Adrenergic Receptors: Team Beta
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Alpha/Beta Receptors in Action
As you slowly climb 400 feet to the peak of the first hill, you are reassured that the long line for this roller coaster was well worth the wait. Your heart is racing as you grasp the handlebar tightly with your sweaty palms.
You let out a scream as you rapidly accelerate down the first hill twisting and turning through several sharp bends. When the ride is over, you climb out of the coaster with a tremor in your hands, a rapid heart rate, and an overwhelmed feeling of adrenaline and excitement.
Beta 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.
Alpha adrenergic receptors were previously discussed.
This post will now focus on the different types of beta adrenergic receptors and the effects they produce.
As with all EZmed topics, you will also learn simple strategies to remember the content.
Adrenergic Receptors
So what are adrenergic receptors?
If you are coming here from the alpha 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.
Beta Receptors
As discussed above, the beta 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 beta receptors, epinephrine has a higher affinity for beta receptors compared to norepinephrine, especially the beta2 receptors in which there is very little to no norepinephrine activity. More on this later.
This is in contrast to what we saw with alpha receptors in which norepinephrine has a higher affinity than epinephrine.
This makes sense when thinking about norepinephrine and epinephrine as pressor medications used to treat various types of shock.
Epinephrine has quite a bit of beta effect and some alpha, while norepinephrine has quite a bit of alpha effect and some beta.
This is why epinephrine has a greater effect on the heart/cardiac output and lungs/bronchodilation (beta receptors) whereas norepinephrine has a greater effect on the vasculature/vasoconstriction (alpha receptors).
This is also why epinephrine is given during anaphylaxis as it has a much higher affinity for the beta2 receptors in the lungs which will lead to bronchodilation and improvement in respiratory distress.
General Function on Smooth Muscle
Now that we have a good understanding of beta receptor affinity, let’s discuss the general effect that beta receptors have on involuntary smooth muscles when activated.
Beta receptor activation leads to smooth muscle relaxation.
For example, one of the main locations of beta receptors is in the lungs and activation will lead to bronchodilation via smooth muscle relaxation.
This is in contrast to what we saw with alpha receptors in which activation led to smooth muscle contraction (vasoconstriction, urethral sphincter constriction, pylorus constriction, prostate contraction, iris dilator muscle contraction, etc)
Below are some tricks to help remember receptor affinity and the effect each receptor has on smooth muscle.
For alpha receptors, think of the alpha in the animal kingdom which is dominant and strong - This will help you remember alpha receptors lead to smooth muscle contraction.
For beta receptors think of a betta fish.
Betta fish can be territorial and fight with one another (to help you remember beta receptors are part of the “fight or flight” response); However, when left alone betta fish are relaxed - This will help you remember beta receptors lead to smooth muscle relaxation.
Epinephrine has a much higher affinity for beta receptors than norepinehrine. Alternatively, norepinephrine has a much 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 betta fish = chill and relaxed (when alone) = smooth muscle relaxation
Beta Receptor Types
Let’s now discuss each of the beta receptors in more detail.
There are 3 main types of beta receptors: beta1, beta2, and beta3.
All beta receptors are coupled with Gs proteins which increase levels of cAMP.
Beta1
Beta1 receptors are fairly easy to remember as there are 2 main locations to know: the heart and kidneys.
Heart
Beta1 receptors on the heart will increase heart rate and cardiac contractility when activated.
Heart rate will be increased through beta1 activation of the SA node, AV node, and conduction system of the heart.
This will increase the phase 4 action potential slope of pacemaker cells resulting in more frequent depolarization.
Beta1 activation will also increase cardiac contractility by influencing phase 2 of the action potential of cardiac myocytes, which will increase stroke volume.
Remember that heart rate and stroke volume are the 2 variables for cardiac output.
If they are both increased, then cardiac output will increase. The increased cardiac output will subsequently augment blood pressure and perfusion.
But wait, I thought we said beta receptors lead to muscle relaxation?
Remember this was for SMOOTH muscle and not cardiac.
Kidneys
Beta1 receptors are also located in the kidneys, specifically the juxtoglomerular (JG) cells.
Activation will lead to release of renin from the JG cells which will initiate the renin-angiotensin-aldosterone system (RAAS).
The RAAS will then lead to angiotensin II production and all of its downstream effects to improve blood pressure.
If you have not checked out the hypotension post, I highly recommend it as this will tie in the synergistic effects the sympathetic nervous system and the RAAS have on increasing blood pressure.
Beta1 receptors are Gs coupled and will increase cAMP levels. Beta1 receptors are mainly found on the heart and kidneys. This will lead to increased heart rate (HR) and cardiac contractility/stroke volume (SV) which will increase cardiac output (CO) and blood pressure (BP). Beta1 receptors on juxtoglomerular (JG) cells of the kidneys will cause renin release and increased blood pressure through the renin-angiotensin-aldosterone system (RAAS).
Beta2
Beta2 receptors are coupled with Gs proteins like beta1.
The increase in cAMP levels in structures with beta2 receptors on them will lead to smooth muscle relaxation as mentioned earlier.
Some of the main locations for beta2 receptors include: the lungs, GI tract, bladder, uterus, pancreas, and blood vessels.
Since we know that beta2 receptors lead to smooth muscle relaxation, we now know that the beta2 receptors on these locations will do just that.
For example:
Lungs
Beta2 activation in the lungs will lead to smooth muscle relaxation and bronchodilation during a sympathetic response.
GI Tract
Smooth muscle relaxation of the stomach and intestines from beta2 activation will lead to decreased gastric contraction and decreased intestinal peristalsis.
This paired with the alpha1 constriction of the pylorus and anal sphincter that we saw in the alpha adrenergic post will lead to decreased digestion during the sympathetic response.
Bladder
Relaxation of the bladder wall through beta2 receptor activation will lead to urinary retention and decreased urination.
We can also combine this with the alpha1 urethral sphincter contraction that we saw.
We can see how alpha1 urethral sphincter constriction combined with the beta2 bladder wall relaxation will synergistically cause urinary retention and decreased urination.
Uterus
Relaxation of the uterus when the beta2 receptors are activated will lead to inhibition of labor.
Blood Vessels
Beta2 receptors are located on the vasculature and will lead to vascular smooth muscle relaxation and vasodilation.
But wait, we learned in the alpha adrenergic post that alpha1 receptors are on blood vessels and lead to vasoconstriction.
Don’t we want vasoconstriction and not vasodilation in order to increase peripheral vascular resistance and blood pressure during the sympathetic response?
Aren’t the alpha1 and beta2 receptors on blood vessels going to cancel each other out?
Here is the answer.
The quantity of alpha1 and beta2 receptors differ on blood vessels depending on the structure they are supplying blood to.
Organs such as the skin and GI tract are not as necessary for immediate survival during the fight or flight response.
Therefore, the arterial supply to these less essential organs will be higher in alpha1 receptors. This will cause vasoconstriction and decreased blood flow to them and will divert perfusion to other more important vital organs.
For example, the heart is an important structure during the sympathetic response.
It would be detrimental if the coronary arteries were predominately alpha1 receptors.
The vasoconstriction during a sympathetic response would cause decreased coronary blood flow and inadequate oxygen delivery to the heart.
As a result, coronary arteries express more beta2 receptors compared to the peripheral vasculature to maintain some degree of vasodilation and blood flow to the heart.
Arterioles to skeletal muscles also express beta2 receptors, and alpha1 receptors are attenuated to allow for increased blood flow to skeletal muscles during a fight or flight response.
In summary, the number of alpha1 and beta2 receptors on blood vessels differ depending on the organ they are supplying.
Furthermore, the overall number of alpha1 receptors far outnumber beta2 receptors which is why blood pressure is ultimately increased during a sympathetic response.
Pancreas, Liver, Eye
Beta2 receptors are also found on the pancreas and liver which will lead to increased insulin release and gluconeogenesis/glycogenolysis respectively in order to increase glucose production and energy during a fight or flight response.
Beta2 receptors are also located in the eye which increases production of aqueous humor.
Beta2 receptors are coupled with Gs proteins that increase cAMP. This will lead to smooth muscle relaxation. Structures with beta2 receptors on them will relax and the liver will increase glucose production.
Beta3
Beta3 receptors are also coupled to Gs protein.
They are less clinically relevant.
They are located mainly in adipose tissue and lipolysis occurs when activated.
It has been recently shown that beta3 receptors may also be located on the detrusor muscle of the bladder which assists in bladder relaxation along with beta2 receptors.
Beta3 receptors are coupled with Gs proteins and increase cAMP. They are primarily in adipose tissue leading to lipolysis as well as on the detrusor muscle of the bladder leading to bladder wall relaxation and decreased urination.
Trick to Remember Beta Heart and Lung Receptors
Beta1 (One)
Heart = There is 1 heart in the body
Beta2 (Two)
Lungs = There are 2 lungs in the body
Simplifying It….
Below is a simplified general summary of the adrenergic receptors. You can find more information about the alpha adrenergic receptors in the alpha 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 beta adrenergic receptors can be a useful target for medications.
Beta Blockers
There are beta blockers, some of which are selective for beta1 and others that are nonselective, that can help treat hypertension, arrhythmias, heart failure, essential tremor, glaucoma, etc.
Beta Agonists
Activating beta adrenergic receptors can be clinically important as well.
For example, epinephrine is useful in anaphylaxis where activation of the beta1 and beta2 receptors improve respiratory distress through bronchodilation and helps to support blood pressure.
Other pressor medications that have higher affinities for the beta receptors, such as dobutamine, can potentially be useful adjuncts in cases of cardiogenic shock.
Beta2 specific agonists such as albuterol can also be useful in asthma or COPD to alleviate shortness of breath.
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 beta adrenergic receptors.
Beta adrenergic receptors are one of two main adrenergic receptors, the other being alpha 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 beta receptors, however epinephrine generally has a higher affinity.
Beta1 receptors are mainly found on the heart and kidneys. They lead to increased inotropy/chronotropy as well as renin release respectively.
Beta2 receptors lead to smooth muscle relaxation. They are in the lungs, bladder, GI tract, vasculature, and uterus and lead to bronchodilation, bladder wall relaxation/urinary retention, intestinal relaxation/decreased digestion, vasodilation, and inhibition of labor respectively.
Beta3 receptors are found in adipose tissue leading to lipolysis and the bladder leading to bladder relaxation.
There are medications that can function either as beta receptor antagonists or agonists to either block or facilitate the sympathetic response.
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