ADRA1A Receptors: Blood vessel reactions under stress

Blood pressure and heart rate regulation are complex and fascinating. Our bodies have multiple ways of increasing or decreasing blood flow, depending on whether we are relaxed, exercising, stressed — or diving into the water.

We need oxygen and blood flow to the brain, heart, and lungs at all times, and when we are under stress, blood flow is prioritized for these crucial organs.

This article digs into one aspect of regulating blood flow via adrenergic receptors when under stress. I’ll touch on what happens when you dunk your face in water (diving reflex), the causes of fainting,  blood pressure under stress, and how genetic variants influence your responses. Members will see their genotype report below, plus additional solutions in the Lifehacks section. Join today 

Alpha-1 Adrenergic receptor: heart rate and vascular constriction

Adrenergic receptors are a class of receptors that bind with catecholamines, such as epinephrine (adrenaline) and norepinephrine (noradrenaline). When a catecholamine binds to these receptors, it generally stimulates the sympathetic nervous system (fight-or-flight).[ref]

There are several types of adrenergic receptors, most of which act to either activate or relax muscles.

The α1-adrenergic receptors (ADRA1A) are essential in how the muscles surrounding your blood vessels contract to change blood pressure and flow. These muscles are called the vascular smooth muscles.

ADRA1A receptors are also important in the control of heart rate, as well as the gastrointestinal and urinary system sphincters.[ref]

We have many systems in place to control blood pressure and heart rate. The α1-adrenergic receptors react to epinephrine (adrenaline) and norepinephrine (noradrenaline) to control blood vessel reactivity when stressed.

But that is only part of the story with α1-adrenergic receptors. Researchers recently discovered they are also important in cognitive function and neurotransmission.[ref]

Blood pressure:

Alpha-1 adrenergic receptor activation causes blood vessels to constrict. For example, if you are stressed out and produce a bunch of adrenaline (epinephrine), your blood vessels in your extremities will constrict, and your blood pressure will rise. The vasoconstriction in your extremities is why your hands and even your face may look pale when you have had a shock or stress. All the blood is being prioritized to go to the heart, brain, and lungs.

You may be somewhat familiar with the alpha-1 adrenergic receptor when it comes to blood pressure medications. Commonly called alpha blockers, blood pressure medications, such as doxazosin, that target the alpha-1 adrenergic receptors have been available for decades. Just like the name implies, alpha blocker are going to block the alpha-1 adrenergic receptor, preventing blood pressure from rising due to catecholamine release.

There is more to this adrenergic receptor story, though, than just blood pressure medicine.

Diving Reflex and Oxygen:

We have an innate reflex that kicks in when going underwater. Called the ‘diving reflex’, this automatic reflex causes babies to hold their breath underwater — and to a lesser extent, applies to the changes in adults as well.

Essentially, the diving reflex is a way mammals save oxygen when underwater through constriction of peripheral blood vessels, redistribution of blood flow to vulnerable organisms, a decrease in heart rate (bradycardia), release of red blood cells from the spleen, and usually an increase in blood pressure. This same reflex happens whether completely submerged in water or just dunking your face into a bowl of cold water. Water going up the nose triggers the trigeminal nerve and the diving reflex.

The constriction of blood vessels in the diving reflex is due to catecholamines binding to the ADRA1A receptor.

A recent study in adults who were not trained in diving looked at how ADRA1A genetic variants affect the diving reflex. The study found that participants with the variant had less vasodilation and, therefore, less blood flow to the lungs when diving.[ref]

Syncope (Fainting)

Fainting (also called syncope) can be caused by a lack of blood flow to the brain.

Vasovagal syncope is fainting caused by abnormal autonomic control of blood circulation. Essentially, the normal regulation of blood circulation is out of wack. The parasympathetic nervous system is overactivated and causes low arterial blood pressure and low blood flow to the brain.[ref]

What triggers vasovagal syncope (fainting)?

Orthostatic stress (standing up), emotional stress, medical manipulations — all can cause autonomic reactions such as flushing and nausea, followed by passing out.[ref]

Genetic variants in the ADRA1A gene (listed below) are linked to an increased risk of vasovagal syncope. Fainting was also a side effect of the initial alpha-blocker medications that became available in the 1970s.[ref]

Long Covid, Spike Protein, and Adrenergic Receptors:

Recently, researchers found that patients with long Covid are more likely to have autoantibodies targeting adrenoceptors – specifically β2- and α1-adrenoceptors.[ref]

Antibodies targeting the α1-adrenoceptors could explain some of the issues with heart rate, POTS, and cognition in people with long Covid or post vaccination.

POTS (postural orthostatic tachycardia syndrome) is also linked in studies to autoantibodies targeting the alpha-1 adrenergic receptor. A 2019 study found that 89% of the POTS patients had autoantibodies to the alpha-1 adrenergic receptors and that most of the patients had developed POTS following a viral infection.[ref]

Pain syndromes and peripheral nerve injury:

In some patients with complex regional pain syndrome, alpha-1 adrenergic receptors are overexpressed, compared to a normal control group. The activation of the alpha-1 adrenergic receptors in the epidermal (skin) cells causes an increase in IL-6, an inflammatory mediator. [ref]

When a nerve is injured, mast cells, white blood cells, and fibroblasts move to the site of injury to start the repair process. Research also shows that alpha-1 adrenoceptors are increased in areas of peripheral nerve injuries.[ref]

Neurological Conditions

Alpha-1 adrenergic antibodies are found at higher levels in people with Alzheimer’s than in people without Alzheimer’s. One study found that 59% of Alzheimer’s dementia patients had alpha-1 and beta-2 adrenergic receptor antibodies, compared to only 17% in an age-matched control group with neurological impairments other than Alzheimer’s or vascular dementia. The study’s authors link the adrenergic receptor antibodies to changes in blood flow to the brain.[ref]

Another study explains why autoantibodies to alpha-1 adrenergic receptors could cause dementia. The researchers explain that the autoantibodies bind to the receptor and cause a chronic activation that raises intracellular calcium levels. “An animal model has shown that agAAB [alpha-1 adrenoceptor agonistic antibodies] causes macrovascular and microvascular impairment in the vessels of the brain. Reduction in blood flow and the density of intact vessels was significantly demonstrated.”[ref]

Colon contractions

The ADRA1A receptors are also found in the muscles surrounding the colon. Norepinephrine release inhibits colonic contractions when binding to ADRA1A.[ref] This is one way that stress affects your gastrointestinal health on an acute basis.


ADRA1A Genotype Report

The following genetic variants have been associated with outcomes that illustrate the various functions of ADRA1A. For example, some variants are linked to blood vessel response to stress, and others are connected to cognitive changes.

Check your genetic data for rs1048101 (23andMe v4, v5; AncestryDNA):

  • G/G: arg/arg (most common genotype in all population groups – except Caucasians) more likely to faint with vagal syncope[ref], lower peripheral vascular response to cold in men, higher increase in heart rate with stress in women[ref], greater desire and response to cocaine[ref]
  • A/G: typical heart rate variability, typical risk of fainting; less vasodilation in lungs with diving reflex
  • A/A: cys/cys lower heart rate variability while lying down[ref], less vasodilation in lungs with diving reflex[ref], higher systolic blood pressure[ref]

Members: Your genotype for rs1048101 is .

Check your genetic data for rs486179 (23andMe v4):

  • C/C typical
  • C/T: associated with increased risk of heroin addiction
  • T/T: associated with increased risk of heroin addiction[ref]

Members: Your genotype for rs486179 is .

Check your genetic data for rs3730287 (23andMe v4; AncestryDNA):

  • C/C: increased risk of memory impairment after heroin use disorder[ref]
  • C/G: increased risk of memory impairment after heroin use disorder
  • G/G: typical

Members: Your genotype for rs3730287 is .

Check your genetic data for rs17426222 (23andMe v4; AncestryDNA):

  • C/C: typical
  • C/T: typical risk
  • T/T: increased risk of generalized anxiety disorder[ref]

Members: Your genotype for rs17426222 is .


Lifehacks:

The rest of this article is for Genetic Lifehacks members only. Consider joining today to see the rest of this article.

Medications that affect ADRA1A:

Member Content:

An active subscription is required to access this content.

Join Here for full access to this article, genotype reports, and much more!


Already a member? Log in below.


Related Articles and Topics:

Small Fiber Neuropathy: Genetics, Causes, and Possible Solutions
In small fiber neuropathy, the tiniest nerve fibers break down and cause burning pain, numbness, odd sensations, or autonomic nervous system issues. Small fiber neuropathy is a type of peripheral neuropathy, but the symptoms can differ from what you would typically think of as neuropathy.

Spike Protein, Mast Cells, and Histamine
Do you know of someone with unexplained heart palpitations, spiking blood pressure, dizziness, and tinnitus? Discover how research is linking these symptoms to histamine, mast cells, and the spike protein.

Fibrinogen: Blood clot risk factor
Fibrinogen is a protein that is essential for creating blood clots when you get a wound. But higher fibrinogen levels are a major risk factor for heart disease and DVT. Learn how your genes impact your fibrinogen level.

Is inflammation causing your depression/anxiety?
Discover why inflammation causes depression and how your genetic variants in inflammatory genes may play a role in depression or anxiety.

References:

Baranova, Tatyana, et al. “Vascular Reactions of the Diving Reflex in Men and Women Carrying Different ADRA1A Genotypes.” International Journal of Molecular Sciences, vol. 23, no. 16, Aug. 2022, p. 9433. PubMed, https://doi.org/10.3390/ijms23169433.

Carruthers, S. G. “Adverse Effects of Alpha 1-Adrenergic Blocking Drugs.” Drug Safety, vol. 11, no. 1, July 1994, pp. 12–20. PubMed, https://doi.org/10.2165/00002018-199411010-00003.

Curtis, Peter J., et al. “Blueberries Improve Biomarkers of Cardiometabolic Function in Participants with Metabolic Syndrome—Results from a 6-Month, Double-Blind, Randomized Controlled Trial.” The American Journal of Clinical Nutrition, vol. 109, no. 6, June 2019, pp. 1535–45. PubMed Central, https://doi.org/10.1093/ajcn/nqy380.

Deji, Cuola, et al. “Association Study of Catechol-o-Methyltransferase and Alpha-1-Adrenergic Receptor Gene Polymorphisms with Multiple Phenotypes of Heroin Use Disorder.” Neuroscience Letters, vol. 748, Mar. 2021, p. 135677. ScienceDirect, https://doi.org/10.1016/j.neulet.2021.135677.

Freitas, Silvia R., et al. “Association of Alpha1a-Adrenergic Receptor Polymorphism and Blood Pressure Phenotypes in the Brazilian Population.” BMC Cardiovascular Disorders, vol. 8, Dec. 2008, p. 40. PubMed Central, https://doi.org/10.1186/1471-2261-8-40.

Hatton, D. C., et al. “Dietary Calcium Modulates Blood Pressure through Alpha 1-Adrenergic Receptors.” American Journal of Physiology-Renal Physiology, vol. 264, no. 2, Feb. 1993, pp. F234–38. journals.physiology.org (Atypon), https://doi.org/10.1152/ajprenal.1993.264.2.F234.

Hernández-Pacheco, Guadalupe, et al. “Arg347Cys Polymorphism of Α1a-Adrenergic Receptor in Vasovagal Syncope. Case-Control Study in a Mexican Population.” Autonomic Neuroscience: Basic & Clinical, vol. 183, July 2014, pp. 66–71. PubMed, https://doi.org/10.1016/j.autneu.2014.01.005.

Jolma, Pasi, et al. “High-Calcium Diet Enhances Vasorelaxation in Nitric Oxide-Deficient Hypertension.” American Journal of Physiology-Heart and Circulatory Physiology, vol. 279, no. 3, Sept. 2000, pp. H1036–43. journals.physiology.org (Atypon), https://doi.org/10.1152/ajpheart.2000.279.3.H1036.

Kelsey, Robert M., et al. “ALPHA-ADRENERGIC RECEPTOR GENE POLYMORPHISMS AND CARDIOVASCULAR REACTIVITY TO STRESS IN BLACK ADOLESCENTS AND YOUNG ADULTS.” Psychophysiology, vol. 49, no. 3, Mar. 2012, pp. 401–12. PubMed Central, https://doi.org/10.1111/j.1469-8986.2011.01319.x.

Kurahashi, Masaaki, et al. “Norepinephrine Has Dual Effects on Human Colonic Contractions Through Distinct Subtypes of Alpha 1 Adrenoceptors.” Cellular and Molecular Gastroenterology and Hepatology, vol. 10, no. 3, 2020, pp. 658-671.e1. PubMed, https://doi.org/10.1016/j.jcmgh.2020.04.015.

Levran, Orna, et al. “Heroin Addiction in African Americans: A Hypothesis-Driven Association Study.” Genes, Brain, and Behavior, vol. 8, no. 5, July 2009, pp. 531–40. PubMed Central, https://doi.org/10.1111/j.1601-183X.2009.00501.x.

Matsunaga, Tetsuro, et al. “Alpha-Adrenoceptor Gene Variants and Autonomic Nervous System Function in a Young Healthy Japanese Population.” Journal of Human Genetics, vol. 52, no. 1, 2007, p. 28. PubMed, https://doi.org/10.1007/s10038-006-0076-3.

MATUŠKOVÁ, Lenka, and Michal JAVORKA. “Adrenergic Receptors Gene Polymorphisms and Autonomic Nervous Control of Heart and Vascular Tone.” Physiological Research, vol. 70, no. Suppl 4, Dec. 2021, pp. S495–510. PubMed Central, https://doi.org/10.33549/physiolres.934799.

Matveeva, Natalia, et al. “Towards Understanding the Genetic Nature of Vasovagal Syncope.” International Journal of Molecular Sciences, vol. 22, no. 19, Sept. 2021, p. 10316. PubMed Central, https://doi.org/10.3390/ijms221910316.

Norton, Cynthia, et al. “Wild Blueberry-Rich Diets Affect the Contractile Machinery of the Vascular Smooth Muscle in the Sprague-Dawley Rat.” Journal of Medicinal Food, vol. 8, no. 1, 2005, pp. 8–13. PubMed, https://doi.org/10.1089/jmf.2005.8.8.

Perez, Dianne M. “Α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition.” Frontiers in Pharmacology, vol. 11, 2020. Frontiers, https://www.frontiersin.org/articles/10.3389/fphar.2020.581098.

Pillay, Yashodani, et al. “Patulin Suppresses Α1-Adrenergic Receptor Expression in HEK293 Cells.” Scientific Reports, vol. 10, no. 1, Nov. 2020, p. 20115. PubMed, https://doi.org/10.1038/s41598-020-77157-0.

Puel, Olivier, et al. “Biosynthesis and Toxicological Effects of Patulin.” Toxins, vol. 2, no. 4, Apr. 2010, pp. 613–31. PubMed Central, https://doi.org/10.3390/toxins2040613.

Shorter, Daryl, et al. “The α-1 Adrenoceptor (ADRA1A) Genotype Moderates the Magnitude of Acute Cocaine-Induced Subjective Effects in Cocaine-Dependent Individuals.” Pharmacogenetics and Genomics, vol. 26, no. 9, Sept. 2016, pp. 428–35. PubMed, https://doi.org/10.1097/FPC.0000000000000234.

Wallukat, Gerd, et al. “Functional Autoantibodies against G-Protein Coupled Receptors in Patients with Persistent Long-COVID-19 Symptoms.” Journal of Translational Autoimmunity, vol. 4, Jan. 2021, p. 100100. ScienceDirect, https://doi.org/10.1016/j.jtauto.2021.100100.

Zhang, Xiaobin, et al. “Preliminary Evidence for a Role of the Adrenergic Nervous System in Generalized Anxiety Disorder.” Scientific Reports, vol. 7, Feb. 2017, p. 42676. PubMed Central, https://doi.org/10.1038/srep42676.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.