differences.

Answer 15

• Muscle Type (Nm) - found at NMJs
• Neuronal Type (Nn) - found on the PM of the somas of postsynpatic membranes in ANS ganglia and in the brain.

They both have similar molecular structure but differ phamacologically

Question 16

Where are muscarinic receptors located?

Answer 16

• On the PM of cells in the CNS
• In organs innervated by PSNS nerves
• On some tissues not innervated by nerves (the endothelial cells that comprise a vessel lumen)
• On tissues innervated by cholinergic postganglionic SNS nerves (sweat glands)

Question 17

Answer 17

Question 18

Describe the basics of how a M2 receptor works.

Answer 18

1. Receptor is bound
2. α subunit exchanges GDP for GTP
3. The β and γ subunits dissociate from receptor and travel along the PM to eventually open a K+ channel

Question 19

List the steps to the M3 signaling cascade that leads to vasodilation.

Answer 19

• An agonist binds to the M3 receptors on vessel endothelial cells
• IP3/DAG cascade leads to increased [Ca++] in the cytosol which leads to NO synthase activation
• NO synthase converts arginine into NO
• NO diffuses into the surrounding smooth muscle cells where it activates guanylyl cyclase
• Guanylyl cyclase converts GTP into cGMP
• cGMP activates cGMP-dependent protein kinases which phosphorylate various enzymes, leading to smooth muscle relaxation and vasodilation

Question 20

All β adrenergic receptors activate ________________ via interaction with ____.

Answer 20

adenylyl cyclase

Gs

Question 21

Important notes about the agonist selectivity of the β adrenergic receptors

Answer 21

• β1 and β3 have equal affinity for E and NE
• β2 has a much higher affinity for E than NE

This means that tissues where β2 receptors predominate (skeletal muscle vasculature) are particularly sensitive to circulating E released by the adrenals

Question 22

Important notes about the location of adrenergic receptors.

Answer 22

• α1 and β1 are located near adrenergic nerve terminals so that they are primarily activated by those nerves
• α2 and β2 receptors are often located far away from nerve terminals so that they are primarily activated by circulating E instead of NE.

Question 23

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Question 24

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Question 25

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Question 26

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Question 27

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Question 28

Important note about the effects of E on pancreatic β cells

Answer 28

Pancreatic β cells possess both β2 and α2 receptors. The β2 receptors cause an increase in insulin secretion while the α2 receptors cause a decrease in insulin secretion. The α2 receptors win this contest which makes sense since you don’t want increased insulin secretion during a fight/flight/fright response

Question 29

Answer 29

Question 30

For the following effector sites, list their predominant receptor types and whether they are predominantly innervated by the SNS or PSNS:

• Urinary Bladder
• Arterioles
• Heart
• Iris
• GIT
• Ciliary Muscles
• Veins
• Salivary Glands
• Sweat Glands

Answer 30

Question 31

T/F - the effect of a drug can be reliably predicted based upon the receptor pathways that drug activates

Answer 31

False

Often the body will respond to the change with a homeostatic reflex response that may actually elicit the opposite expected response

Question 32

Describe the primary example used to illustrate the case where a drug may have the opposite expected effect.

Answer 32

If NE is given, it is expected to have two major effects:

1. A marked increase in TPR because it is a potent vasoconstriction, the α1 effect
2. An increase in HR and force of contraction, the β1 effect

However, the negative feedback baroreceptor response, caused by the increase in MAP, leads to a large decrease in SNS stimulation of the heart. This will be seen as a decrease in HR instead of the expected increase

Question 33

Answer 33

A

Question 34

Answer 34

C