α1-adrenergic receptor; α2-adrenergic receptor; Beta-1 adrenergic receptor; Microbial Metabolite; Human Endogenous Metabolite

Norepinephrine (NE) is typically thought to be a β2-initiator receptor and an β1-subtype β1-initiator agonist. At lower concentrations, norepinephrine (NE) also exhibits direct activity on β2-initiator receptors [1]. From newborn wild-type C57BL/6J mice, the inguinal fat pad (iWA) or intershoulder fat pad (BA) were separated and cultured. cAMP production in response to co-treatment with norepinephrine (NE, 10 μM) with or without CGP (10 nM) was first measured in order to investigate the impact of activating AT2 on β-primergic signaling. NE, or norepinephrine, raises cAMP. As anticipated in iWA, CGP doesn't change this result. In addition to stimulating heat production and requiring released media for the functional activation of the UCP1 protein, norepinephrine (NE) is also known to cause fat loss.

Norepinephrine can be utilized to create animal models in animal models.

Subcutaneous preadipocytes are immortalized with TERT and HPV E6/E7 from a 38-year-old female donor who is not diabetic. To facilitate the current investigations, ring cloning is used to isolate a stable diploid clone (called clone B) with a constant capacity for differentiation. Proadipocyte PGM2 medium is used to cultivate cells. Incubation in differentiation media containing dexamethasone, IBMX, indomethacin, and extra insulin induces differentiation in cells once they are confluent. During ten days, cells differentiate. The media used for treatments is changed to serum-free media overnight after being replaced with PGM2 media for a day. NE (10 μM), CGP (10 nM), vehicle, or NE and CGP are the treatments given to adipocytes for six hours[2].

Absorption, Distribution and Excretion
Norepinephrine is primarily distributed in sympathetic nerve tissue. It can cross the placental barrier but not the blood-brain barrier. Orally administered norepinephrine is destroyed in the gastrointestinal tract and poorly absorbed after subcutaneous injection. After intravenous injection, a pressor response occurs rapidly. The duration of action is short, disappearing within 1-2 minutes after discontinuation. Like epinephrine, norepinephrine is ineffective orally and poorly absorbed at the subcutaneous injection site. It is rapidly inactivated in the body by enzymes that perform methylation and oxidative deamination similar to those used for epinephrine. Small amounts of norepinephrine are usually present in urine. Excretion may be significantly increased in patients with pheochromocytoma. Metabolism/Metabolites The pharmacological action of norepinephrine is primarily terminated through uptake and metabolism at sympathetic nerve endings. This drug is metabolized in the liver and other tissues through a series of reactions by enzymes such as catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The main metabolites are norepinephrine and 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid, VMA), both of which are inactive. Other inactive metabolites include 3-methoxy-4-hydroxyphenylethylene glycol, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylethylene glycol. Norepinephrine metabolites are primarily excreted in the urine as sulfate conjugates, with a small amount excreted as glucuronide conjugates. Only a small amount of norepinephrine is excreted unchanged. Uremic toxins often accumulate in the blood due to overeating or poor kidney filtration. Most uremic toxins are metabolic waste products and are usually excreted in the urine or feces.

Toxicity Summary
Uremic toxins (such as norepinephrine) are actively transported to the kidneys via organic ion transporters, particularly OAT3. Elevated uremic toxin levels can stimulate the production of reactive oxygen species (ROS). This appears to be mediated by the direct binding of uremic toxins to or inhibition of NADPH oxidases, particularly NOX4, which is abundant in the kidneys and heart (A7868). ROS can induce a variety of different DNA methyltransferases (DNMTs) involved in the silencing of the KLOTHO protein. KLOTHO has been shown to play an important role in anti-aging, mineral metabolism, and vitamin D metabolism. Multiple studies have shown that in acute or chronic kidney disease, KLOTHO mRNA and protein levels are decreased due to elevated local ROS levels (A7869). Norepinephrine exerts a peripheral vasoconstrictive effect by acting on α-adrenergic receptors. It also exerts a positive inotropic effect by acting on β-adrenergic receptors and dilates coronary arteries.

---

Use during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information regarding the use of norepinephrine during lactation. Due to its low oral bioavailability and short half-life, norepinephrine in breast milk is unlikely to affect the infant. High-dose intravenous administration of norepinephrine may reduce milk production or the milk ejection reflex and decrease the concentration of β-casein in breast milk.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
Norepinephrine inhibits the synthesis of β-casein by stimulating adrenergic β2 receptors. Animal data indicate that norepinephrine can reduce serum prolactin levels and decrease milk production, while inhibiting the release of oxytocin, thereby suppressing the milk ejection reflex.

---

Interactions
Cyclopropane and halothane anesthetics increase the excitability of the cardiac autonomic nervous system, and therefore appear to make the myocardium more sensitive to the effects of intravenously injected epinephrine or norepinephrine tartrate. Therefore, the use of norepinephrine tartrate injections during cyclopropane and halothane anesthesia is generally considered contraindicated due to the risk of ventricular tachycardia or ventricular fibrillation.
Patients taking monoamine oxidase (MAO) inhibitors may experience an enhanced pressor response due to the inhibition of neuronal metabolic degradation.
Use of furosemide or other diuretics may reduce the responsiveness of arteries to pressor drugs such as norepinephrine.
Tricyclic antidepressants (e.g., imipramine), certain antihistamines (especially diphenhydramine, tripachlor, and dextrochlorpheniramine), injectable ergot alkaloids, guanethidine, or methyldopa may enhance the pressor effect of norepinephrine, leading to severe, persistent hypertension. Low doses of norepinephrine should be used with caution in patients taking these medications. The synergistic effect of norepinephrine may stem from the inhibition of norepinephrine uptake by tissues or increased sensitivity of adrenaline receptors to the drug. Monoamine oxidase (MAO) is one of the enzymes responsible for norepinephrine metabolism. Although some clinicians have reported that MAO inhibitors do not appear to significantly enhance the effects of norepinephrine, manufacturers note that norepinephrine should be used with extreme caution in patients taking MAO inhibitors, as this may lead to severe, persistent hypertension. For more complete data on norepinephrine interactions (8 items in total), please visit the HSDB record page. Non-human toxicity values: Rat intravenous LD50 100 μg/kg; Mouse oral LD50 20 mg/kg; Mouse intraperitoneal LD50 6 mg/kg; Mouse subcutaneous LD50 5 mg/kg; Mouse intravenous LD50 550 μg/kg

[1]. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther. 2007 Mar;113(3):523-36.

[2]. Relative efficacy and potency of beta-adrenoceptor agonists for generating cAMP in human lymphocytes. Chest. 1996 Jan;109(1):194-200.

[3]. Suppression of Resting Metabolism by the Angiotensin AT2 Receptor. Cell Rep. 2016 Aug 9;16(6):1548-60.

[4]. Binding pathway determines norepinephrine selectivity for the human β 1 AR over β 2 AR. Cell Res. 2021 May;31(5):569-579.

Therapeutic Uses
Norepinephrine is used to produce vasoconstrictive and cardiac stimulating effects as an adjunct to correct hemodynamic imbalances in patients with persistent shock after adequate fluid resuscitation. /US Product Label Includes/
Epinephrine is the first-line drug for the emergency treatment of severe acute anaphylactic reactions, including anaphylactic shock. Once adequate ventilation is ensured, other vasopressors (such as norepinephrine) can be used to maintain blood pressure in patients with anaphylactic shock. /US Product Label Includes/
In cases of hypotension associated with myocardial infarction, the cautious use of norepinephrine may be effective, and some clinicians consider it the first-line vasopressor. However, even with vasopressors, the prognosis for this type of shock is generally poor, and the increased myocardial oxygen consumption and cardiac workload caused by norepinephrine may offset the drug's beneficial effects. Furthermore, patients with myocardial infarction are more prone to drug-induced arrhythmias. If severe congestive heart failure is also present, dopamine may be more appropriate because it increases renal blood flow and stroke volume. If peripheral vascular resistance is elevated, isoproterenol can be used in combination with norepinephrine, but the dosage of both drugs must be carefully adjusted according to the specific hemodynamic imbalance. /US Product Label Content/
Norepinephrine can be used to treat hypotension occurring during spinal anesthesia, but other vasopressors with longer duration of action and intramuscular administration, such as metaraminol, methoxamine, or phenylephrine, are more commonly used. Norepinephrine can also be used to treat hypotension occurring during general anesthesia; however, the possibility of arrhythmias should be considered. /Included in US Product Label/
For more complete data on the therapeutic uses of norepinephrine (7 types), please visit the HSDB record page.

---

Drug Warning
Norepinephrine can cause severe peripheral and visceral vasoconstriction, reduced blood flow to vital organs, and reduced renal perfusion, resulting in decreased urine output, tissue hypoxia, and metabolic acidosis. These effects are most likely to occur in patients with hypovolemia. Furthermore, long-term use of norepinephrine may lead to a decrease in plasma volume, potentially resulting in persistent shock or recurrence of hypotension after discontinuation. Long-term use of norepinephrine can cause edema, hemorrhage, focal myocarditis, subcardiac hemorrhage, intestinal necrosis, or liver and kidney necrosis. These adverse reactions typically occur in patients with severe shock, and it is unclear whether they are caused by the drug itself or the shock state. Norepinephrine can cause tissue necrosis and sloughing at the injection site due to local vasoconstriction. Circulatory disturbances and tissue sloughing may occur even without obvious extravasation. Rare cases of limb gangrene have been reported, such as in the lower extremities following intravenous injection of norepinephrine into the ankle. Norepinephrine increases myocardial oxygen consumption and cardiac work. With prolonged use or high doses, cardiac output may decrease due to reduced venous return caused by increased peripheral vascular resistance. Decreased cardiac output is particularly harmful to elderly patients or those with pre-existing poor cerebral or coronary circulation. Norepinephrine may cause palpitations and bradycardia, as well as potentially fatal arrhythmias, including ventricular tachycardia, bigeminy, junctional rhythms, atrioventricular dissociation, and ventricular fibrillation. Bradycardia can be treated with atropine. Patients with acute myocardial infarction, hypoxia, or hypercapnia, as well as those taking other medications that may increase cardiac excitability (such as cyclopropane or halogenated hydrocarbon general anesthetics), are particularly susceptible to arrhythmias. For more complete data on norepinephrine (19 in total), please visit the HSDB record page. Pharmacodynamics: Norepinephrine acts on α1 and α2 adrenergic receptors, causing vasoconstriction. Its in vitro effects are generally limited to raising blood pressure by antagonizing α-1 and α-2 receptors, resulting in increased systemic vascular resistance.

C8H11NO3

169.1778

169.073

C, 56.80; H, 6.55; N, 8.28; O, 28.37

51-41-2

Norepinephrine hydrochloride; 329-56-6; Norepinephrine bitartrate monohydrate; 108341-18-0; Norepinephrine tartrate; 51-40-1; (Rac)-Norepinephrine-d3 (formate)

439260

White to yellow solid powder

1.4±0.1 g/cm3

442.6±40.0 °C at 760 mmHg

220-230°C

221.5±27.3 °C

0.0±1.1 mmHg at 25°C

1.659

-0.88

4

4

2

12

142

1

OC1=CC=C([C@@H](O)CN)C=C1O

SFLSHLFXELFNJZ-QMMMGPOBSA-N

InChI=1S/C8H11NO3/c9-4-8(12)5-1-2-6(10)7(11)3-5/h1-3,8,10-12H,4,9H2/t8-/m0/s1

4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol

Norepinephrine; Noradrenaline; Noradrenalin; Levarterenol; Levophed Arterenol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~25 mg/mL (~147.8 mM) H2O: < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (12.29 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.08 mg/mL (12.29 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (12.29 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)