Adrenergic Receptors: Team Alpha
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Alpha/Beta Receptors in Action
You’re amped up. You have finally mustered up the courage (or insanity) to go skydiving. As the plane reaches target elevation, the side door is opened and the ground below appears minuscule.
Your legs tremor as you shuffle your feet to the edge of the door. You grasp each parachute strap tightly with your sweaty palms. Your heart is racing and you are breathing rapidly in anticipation of the leap. You turn back to the crew, and with a dry mouth attempt to tell them you are ready. After giving the thumbs up you plunge out the door.
Alpha Adrenergic Receptors
Situations similar to above that provoke fear, anxiety, danger, excitement, or stress will activate our sympathetic nervous system to act on adrenergic receptors, and generate a fight or flight response.
There are 2 main types of adrenergic receptors: alpha and beta.
Beta adrenergic receptors were previously discussed.
This post will now focus on the different types of alpha adrenergic receptors and the effects they produce.
As with all EZmed topics, you will also learn simple tricks to remember the content.
Adrenergic Receptors
So what are adrenergic receptors?
If you are coming here from the beta adrenergic receptor blog post, then you can skip to the next section below as this is a refresher.
Adrenergic receptors are located on cells of tissues and organs throughout the body, and are the targets of catecholamines such as epinephrine and norepinephrine.
These catecholamines are primarily influenced by the sympathetic nervous system.
When sympathetic activity increases, postganglionic sympathetic neurons release norepinephrine onto adrenergic receptors of target tissues and organs.
Additionally, sympathetic preganglionic neurons that terminate on the adrenal medulla will cause adrenal secretion of norepinephrine and epinephrine into the bloodstream.
The norepinephrine released by postganglionic sympathetic neurons, and the epinephrine and norepinephrine released by the adrenal medulla will bind to adrenergic receptors on target organs and generate a sympathetic fight or flight response.
For example:
Activation of adrenergic receptors in the heart will modify the cardiac action potentials of pacemaker cells and contractile myocytes to increase heart rate and cardiac contractility, which will improve cardiac output.
Activation of adrenergic receptors on the vasculature will lead to vasoconstriction and increased systemic vascular resistance. Vasoconstriction in addition to the increased cardiac output above will increase blood pressure to improve perfusion to vital organs.
Activation of adrenergic receptors will also lead to bronchodilation to open the airways, mydriasis to optimize vision, and gluconeogenesis to increase glucose levels to meet the needs of increased metabolism during the fight or flight response.
Below is a reminder of the sympathetic events that occur leading up to adrenergic receptor activation discussed previously in the autonomic nervous system.
This blog will now serve as a continuation and discuss the adrenergic receptors in more detail, their location, and the effects they produce.
Of note, there will be a future similar post discussing cholinergic receptors on the parasympathetic side.
Postganglionic sympathetic neurons release norepinephrine onto adrenergic receptors of target organs to generate the sympathetic response. Postganglionic parasympathetic neurons release acetylcholine onto muscarinic receptors of target organs to generate the parasympathetic response.
Preganglionic neurons arise from the central nervous system at the thoracolumbar level. They release acetylcholine onto nicotinic cholinergic receptors on the cell bodies of the postganglionic neurons. Postganglionic neurons then release norepinephrine onto adrenergic receptors on the target organs.
Preganglionic neurons also terminate on the adrenal medulla which causes secretion of epinephrine and norepinephrine into the bloodstream. These circulating catecholamines will also bind to adrenergic receptors to produce a sympathetic response.
Alpha Receptors
As discussed above, the alpha adrenergic receptors are involved in generating a sympathetic fight or flight response when catecholamines such as norepinephrine and epinephrine bind to them.
Affinity
While both norepinephrine and epinephrine can act on alpha receptors, norepinephrine generally has a higher affinity for alpha receptors compared to epinephrine.
This is in contrast to what we saw with beta receptors in which epinephrine generally has a higher affinity than norepinephrine, especially on beta2 receptors.
This makes sense when thinking about norepinephrine and epinephrine as pressor medications used to treat various types of shock.
Norepinephrine has quite a bit of alpha effect and some beta, while epinephrine has quite a bit of beta effect and some alpha.
This is why norepinephrine generally has a greater effect on the vasculature/vasoconstriction (alpha receptors), whereas epinephrine tends to have a greater effect on the heart/cardiac output and lungs/bronchodilation (beta receptors).
General Function on Smooth Muscle
Now that we have a good understanding of alpha receptor affinity, let’s discuss the general effect that alpha receptors have on involuntary smooth muscles when activated.
Alpha receptor activation leads to smooth muscle contraction.
For example, one of the main alpha receptor locations is on the vasculature and activation will lead to smooth muscle contraction and vasoconstriction.
This is in contrast to what we saw with beta receptors in which activation led to smooth muscle relaxation (bronchodilation, vasodilation, bladder relaxation, GI tract relaxation, relaxation of uterus, etc).
Below are some tricks to help remember receptor affinity and the effect each receptor has on smooth muscles.
Epinephrine has a higher affinity for beta receptors than norepinehrine. Alternatively, norepinephrine has a higher affinity for alpha receptors than epinephrine. Alpha receptors lead to smooth muscle contraction and beta receptors lead to smooth muscle relaxation.
Trick to Remember Receptor Affinity
alpha = NO E = NOrEpinephrine (no E in alpha) = higher affinity for norepinephrine
bEta = has an E = Epinephrine (beta has an E) = higher affinity for epinephrine
Trick to Remember Alpha/Beta Smooth Muscle Effect
Alpha = Think of alpha in animal kingdom = strong/dominant = smooth muscle contraction
Beta = Think of a beta fish = chill and relaxed = smooth muscle relaxation
Alpha Receptor Types
Let’s now discuss each of the alpha receptors in more detail.
There are 2 main types of alpha receptors: alpha1 and alpha2.
Alpha1
Alpha1 receptors are coupled with Gq proteins which cause increased release of calcium from calcium storage structures.
Increased intracellular calcium will lead to muscle contraction and is why alpha1 receptors do just that. They are primarily located on smooth muscle throughout the body, which will lead to smooth muscle contraction when activated.
The main locations of alpha1 receptors are on the vasculature, iris dilator muscle, prostate, urethral sphincter, pylorus, and anal sphincter.
Blood Vessels
As we mentioned above, alpha1 receptors are Gq coupled which will lead to smooth muscle contraction.
Therefore, alpha1 receptors on blood vessels will lead to vasoconstriction.
The arterial supply to organs that are noncritical for immediate survival and less necessary during a fight or flight response will have higher quantities of alpha receptors on them.
The increased level of alpha1 receptors will lead to vasoconstriction and decreased blood flow to unnecessary structures and will divert perfusion to more vital tissues and organs such as the heart.
For example, the skin, GI tract, and kidneys are noncritical for immediate survival. The skin will not provide much utility during a fight or flight response. Furthermore, digestion and urination are not critical actions for immediate survival either.
Alpha1 receptor activation on the blood vessels supplying these structures will lead to vasoconstriction and decreased blood flow and perfusion to them and will divert blood flow to more vital structures.
This is why patient’s skin can often appear pale during a sympathetic response.
We can also see how this all comes together with the kidneys.
We discussed in previous posts that decreased renal perfusion will activate the renin-angiotensin-aldosterone system (RAAS).
If we are diverting blood away from the kidneys, this will decrease renal perfusion and activate the RAAS. Activation of the RAAS will lead to angiotensin II induced vasoconstriction and water reabsorption from the renal tubules.
Vasoconstriction from alpha1 receptor and angiotensin II receptor activation will increase systemic vascular resistance which in turn increases blood pressure.
So now not only is blood flow being diverted to more vital tissues and organs, but mean arterial blood pressure is also increasing to allow for adequate perfusion to these vital structures.
Therefore, the effects of the RAAS in addition to the sympathetic response will synergistically work together to increase blood pressure during a fight or flight response.
Iris Dilator Muscle
Activation of the alpha1 receptors on the iris dilator muscle will lead to smooth muscle contraction and pupillary dilation/mydriasis.
Pupillary dilation will be important to optimize vision during the fight or flight response.
Prostate
Alpha1 receptor activation will lead to smooth muscle contraction of the prostate to release prostatic fluid, a component of semen.
Similarly, the seminal vesicles have alpha1 receptors that allow for smooth muscle contraction and release of fluid that makes up semen as well.
Lastly, the vas deferens contain alpha1 receptors which makes sense because smooth muscle contraction will assist with ejaculation.
Urethral Sphincter
As we mentioned above when discussing the vasculature and blood supply to the kidney, urination is not an important critical action for immediate survival in a fight or flight response.
Not only is there vasoconstriction to the kidneys but the urethral sphincter contains alpha1 receptors as well.
Activation will lead to smooth muscle sphincter contraction. This will prevent urine from exiting the bladder and will lead to urinary retention.
Pylorus and Anal Sphincter
Similar to how urination is not an important function during a fight or flight response, neither is digestion.
Therefore, the pylorus and anal sphincter will contract through alpha1 receptor activation to limit the progression and travel of food content and/or stool.
Alpha1 receptors are Gq protein-coupled and will increase release of calcium from calcium storage structures. This will lead to smooth muscle contraction. Alpha1 receptors on blood vessels will lead to vasoconstriction. Alpha1 receptors on the pylorus and urethral sphincter will lead to contraction and decreased digestion and urination respectively. Alpha1 receptors of the iris dilator muscle will lead to pupillary dilation (mydriasis).
Alpha2
Alpha 2 receptors are Gi protein-coupled and lead to decreased cAMP levels and are inhibitory.
Nerve Terminals
They are mainly located on peripheral pre-synaptic nerve terminals.
We know that the postganglionic neurons of the sympathetic nervous system release norepinephrine onto adrenergic receptors of the target organs.
Alpha2 receptors are located on these presynaptic nerve terminals and when activated by catecholamines will decrease further release of norepinephrine.
Therefore, it acts as a negative feedback system.
Alpha2 receptors are coupled with Gi proteins and decrease cAMP levels . They are primarily found on presynaptic nerve terminals and lead to inhibition of further norepinephrine release.
Platelets
This is less discussed, but there are also alpha2 receptors on platelets.
When catecholamines bind to the alpha2 receptors on platelets, it causes release of platelet mediators such as thromboxane A2, ADP, and serotonin that promote platelet aggregation and thrombus formation.
This makes sense as we do not want bleeding to occur during a fight or flight response.
Simplifying It….
Below is a simplified general summary of the adrenergic receptors. You can find more information about the beta adrenergic receptors in the beta post.
Alpha1 receptors are located on structures such as the vasculature, prostate, urethral sphincter, pylorus and will cause smooth muscle contraction. Alpha2 receptors are found on presynaptic nerve terminals and inhibit further release of norepinephrine.
Beta1 receptors are on the heart and kidneys and lead to increased inotropy/chronotropy and renin release respectively. Beta2 receptors are located on lungs, bladder, uterus, GI tract, blood vessels and lead to smooth muscle relaxation. Beta3 receptors are located on adipose tissue leading to lipolysis and possibly the bladder which leads to smooth muscle relaxation.
Practical Applications
This will be discussed further in future posts, however you can appreciate how alpha adrenergic receptors can be a useful target for medications.
Alpha Antagonists
Alpha blockers such as phentolamine can be used to treat hypertension as this will antagonize vasoconstriction.
There are other alpha blockers that are more selective or have a higher affinity for the prostate and can help to treat benign prostatic hyperplasia.
As mentioned above, alpha receptor activation on the prostate leads to smooth muscle contraction. The urethra travels through the prostate and prostate smooth muscle contraction can lead to urination problems.
Relaxing the prostate through alpha blockers can help alleviate some of those urinary issues.
Alpha Agonists
In addition to the benefits from antagonizing alpha receptors, there are also medications that can be used to activate the receptors.
For example, pressor medications such as phenylephrine (purely alpha) or norepinephrine (mostly alpha but also has some beta effects) can help improve perfusion in various types of shock.
Diseases/Pathology
Pheochromocytoma is an adrenal tumor that causes increased levels of epinephrine and norepinephrine which will lead to overactivity of the sympathetic nervous system.
Anticholinergic toxicity will lead to unopposed sympathetic activity through cholinergic receptor blockade.
Cocaine, methamphetamine use, and stimulant use can also lead to a sympathetic presentation.
Conclusion
Hopefully that helped to simplify alpha adrenergic receptors.
Alpha adrenergic receptors are one of two main adrenergic receptors, the other being beta receptors.
They are involved in generating a sympathetic response when activated by catecholamines such as norepinephrine or epinephrine.
Both norepinephrine and epinephrine can act on alpha receptors, however norepinephrine generally has a higher affinity.
Alpha1 receptors lead to smooth muscle contraction and are located mainly on blood vessels, iris dilator muscle, prostate, seminal vesicles, vas deferens, urethral sphincter, pylorus, and anal sphincter.
This will lead to vasoconstriction, mydriasis, ejaculation, urinary retention/decreased urination, and constipation/decreased digestion respectively.
Alpha2 receptors are primarily found on presynaptic nerve terminals and when activated by catecholamines lead to decreased norepinephrine release as a negative feedback system.
Alpha2 receptors are also located on platelets and facilitate platelet aggregation.
There are medications that function as alpha receptor antagonists or agonists to either block or facilitate the sympathetic response.
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