Physiology, Catecholamines

Issues of Concern

Catecholamines are critical to homeostasis. Dysregulation in catecholamine signaling, either by upregulation or downregulation, can have significant physiological and pathological consequences. Understanding catecholamines' precise roles and regulation is critical in diagnosing and managing catecholamine-related disorders.

Cellular Level

Catecholamines are synthesized through a series of enzymatic reactions starting from the amino acid tyrosine in specific cells.

• Dopamine is primarily synthesized in dopaminergic neurons of the brain, particularly in the substantia nigra and ventral tegmental area. Dopamine is also produced in smaller amounts in the hypothalamus and the enteric nervous system of the gastrointestinal tract. Synthesis begins with the conversion of tyrosine to levo-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase. L-DOPA is then converted to dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as dihydroxyphenylalanine (DOPA) decarboxylase.

• Norepinephrine is synthesized by sympathetic neurons in various tissues, the chromaffin cells of the adrenal medulla, and noradrenergic neurons in the central nervous system, particularly the locus coeruleus of the brainstem. Within these cells, dopamine is converted to norepinephrine by the enzyme dopamine β-hydroxylase, which is located inside vesicles.

• Epinephrine is primarily synthesized in the chromaffin cells of the adrenal medulla, where norepinephrine is converted to epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT). The presence of this enzyme is a key feature of chromaffin cells, allowing them to produce epinephrine from norepinephrine. Epinephrine is stored in vesicles and released into the bloodstream as a hormone.

Upon termination of their action, catecholamines are taken up by neurons or other tissues to be transformed into inactive metabolites (see Image. Catecholamine Metabolism).

Organ Systems Involved

Catecholamines have widespread effects across multiple organ systems, the most crucial of which include the following:

• In the cardiovascular system, epinephrine and norepinephrine increase cardiac output and blood pressure.
• In the nervous system, dopamine influences mood, attention, and arousal. Dopamine is also crucial for the brain’s reward system and motor control.
• In the endocrine system, epinephrine and norepinephrine influence the release of other hormones, such as insulin and glucagon, to regulate blood sugar levels.
• In the respiratory system, epinephrine and norepinephrine dilate bronchioles and improve airflow.
• In the musculoskeletal system, epinephrine increases blood flow to skeletal muscles.
• In the gastrointestinal system, dopamine acts as a vasodilator, increasing blood flow to the digestive tract. Dopamine also regulates gastrointestinal motility, modulates sodium absorption, and influences mucosal blood flow. Epinephrine and norepinephrine reduce blood flow to the gastrointestinal tract, slowing digestion during stress responses.
• In the renal system, dopamine influences renal blood flow and sodium excretion.

Function

Epinephrine and norepinephrine play a central role in the body’s “fight-or-flight” response. When the body perceives a threat, these hormones are rapidly released from the adrenal medulla and sympathetic nerve endings. Epinephrine primarily increases heart rate, cardiac output, and blood glucose levels by stimulating glycogenolysis and lipolysis. This catecholamine also dilates the airways to improve oxygen intake. Norepinephrine, on the other hand, primarily acts as a vasoconstrictor, increasing blood pressure by narrowing blood vessels. Epinephrine and norepinephrine work together to prepare the body to respond to acute stress by enhancing physical performance and alertness, ensuring that energy and oxygen are efficiently delivered to vital organs and muscles.[3]

Dopamine is a versatile catecholamine that functions as both a neurotransmitter and a hormone. In the central nervous system, dopamine is crucial for regulating mood, motivation, and reward, playing a significant role in the brain’s pleasure and reward pathways. This chemical messenger is also essential for motor control and acts as a vasodilator, particularly in the kidneys, where it helps regulate blood flow and sodium excretion. Additionally, dopamine influences gastrointestinal motility and modulates the release of various hormones, making it integral to multiple physiological processes.[4]

Mechanism

Epinephrine and Norepinephrine

Epinephrine and norepinephrine influence cells by binding to adrenergic receptors, a class of G protein-coupled receptors (GPCRs). These receptors are broadly categorized into 2 main types: α- and β-adrenergic receptors, each further classified into subtypes. Epinephrine and norepinephrine have varying affinities for these receptors, which determine their physiological effects.

α-adrenergic receptors

α-adrenergic receptors include α1- and α2-adrenergic receptors. These receptors are GPCRs that work with different types of G proteins.

α1-adrenergic receptors are GPCRs coupled to Gq proteins and are primarily found in vascular smooth muscle cells. Both epinephrine and norepinephrine activate these receptors, but norepinephrine has a higher affinity. Triggering α1-receptors activates the Gq protein, stimulating phospholipase C (PLC), which converts phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 releases calcium from intracellular stores, leading to smooth muscle contraction and vasoconstriction. 

α2-adrenergic receptors are GPCRs coupled to Gi proteins and are activated by both epinephrine and norepinephrine. Activating α2-receptors inhibits adenylate cyclase via the Gi protein, reducing cyclic adenosine monophosphate (cAMP) levels and inhibiting protein kinase A (PKA). These receptors are located on presynaptic nerve terminals of noradrenergic neurons in the central nervous system (especially in the locus coeruleus, medulla oblongata, and hypothalamus) and sympathetic nerve endings in the peripheral nervous system. Activation of α2-receptors in presynaptic nerve terminals creates a negative feedback that inhibits the release of norepinephrine. α2-receptors are also found on the pancreatic β-cells and cells of the gastrointestinal tract, where their stimulation inhibits insulin secretion and digestive functions, respectively.

β-adrenergic receptors

β-adrenergic receptors include β1-, β2-, and β3-adrenergic receptors. All β-adrenergic receptors are GPCRs coupled to Gs proteins, the activation of which stimulates adenylate cyclase activity, increasing cAMP levels and activating PKA.

β1-adrenergic receptors are predominantly found in the heart and bind to both epinephrine and norepinephrine. Activating β1 receptors increases heart rate, stroke volume, and cardiac output. β2-adrenergic receptors are found in the lungs, skeletal muscle, and blood vessels. These receptors are mainly stimulated by epinephrine, resulting in bronchodilation and vasodilation in skeletal muscles. β3-adrenergic receptors are found in adipose tissue and are more responsive to epinephrine, although they can be triggered by norepinephrine at higher concentrations. Activating β3 receptors promotes lipolysis.

Dopamine

Dopamine exerts its effects on cells through 5 types of dopamine receptors. These receptors are GPCRs divided into 2 main families: D1-like receptors and D2-like receptors.[5]

D1-like receptors, which include D1 and D5, are GPCRs coupled to Gs proteins, which activate adenylate cyclase, increasing cAMP levels and activating PKA, producing primarily excitatory effects. D1 receptors are abundant in the basal ganglia, where they facilitate motor activity by promoting excitatory pathways. D1 receptors are also present in renal and mesenteric vascular smooth muscle. Low-dose dopamine activates D1 receptors on the smooth muscle cells of renal arterioles, leading to vasodilation and increasing renal blood flow and glomerular filtration rate. Additionally, D1 receptors on T lymphocytes modulate immune responses, influencing T-cell activation and cytokine production. 

D2-like receptors, which include D2, D3, and D4, are GPCRs coupled to Gi proteins. These receptors inhibit adenylate cyclase, reducing cAMP production and inhibiting PKA, giving rise to primarily inhibitory effects. D2 receptors are widely distributed in the brain, particularly in the basal ganglia, where they play a critical role in inhibiting motor activity and fine-tuning movement. In the mesolimbic and mesocortical pathways, D2 and D3 receptors regulate reward, motivation, and emotional responses. In the anterior pituitary gland, D2 receptors inhibit the release of prolactin. Additionally, D2 receptors on sympathetic nerve terminals inhibit norepinephrine release. In the immune system, D2 receptor activation modulates immune responses by influencing T-cell activity.

Although dopamine primarily acts on dopamine receptors, it can also interact with adrenergic receptors, especially in peripheral tissues. At moderate concentrations, dopamine can stimulate β1-adrenergic receptors, increasing heart rate and contractility. At high concentrations, dopamine may also activate α1-adrenergic receptors, leading to vasoconstriction and increased blood pressure.

Related Testing

Testing for catecholamine levels and their metabolites is crucial in diagnosing and managing various medical conditions, including autonomic nervous system and adrenal dysfunction, as well as neuroendocrine tumors. Plasma and urinary catecholamine measurements are commonly used to assess the levels of dopamine, norepinephrine, and epinephrine. These tests are particularly important in the diagnosis of catecholamine-secreting tumors, such as pheochromocytoma and paraganglioma. Elevated levels of catecholamines or their metabolites, such as metanephrine and vanillylmandelic acid (VMA), are indicative of these conditions.[6]

Clonidine suppression testing is sometimes employed to differentiate between true catecholamine excess, such as that seen in pheochromocytoma, and other causes of catecholamine elevation, such as stress and certain medications. This test measures the catecholamine response to clonidine, an α2-adrenergic agonist that normally suppresses sympathetic outflow.[7]

Dopamine transporter imaging (eg, DaTscan) is used to evaluate dopamine activity in the brain, which is particularly useful when diagnosing Parkinson disease. This imaging technique uses a radiotracer that binds to dopamine transporters, providing visual evidence of dopamine neuron integrity.[8]

Pathophysiology

Given their pivotal role in multiple body systems, including the cardiovascular and nervous systems, catecholamine signaling dysregulation can lead to various pathophysiological disorders. These conditions include pheochromocytoma, paraganglioma, neurogenic shock, Parkinson disease, heart failure, and cardiomyopathy.

Pheochromocytoma and paraganglioma are conditions arising from catecholamine-secreting tumors. Pheochromocytomas occur in the adrenal medulla, while paragangliomas develop from extraadrenal chromaffin cells. Both tumors can lead to excessive catecholamine production, primarily norepinephrine, with smaller increases in epinephrine and dopamine. The excess catecholamines cause episodic or sustained hypertension, headaches, palpitations, and sweating.[9]

Neurogenic shock results from the loss of sympathetic nervous system activity, often due to spinal cord injury. The loss of catecholamine-releasing sympathetic neurons leads to vasodilation, hypotension, and bradycardia.[10]

Parkinson disease is a neurodegenerative disorder characterized by the progressive loss of dopamine-producing neurons in the substantia nigra. The resulting dopamine deficiency disrupts the balance between excitatory and inhibitory pathways in the basal ganglia, leading to the classic motor symptoms of tremor, rigidity, bradykinesia, and postural instability.

In chronic heart failure, the sympathetic nervous system is activated to compensate for decreased cardiac output. Initially, this mechanism increases cardiac output by norepinephrine-mediated activation of β1-adrenergic receptors in the heart. However, chronic norepinephrine exposure can lead to downregulation of β1-adrenergic receptors and direct myocardial toxicity, contributing to worsening heart failure and the development of catecholamine-induced cardiomyopathy.[11]

Clinical Significance

Drugs that target catecholamine signaling are used in various clinical conditions involving the cardiovascular, respiratory, nervous, and endocrine systems. Depending on the therapeutic need, these drugs either enhance or inhibit catecholamine action.

In the case of hypertension, β-blockers primarily block β1-receptors in the heart, reducing the heart rate, stroke volume, and, ultimately, cardiac output. β-blockers are commonly used for the long-term management of hypertension. α-blockers, on the other hand, block α1-adrenergic receptors in vascular smooth muscle cells, lowering blood pressure by causing vasodilation and reducing peripheral vascular resistance.

In heart failure, β-blockers reduce the harmful effects of chronic sympathetic stimulation on the heart, including catecholamine-induced cardiomyopathy. These drugs improve survival by decreasing the workload on the heart and preventing further remodeling. In acute decompensated heart failure, moderate-dose dopamine stimulates β1-adrenergic receptors to increase cardiac output. This drug is used as an inotropic agent to improve heart function.

In the management of arrhythmias, β-blockers are used to treat conditions such as supraventricular tachycardia and atrial fibrillation by slowing conduction through the atrioventricular node and reducing the heart rate.[12] For asthma and chronic obstructive pulmonary disease, β2-agonists selectively stimulate β2-adrenergic receptors in the lungs, causing bronchodilation and improving airflow.[13]

Epinephrine is used in anaphylactic shock to stimulate both α- and β-receptors, leading to vasoconstriction, bronchodilation, and increased heart rate and cardiac output. Norepinephrine is a first-line vasopressor in septic shock, primarily stimulating α1-receptors to increase vascular tone and blood pressure while having less impact on heart rate than other agents. Dopamine causes vasodilation at low doses but stimulates β1- and α1-adrenergic receptors at higher doses, increasing cardiac output and blood pressure.

Levodopa, a dopamine precursor, is the most effective treatment for Parkinson disease. This drug replenishes dopamine levels in the brain, compensating for the loss of dopaminergic neurons in the substantia nigra. Dopamine agonists directly stimulate dopamine receptors in the central nervous system, mimicking the neurotransmitter's effects and improving motor function.

In patients with pheochromocytoma, α-blockers are used to prevent hypertensive crises and associated symptoms mainly due to their ability to inhibit α1 adrenergic receptors. Blocking these receptors causes vasodilation, reduces peripheral vascular resistance, and lowers blood pressure. β-blockers are added after α-blockers to control heart rate and prevent arrhythmias. However, β-blockers should not be used alone to treat pheochromocytoma, as blocking only β-receptors prevents β2-mediated vasodilation, leading to increased vascular resistance from unopposed α1-receptor stimulation and worsening hypertension.

For glaucoma, β-blockers decrease the production of aqueous humor in the eye, lowering intraocular pressure, which is beneficial in managing open-angle glaucoma.[14] In thyroid storm, where excessive thyroid hormone increases catecholamine sensitivity, β-blockers reduce the cardiovascular effects of hyperthyroidism, including tachycardia, hypertension, and arrhythmias.[15] In hyperadrenergic states, α2-agonists reduce sympathetic outflow by stimulating α2-adrenergic receptors in the central nervous system, helping manage conditions like hyperadrenergic hypertension and withdrawal syndromes, such as opioid or alcohol withdrawal.[16]