Week 2: Adrenergics I Flashcards
What system innervates the blood vessels?
The sympathetic nervous system
I.e. diastolic pressure derives from an increase in tone of arterioles
How does the nervous system “know” what the blood pressure is?
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)
What non-adrenergic receptors are located on blood vessels?
M3 muscarinic receptors allow for vasodilation in endothelial cells, mediated by nitric oxide
What receptors are involved in the adrenergic nervous system?
SNS alpha and beta receptors in cardiac & smooth muscle, gland cells, and nerve terminals as well as the adrenal medulla
Why are receptors in the kidney “different” than in other organs? Describe the stimulation and inhibition of kidney activity via these three receptor types.
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.
What is the action and physiology of alpha-1 receptors?
They mediate smooth muscle contraction and are innervated. Ultimately, they are activated by EPI & NE.
What is the action and physiology of beta-1 receptors?
They are located in the heart and kidney, and mediate cardiac muscle contraction (increase BP). They are stimulated by NE & EPI.
What is the action and physiology of the beta-2 receptors?
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.
What are the different alpha receptors? Why is important that different classes exist?
a1a, b and d
a2a, b and c
This is important because we can design drugs that target certain alpha receptors while avoiding others
What happens at a1, b1, b2 and b3 receptors during the sympathetic nervous response/release of epi/NE?
a1: pupodilation of eyes, contraction of GI/bladder sphincters, contraction of prostate, (+ a2b) 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
What is the mechanism that allows alpha1 receptors to contract muscles?
Gq coupled to PLC allows for Ca2+ release, which helps initiate muscular contraction of elements like pupils, GI/bladder sphincters, prostate and BVs
Why is it important for K+ to be taken up into skeletal muscle cells during the sympathetic response?
Increased intracellular K+ prevents ionic imbalance and serves to protect the cell from damage
What receptors initiate constriction of vascular beds, and what are they stimulated by?
a1 and a2b, which are stimulated by EPI/NE equally
How do beta and dopamine receptors initiate dilation activity? How do a2 receptors counter this?
All beta receptors and dopamine1 (D1) receptors act via Gs 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 Gi pathway to block this activity, decreasing [cAMP]
Result:
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.
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
What is the effect of increased or decreased [cAMP] on the different muscles affected by alpha or beta receptors?
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]
Where are a2A receptors located? What are they involved in?
The vasomotor center and nerve terminal. They are pacemaker receptors for baroreceptive elements of the vascular system. Stimulation of a2A 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 a2A receptors, causing a decrease in NE release.
What drug decreases SNS activity via the brain, and how does it accomplish this?
Clonidine acts on a2A receptors in the CNS and decreases SNS activity
Explain the concept of reciprocal inhibition of NT release
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)
Where are the different forms of alpha receptors located and what do they do?
a1a = contraction in the prostate
a2A = CNS adrenoceptors cause a decrease in SNS outflow
also presynaptic adrenergic and cholinergic nerve terminals, causing inhibition of NT release
a2B = contraction of vascular smooth muscle
What do PDE inhibitors do? Why is this a key activity in drugs like Viagra?
PDE inhibitors block activity of phosphodiesterases, allowing [cAMP] to remain high. This allows for continued vasodilation in penile tissues, and for erection to occur.
What is the rate-limiting step in dopamine/NE/EPI synthesis? Why is this important?
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
What primarily affects patients with Parkinson’s disease? How can this be remedied with drug delivery?
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.
Why can’t dopamine, NE and EPI be given directly as drugs, in some cases?
They all contain a catechol ring, which can be metabolized by certain enzymes, rendering the drugs ineffective
What drug is commonly given for tumors of the adrenal medulla?
Metyrosine is given to block the tyrosine hydroxylase step of NE/EPI formation in tumors of the adrenal medulla, which overproduce those NTs selectively
How do a1, a2, b1 and calcium channels act at nerve terminals?
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
What acts to move dopamine into vesicles, and what converts it to NE? After release into the cleft, what happens to NE?
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
What would drugs that block the NET do? What are some examples?
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.
What would drugs that block MAO do? What are some examples?
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)
What is the effect of stimulation of M3 receptors on BVs? What receptors are always found in BVs?
a1 and a2b are always found on BVs
M3 receptors on endothelial cells for BVs of the skin cause the release of NO and vasodilation
What is the effect of stimulation of b2 receptors and what areas of the body does this effect?
Stimulation of b2 receptors on skeletal muscle and liver BVs causes vasodilation (NOT innervated, stim by EPI)
What does stimulation of dopamine receptors in blood vessels do?
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 a2a receptors and cause contraction due to the inhibitory effect of a2a
Stimulation of _______ receptors causes increased peripheral resistance (TPR)
a1 and a2B
Stimulation of _________ or inhibition of _________ causes increased HR
b1/b2
M2
Stimulation of _______ and ________ increases venous tone
a1 and a2B
Stimulation of ________ increases blood volume by __________
b1
increasing renin secretion
Contractility is increased by increasing stimulation of ________ and _________
b1
b2
How does the baroreceptor reflex work, and what are the main components?
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.
