Week 2: Adrenergics I

Question 1

What system innervates the blood vessels?

Answer 1

The sympathetic nervous system

I.e. diastolic pressure derives from an increase in tone of arterioles

Question 2

How does the nervous system “know” what the blood pressure is?

Answer 2

Baroreceptors in the carotid sinus and aortic arch send information into the vagus nerve (which is 80% a sensory nerve and 20% a motor nerve for the ANS)

Question 3

What non-adrenergic receptors are located on blood vessels?

Answer 3

M3 muscarinic receptors allow for vasodilation in endothelial cells, mediated by nitric oxide

Question 4

What receptors are involved in the adrenergic nervous system?

Answer 4

SNS alpha and beta receptors in cardiac & smooth muscle, gland cells, and nerve terminals as well as the adrenal medulla

Question 5

Why are receptors in the kidney “different” than in other organs? Describe the stimulation and inhibition of kidney activity via these three receptor types.

Answer 5

Stimulation of increased activity:

The kidney contains dopamine (D1) and b1 receptors, which, when stimulated, cause vasodilation (D1) and renin release (b1). NE and dopamine act on the kidney.

Inhibition of activity:

a2a receptors located presynaptically act to inhibit renin release from the kidneys, decreasing BP.

Question 6

What is the action and physiology of alpha-1 receptors?

Answer 6

They mediate smooth muscle contraction and are innervated. Ultimately, they are activated by EPI & NE.

Question 7

What is the action and physiology of beta-1 receptors?

Answer 7

They are located in the heart and kidney, and mediate cardiac muscle contraction (increase BP). They are stimulated by NE & EPI.

Question 8

What is the action and physiology of the beta-2 receptors?

Answer 8

The beta-2 receptors stimulate smooth muscle relaxation and dilation of skeletal muscle BVs. They also increase HR and contractiility.They are most/only sensitive to EPI. They are not innervated.

Question 9

What are the different alpha receptors? Why is important that different classes exist?

Answer 9

a₁a, b and d

a₂a, b and c

This is important because we can design drugs that target certain alpha receptors while avoiding others

Question 10

What happens at a₁, b₁, b₂ and b₃ receptors during the sympathetic nervous response/release of epi/NE?

Answer 10

a₁: pupodilation of eyes, contraction of GI/bladder sphincters, contraction of prostate, (+ a_2b) constriction of vascular beds in smooth muscle

b₁: increased HR/AV conduction/contractility of atria/ventricles, increased renin secretion (inc. Na/H2O retention)

b₂: bronchodilation, increased liver/skel muscle glycogen breakdown, increased K+ uptake into skeletal muscle, dilation of skeletal muscle BVs

b₃: decreased bladder contractility (similar to delivery of tolterodine (Detrol LA), a muscarinic blocker that prevents overactive bladder), mobilization of FAs

Question 11

What is the mechanism that allows alpha1 receptors to contract muscles?

Answer 11

Gq coupled to PLC allows for Ca2+ release, which helps initiate muscular contraction of elements like pupils, GI/bladder sphincters, prostate and BVs

Question 12

Why is it important for K+ to be taken up into skeletal muscle cells during the sympathetic response?

Answer 12

Increased intracellular K+ prevents ionic imbalance and serves to protect the cell from damage

Question 13

What receptors initiate constriction of vascular beds, and what are they stimulated by?

Answer 13

a₁ and a_2b, which are stimulated by EPI/NE equally

Question 14

How do beta and dopamine receptors initiate dilation activity? How do a₂ receptors counter this?

Answer 14

All beta receptors and dopamine₁ (D₁) receptors act via G_s receptor proteins to increase adenylyl cyclase activity, increasing [cAMP]

Result: Increased heart contractility (b1/2 in heart)

Dilation in BV (b2)

Takeaway: result depends on cell type

a₂ receptors act via the G_i pathway to block this activity, decreasing [cAMP]

Result:

Question 15

How do beta receptors affect smooth vs cardiac muscles? If you were giving someone a beta blocker to control hypertension, what kind would you want to give? Note: there are four receptor types involved.

Answer 15

See image

For hypertension/high BP, you would want to give a b₁ blocker. This is because this would selectively block b₁ receptors in the heart, which normally act to increase HR and contractility, and thus increase BP

Question 16

What is the effect of increased or decreased [cAMP] on the different muscles affected by alpha or beta receptors?

Answer 16

Activation of b₁ and dopamine receptors (Gs) causes cardiac muscle contraction and smooth muscle relaxation via increased [cAMP]

Activation of a2 (Gi) causes smooth muscle (vascular) contraction via decreased [cAMP]

Question 17

Where are a_2A receptors located? What are they involved in?

Answer 17

The vasomotor center and nerve terminal. They are pacemaker receptors for baroreceptive elements of the vascular system. Stimulation of a_2A in the vasomotor center decreases SNS activity and decreases NT release from the nerve terminal, preventing smooth muscle contraction.

In the nerve terminal, they act as autoregulators and regulate the amount of NE released from the nerve terminal to prevent excessive activity. Excessive NE release in the nerve terminal acts retroactively on a_2A receptors, causing a decrease in NE release.

Question 18

What drug decreases SNS activity via the brain, and how does it accomplish this?

Answer 18

Clonidine acts on a_2A receptors in the CNS and decreases SNS activity

Question 19

Explain the concept of reciprocal inhibition of NT release

Answer 19

Sympathetic, adrenergic nerves (A) not only act on smooth and cardiac muscle, but also have inhibitory branches that inhibit the release of ACh from cholinergic nerves (B)

Conversely, parasympathetic, cholinergic nerves (B) act on glands and endothelial cells, and also branch and inhibit sympathetic, adrenergic nerves (A)

Question 20

Where are the different forms of alpha receptors located and what do they do?

Answer 20

a_1a = contraction in the prostate

a_2A = CNS adrenoceptors cause a decrease in SNS outflow

also presynaptic adrenergic and cholinergic nerve terminals, causing inhibition of NT release

a_2B = contraction of vascular smooth muscle

Question 21

What do PDE inhibitors do? Why is this a key activity in drugs like Viagra?

Answer 21

PDE inhibitors block activity of phosphodiesterases, allowing [cAMP] to remain high. This allows for continued vasodilation in penile tissues, and for erection to occur.

Question 22

What is the rate-limiting step in dopamine/NE/EPI synthesis? Why is this important?

Answer 22

The tyrosine hydroxylase activity that converts tyrosine to dopa is rate-limiting. This is important because inhibiting this step, or slowing it down, can slow the rate of formation for dopamine, NE and EPI

Question 23

What primarily affects patients with Parkinson’s disease? How can this be remedied with drug delivery?

Answer 23

Parkinson’s patients are deficient in dopamine. This is remedied by delivery of L-DOPA, which can be uptaken into the brain by specialized transport molecules.

Question 24

Why can’t dopamine, NE and EPI be given directly as drugs, in some cases?

Answer 24

They all contain a catechol ring, which can be metabolized by certain enzymes, rendering the drugs ineffective

Question 25

What drug is commonly given for tumors of the adrenal medulla?

Answer 25

Metyrosine is given to block the tyrosine hydroxylase step of NE/EPI formation in tumors of the adrenal medulla, which overproduce those NTs selectively

Question 26

How do a₁, a₂, b₁ and calcium channels act at nerve terminals?

Answer 26

a₁ and b₁ receptors on effector (postsyn) cells are activated by NE stimulation, and can create effects depending on the concentration of either receptor on that postsynaptic terminal.

a₂ receptors are on the presynaptic terminal, and can deactivate NE release if too much is in the cleft (autoinhibitory effect)

Ca2+ channels act to stimulate SNARE protein activity and the release of NE

Question 27

What acts to move dopamine into vesicles, and what converts it to NE? After release into the cleft, what happens to NE?

Answer 27

vesicular monoamine transporters (VMATs) act to take up dopamine into vesicles (vesicle proteccs from MAO breakdown) and

dopamine beta-hydroxylase (DBH) converts dopamine to NE in the vesicle

NE in the synaptic cleft is taken back up into the presynaptic cell via a norepinephrine transporter (NET) where it can be repackaged or degraded by MAO

Question 28

What would drugs that block the NET do? What are some examples?

Answer 28

Drugs that block transporters like DAT (dopamine transporter), SERT (serotonin transporter), and NET (norepinephrine transporter) would allow NE to stay in the cleft longer, prolonging it’s effects on target cells

Cocaine blocks the reuptake AND breakdown of several NTs (NE, dopamine, and serotonin), antidepressants like Desipramine block reuptake of NE, (no abuse because it had no effect on dopamine). SSRIs block the reuptake of serotonin.

Question 29

What would drugs that block MAO do? What are some examples?

Answer 29

Allows for more NT (serotonin, dopamine, NE, EPI0 to stick around, and with more in the synapse you get a similar effect to blocking the NET

Phenylzine: Depression (MAO-A/B blocker)

Selegiline: Parkinson’s disease (MAO-B blocker)

Amphetamines: ADHD, narcolepsy (MAO and VMAT, can be addictive due to dopamine increase)

Question 30

What is the effect of stimulation of M3 receptors on BVs? What receptors are always found in BVs?

Answer 30

a₁ and a_2b are always found on BVs

M3 receptors on endothelial cells for BVs of the skin cause the release of NO and vasodilation

Question 31

What is the effect of stimulation of b2 receptors and what areas of the body does this effect?

Answer 31

Stimulation of b2 receptors on skeletal muscle and liver BVs causes vasodilation (NOT innervated, stim by EPI)

Question 32

What does stimulation of dopamine receptors in blood vessels do?

Answer 32

Low doses of dopamine on D1 receptors cause relaxation (only act on D1) and, thus, vasodilation in the kidneys

High doses act on both D1 and a_2a receptors and cause contraction due to the inhibitory effect of a_2a

Question 33

Stimulation of _______ receptors causes increased peripheral resistance (TPR)

Answer 33

a₁ and a_2B

Question 34

Stimulation of _________ or inhibition of _________ causes increased HR

Answer 34

b1/b2

M2

Question 35

Stimulation of _______ and ________ increases venous tone

Answer 35

a1 and a2B

Question 36

Stimulation of ________ increases blood volume by __________

Answer 36

b1

increasing renin secretion

Question 37

Contractility is increased by increasing stimulation of ________ and _________

Answer 37

b1

b2

Question 38

How does the baroreceptor reflex work, and what are the main components?

Answer 38

Baroreceptors on the aorta and other blood vessels detect blood pressure. When blood pressure goes up, this sends signals to nerves in the medulla of the CNS to increase PNS tone (vagal nerve activity) and decrease SNS tone (HR and contractility). Thus, when BP goes up, HR and contractility go down in an attempt to lower BP.