Norepinephrine

Norepinephrine
Systematic (IUPAC) name
4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol
Clinical data
Trade names Levarterenol, Levophed, Norepin
AHFS/Drugs.com monograph
Licence data US FDA:link
  • AU: B3
  • US: C (Risk not ruled out)
Intravenous
Pharmacokinetic data
Metabolism Hepatic
Excretion Urine (84-96%)
Identifiers
51-41-2 Yes
C01CA03
PubChem CID 439260
DrugBank DB00368 Yes
ChemSpider 388394 Yes
UNII X4W3ENH1CV Yes
KEGG D00076 Yes
ChEBI CHEBI:18357 Yes
ChEMBL CHEMBL1437 Yes
Synonyms Noradrenaline
(R)-(–)-Norepinephrine
l-1-(3,4-Dihydroxyphenyl)-2-aminoethanol
Chemical data
Formula C8H11NO3
169.18 g/mol
Physical data
Density 1.397±0.06 g/cm3
Melting point 217 °C (423 °F) (decomposes)
Boiling point 442.6 °C (828.7 °F) ±40.0°C
 Yes (what is this?)  (verify)

Norepinephrine (INN) (abbreviated norepi or NE), also called noradrenaline (BAN) (abbreviated NA, NAd, or norad), or 4,5-β-trihydroxy phenethylamine is a catecholamine with multiple roles including those as a hormone and a neurotransmitter.[1] It is the hormone and neurotransmitter most responsible for vigilant concentration in contrast to the chemically similar hormone, dopamine, which is most responsible for cognitive alertness.[2]

Medically it is used in those with severe hypotension. It does this by increasing vascular tone (tension of vascular smooth muscle) through α-adrenergic receptor activation.

Areas of the body that produce or are affected by norepinephrine are described as noradrenergic. The terms noradrenaline (from the Latin) and norepinephrine (from the Greek) are interchangeable, with noradrenaline being the common name in most parts of the world. However the U.S. National Library of Medicine[3] has promoted norepinephrine as the favored name. It was discovered by Ulf von Euler in 1946.[4]

One of the most important functions of norepinephrine is its role as the neurotransmitter released from the sympathetic neurons to affect the heart. An increase in norepinephrine from the sympathetic nervous system increases the rate of contractions in the heart.[5] As a stress hormone, norepinephrine affects parts of the brain, such as the amygdala, where attention and responses are controlled.[6] Norepinephrine also underlies the fight-or-flight response, along with epinephrine, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle.

Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase in the secretory granules of the medullary chromaffin cells.[7] It is released from the adrenal medulla into the blood as a hormone, and is also a neurotransmitter in the central nervous system and sympathetic nervous system, where it is released from noradrenergic neurons in the locus coeruleus. The actions of norepinephrine are carried out via the binding to adrenergic receptors.

Medical uses

Norepinephrine is used as a vasopressor medication for patients with critical hypotension. It is given intravenously and acts on both α1 and α2 adrenergic receptors to cause vasoconstriction. Its effects are often limited to the increasing of blood pressure through agonist activity on α1 and α2 receptors, and causing a resultant increase in peripheral vascular resistance. At high doses, and especially when it is combined with other vasopressors, it can lead to limb ischemia and limb death. Norepinephrine is used mainly to treat patients in vasodilatory shock states such as septic shock and neurogenic shock, while showing fewer adverse side-effects compared to dopamine treatment.[8]

Physiological effects

Norepinephrine is released when a host of physiological changes are activated by a stressful event.

In the brain, this is caused in part by activation of an area of the brain stem called the locus coeruleus (LC). This nucleus is the origin of most norepinephrine pathways in the brain. Noradrenergic neurons project bilaterally (send signals to both sides of the brain) from the locus coeruleus along distinct pathways to many locations, including the cerebral cortex, limbic system, and the spinal cord, forming a neurotransmitter system.

Norepinephrine is also released from postganglionic neurons of the sympathetic nervous system, to transmit the fight-or-flight response in each tissue, respectively. The adrenal medulla can also contribute to such post-ganglionic nerve cells, although they release norepinephrine into the blood.

Norepinephrine system

The noradrenergic neurons in the brain form a neurotransmitter system, that, when activated, exerts effects on large areas of the brain. The effects are manifested in alertness, arousal, and influences on the reward system.

The noradrenergic neurons originate both in the locus coeruleus and the lateral tegmental field. The axons of the neurons in the locus coeruleus act on adrenergic receptors in:

On the other hand, axons of neurons of the lateral tegmental field act on adrenergic receptors in hypothalamus, for example.

This structure explains some of the clinical uses of norepinephrine, since a modification of this system affects large areas of the brain.

Role in cognition

Cortical norepinephrine (NE) release during attention paradigms (patterns) can increase the alteration detection rate (frequency at which an alteration was selected) in multiple-cue probability learning during tasks involving giving predictive cues (such as auditory or visual), and thereby enhance subsequent learning.[9] A. J. Yu et al. developed a Bayesian framework to examine NE release in instances of "unexpected uncertainty", wherein a drastic alteration in sensory information produces a large disparity between top-down expectations and what actually occurs.[10] The model predicts that NE levels spike when the predictive context is switched, then subside. It has also been shown that lesions of the locus coeruleus impair this attentional shift.[10]

Similarly, several studies have implicated the LC-NE system in eliciting the P300, a cortical event-related potential that responds to environmental stimuli with behaviorally relevant, motivational, or attention-grabbing properties.[11][12][13][14][15] The P300 may reflect updating of prior knowledge regarding stimuli relevant for accurate and efficient decision making. Several studies have searched for a P300 generator within the brain and have ultimately concluded that the potential must have a source that is distributed, synchronous and localized in cortex.[16] This definition is ideally satisfied both functionally and anatomically by the LC neuromodulatory system. Given its broad projection pattern and the correlation between NE release and increased sensory signal transmission,[17] it seems likely that noradrenergic cortical release is the neuronal mechanism of the P300.

Examination of the LC’s tonic firing pattern has led to speculation that it is important for the exploratory behavior essential for learning relations between sensory input, decision processing, motor output, and behavioral feedback.[18] Tonic activation within the range of 0–5 Hz has been shown to correlate with levels of drowsiness, accurate task performance, and, when slightly more elevated, distractibility and erratic task performance. Furthermore, phasic activation of the LC is observed in response to both highly salient, unconditioned and task-relevant stimuli. The phasic response occurs after stimulation and precedes a behavioral response in a time-locked fashion.[19] As such, phasic activation of the LC-NE system is proposed to enhance signal processing and behavioral responses specifically to task-relevant stimuli. Given the contrasting functional roles of LC tonic and phasic activity, it is plausible that projections from this brain region are important for maintaining a balance between exploratory and goal-directed behaviors that regulate probabilistic, environmental learning and corresponding decision making.

The LC-NE system receives convergent input from the orbitofrontal (OFC) and anterior cingulate cortices (ACC). The OFC has been associated with evaluation of reward. For example, Tremblay et al. found that the response magnitude of single-units in this region is varied with the hedonic value of a stimulus.[20] Additionally, neurons in this region are activated by rewarding stimuli, but not by identification of the stimulus nor corresponding response-preparation. Activation of the ACC appears to reflect some evaluation of cost-benefit. Several studies show ACC activation in response to performance error, negative feedback, or monetary loss.[21][22][23] Additionally, ACC responds to task difficulty.[24] Therefore, ACC activation may serve to integrate evaluations of task difficulty with corresponding outcome information to gauge the benefits of taking an action in regards to a particular environmental stimulus. Conceivably, the functions of the ACC and OFC are directly related to decision-making, and their projections to LC may modulate the phasic release of NE in order to gain-modulate cortical responses to decision outcomes.

LC-NE may play a significant role in synchronizing cortical activity in response to a decision process. In computational modeling of decision, the most accurate and efficient decision mechanisms are mathematically defined random walk or drift-diffusion processes that utilize single-layer neural networks to calculate the disparity in evidence between two options.[25] NE release gated by the LC-NE system is elicited after neurons processing sensory information have presumably reached a decision threshold.[26] Thus, the phasic burst can alter activation in all cortical processing layers in a temporally dependent manner, essentially collapsing the vast information-processing circuit to the outcome of a single-decision layer. Brown et al. found that the addition of a phasic LC mechanism was sufficient to yield optimal performance from a single-layer decision network.[27]

Fasting

A study has shown that fasting leads to increased levels of norepinephrine (NE) in the blood for up to 4 days of fasting.[28]

Macronutrient intake

Glucose intake was found to significantly increase plasma NE levels. In contrast, protein and fat intake was found to have no effect.[29]

Drug interactions

Different medications affecting norepinephrine function have their targets at different points in the mechanism, from synthesis to signal termination.

Synthesis modulators

α-Methyltyrosine is a substance that intervenes in norepinephrine synthesis by substituting tyrosine for tyrosine hydroxylase, and blocking this enzyme.

Vesicular transport modulators

This transportation can be inhibited by reserpine and tetrabenazine.[30]

Release modulators

Inhibitors of norepinephrine release
Substance[31] Receptor[31]
acetylcholine muscarinic receptor
norepinephrine (itself)/epinephrine α2 receptor
5-HT 5-HT receptor
adenosine P1 receptor
PGE EP receptor
histamine H2 receptor
enkephalin δ receptor
dopamine D2 receptor
ATP P2 receptor
Stimulators of norepinephrine release
Substance[31] Receptor[31]
epinephrine β2 receptor
angiotensin II AT1 receptor

Receptor binding modulators

Examples include alpha blockers for the α-receptors, and beta blockers for the β-receptors.

Termination modulators

Uptake modulators

Inhibitors[30] of uptake 1 include:

Inhibitors[30] of uptake 2 include:

Alzheimer's disease

The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally diffuses from "varicosities". As such, it provides an endogenous anti-inflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus.[32] Up to 70% of norepinephrine projecting cells are lost in Alzheimer’s Disease. It has been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines and their phagocytosis of Aβ, suggesting this loss might have a role in causing this disease.[32]

Chemistry

Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is L-(−)-(R)-norepinephrine. The prefix nor- indicates that norepinephrine is the next-lower homolog of epinephrine. The two structures differ only in that epinephrine has a methyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix nor- is derived as an abbreviation of the word "normal", used to indicate a demethylated compound.[33][34][35]

Mechanism

Norepinephrine is synthesized from tyrosine as a precursor, and packed into synaptic vesicles. It performs its action by being released into the synaptic cleft, where it acts on adrenergic receptors, followed by the signal termination, either by degradation of norepinephrine or by uptake by surrounding cells.

Biosynthesis

Norepinephrine is synthesized by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of the sympathetic nervous system from the amino acid tyrosine. While the conversion steps of L-tyrosine to dopamine occurs predominantly in the cytoplasm, the conversion of dopamine to norepinephrine by dopamine β-hydroxylase occurs predominantly in the neurotransmitter vesicle.

Biosynthesis of norepinephrine

Vesicular transport

Between the decarboxylation and the final β-oxidation, norepinephrine is transported into synaptic vesicles. This is accomplished by vesicular monoamine transporter (VMAT) in the lipid bilayer. This transporter has equal affinity for norepinephrine, epinephrine and isoprenaline.[30]

Release

To perform its functions, norepinephrine must be released from synaptic vesicles. Many substances modulate this release, some inhibiting it and some stimulating it. An action potential reaches the presynaptic membrane, which changes the membrane polarisation. Calcium ions thus enter, resulting in vesicular fusion, releasing norepinephrine.

For instance, there are inhibitory α2 adrenergic receptors presynaptically that give negative feedback on release by homotropic modulation.

Receptor binding

Main articles: Adrenergic receptor and TAAR1

Norepinephrine performs its actions on the target cell by binding to and activating adrenergic receptors on the cell membrane. Norepinephrine also binds to TAAR1 as a partial agonist. The target cell expression of different types of receptors determines the ultimate cellular effect, and thus norepinephrine has different actions on different cell types.

Termination

Signal termination is a result of reuptake and degradation.

Uptake

Extracellular uptake of norepinephrine into the cytosol is done either presynaptically (uptake 1) or by non-neuronal cells in the vicinity (uptake 2). Furthermore, there is a vesicular uptake mechanism from the cytosol into synaptic vesicles.

Comparison of norepinephrine uptake
Uptake Transporter Vmax (n mol/g/min)[36] KM[36] Specificity[37] Location Other substrates[37] Inhibitors [38]
Uptake 1 Norepinephrine transporter[38] 1.2 0.3 norepinephrine > epinephrine > isoprenaline presynaptic
Uptake 2 100 250 epinephrine > norepinephrine > isoprenaline cell membrane of non-neuronal cells[30]
Vesicular VMAT[38] -[38] ~0.2[38] norepinephrine > epinephrine > isoprenaline[38] Synaptic vesicle membrane[38]

Degradation

Norepinephrine degradation. Enzymes are shown in boxes.[39]

In mammals, norepinephrine is rapidly degraded to various metabolites. The principal metabolites are:

In the periphery, VMA is the major metabolite of catecholamines, and is excreted unconjugated in the urine. A minor metabolite (although the major one in the central nervous system) is MHPG, which is partly conjugated to sulfate or glucuronide derivatives and excreted in the urine.[41]

Nutritional sources

Shown here is the chemical structure of L-tyrosine. The biosynthesis of norepinephrine depends upon the presence of L-tyrosine, an amino acid building-block of many proteins in meat, nuts, and eggs, for example.

The synthesis of norepinephrine depends on the presence of tyrosine, an amino acid found in proteins such as meat, nuts, and eggs. Dairy products such as cheese also contain high amounts of tyrosine (the amino acid is named for "tyros", the Greek word for cheese). However, adult humans readily synthesize tyrosine from phenylalanine, an essential amino acid. Tyrosine is the precursor to dopamine, which in turn is a precursor to epinephrine and norepinephrine.

See also

References

  1. ↑ "Norepinephrine definition". dictionary.reference.com. Retrieved 24 November 2008.
  2. ↑ http://www.medscape.org/viewarticle/523887_4[]
  3. ↑ "RxNorm_full_prescribe_01072013.zip". U.S. National Library of Medicine. Retrieved 22 January 2013.
  4. ↑ von Euler, U. S. (December 12, 1970). "Adrenergic Neurotransmitter Functions". Nobel Lecuture. Republished as: von Euler, U. S. (1971). "Adrenergic Neurotransmitter Functions". Science 173 (3993): 202–6. Bibcode:1971Sci...173..202V. doi:10.1126/science.173.3993.202. JSTOR 1732662. PMID 4103433.
  5. ↑ Guyton, Arthur; Hall, John (2006). "Chapter 10: Rhythmical Excitation of the Heart". In Gruliow, Rebecca. Textbook of Medical Physiology (Book) (11th ed.). Philadelphia, Pennsylvania: Elsevier Inc. p. 122. ISBN 0-7216-0240-1.
  6. ↑ Tanaka M, Yoshida M, Emoto H, Ishii H (September 2000). "Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies". Eur. J. Pharmacol. 405 (1-3): 397–406. doi:10.1016/S0014-2999(00)00569-0. PMID 11033344.
  7. ↑ Katzung, Bertram G. (2015). "Introduction to Autonomic Pharmacology". In Katzung, Bertram G.; Trevor, Anthony J. Basic & Clinical Pharmacology (13th ed.). McGraw-Hill Education. ISBN 978-0-07-182505-4.
  8. ↑ De Backer, Daniel et al. (4 March 2010). "Comparison of Dopamine and Norepinephrine in the Treatment of Shock". New England Journal of Medicine 362 (9): 11. doi:10.1056/nejmoa0907118.
  9. ↑ Devauges, Valerie; Sara, Susan J. (1990). "Activation of the noradrenergic system facilitates an attentional shift in the rat". Behavioural Brain Research 39 (1): 19–28. doi:10.1016/0166-4328(90)90118-X. PMID 2167690.
  10. ↑ 10.0 10.1 Yu, Angela J.; Dayan, Peter (2005). "Uncertainty, Neuromodulation, and Attention". Neuron 46 (4): 681–92. doi:10.1016/j.neuron.2005.04.026. PMID 15944135.
  11. ↑ Johnson, RAY (2007). "On the neural generators of the P300 component of the event-related potential". Psychophysiology 30 (1): 90–7. doi:10.1111/j.1469-8986.1993.tb03208.x. PMID 8416066.
  12. ↑ Pineda, J. A.; Foote, S. L.; Neville, H. J. (1989). "Effects of locus coeruleus lesions on auditory, long-latency, event-related potentials in monkey". The Journal of Neuroscience 9 (1): 81–93. PMID 2563282.
  13. ↑ Swick, D.; Pineda, J.A.; Schacher, S.; Foote, S.L. (1994). "Locus coeruleus neuronal activity in awake monkeys: Relationship to auditory P300-like potentials and spontaneous EEG". Experimental Brain Research 101. doi:10.1007/BF00243219.
  14. ↑ Duncan-Johnson, Connie C.; Donchin, Emanuel (1977). "On Quantifying Surprise: The Variation of Event-Related Potentials with Subjective Probability". Psychophysiology 14 (5): 456–67. doi:10.1111/j.1469-8986.1977.tb01312.x. PMID 905483.
  15. ↑ Pineda, J.A.; Shafer, K.; Belamonte, M (1993). "Noradrenergic modulation of auditory and visual P300 in parietal-temporal cortex". Society for Neuroscience Abstracts 19. OCLC 795605830.
  16. ↑ Lutzenberger, W.; Elbert, T.; Rockstroh, B. (1987). "A brief tutorial on the implications of volume conduction for the interpretation of the EEG". Journal of Psychophysiology 1: 81–9.
  17. ↑ Berridge, Craig W; Waterhouse, Barry D (2003). "The locus coeruleus–noradrenergic system: Modulation of behavioral state and state-dependent cognitive processes". Brain Research Reviews 42 (1): 33–84. doi:10.1016/S0165-0173(03)00143-7. PMID 12668290.
  18. ↑ Usher, M.; Cohen, Jonathan D.; Servan-Schreiber, David; Rajkowski, Janusz; Aston-Jones, Gary (1999). "The Role of Locus Coeruleus in the Regulation of Cognitive Performance". Science 283 (5401): 549–54. Bibcode:1999Sci...283..549U. doi:10.1126/science.283.5401.549. PMID 9915705.
  19. ↑ Clayton, E. C.; Rajkowski, J; Cohen, J. D.; Aston-Jones, G (2004). "Phasic Activation of Monkey Locus Ceruleus Neurons by Simple Decisions in a Forced-Choice Task". Journal of Neuroscience 24 (44): 9914–20. doi:10.1523/JNEUROSCI.2446-04.2004. PMID 15525776.
  20. ↑ Schultz, Wolfram; Tremblay, Léon (1999). "Relative reward preference in primate orbitofrontal cortex". Nature 398 (6729): 704–8. Bibcode:1999Natur.398..704T. doi:10.1038/19525. PMID 10227292.
  21. ↑ Eisenberger, N. I.; Lieberman, Matthew D.; Williams, Kipling D. (2003). "Does Rejection Hurt? An fMRI Study of Social Exclusion". Science 302 (5643): 290–2. Bibcode:2003Sci...302..290E. doi:10.1126/science.1089134. PMID 14551436.
  22. ↑ Falkenstein, M.; Hohnsbein, J.; Hoormann, J.; Blanke, L. (1991). "Effects of crossmodal divided attention on late ERP components. II. Error processing in choice reaction tasks". Electroencephalography and Clinical Neurophysiology 78 (6): 447–55. doi:10.1016/0013-4694(91)90062-9. PMID 1712280.
  23. ↑ Gehring, William J.; Goss, Brian; Coles, Michael G.H.; Meyer, David E.; Donchin, Emanuel (1993). "A Neural System for Error Detection and Compensation". Psychological Science 4 (6): 385. doi:10.1111/j.1467-9280.1993.tb00586.x.
  24. ↑ Barch, Deanna M.; Braver, Todd S.; Nystrom, Leigh E.; Forman, Steven D.; Noll, Douglas C.; Cohen, Jonathan D. (1997). "Dissociating working memory from task difficulty in human prefrontal cortex". Neuropsychologia 35 (10): 1373–80. doi:10.1016/S0028-3932(97)00072-9. PMID 9347483.
  25. ↑ Bogacz, Rafal; Cohen, Jonathan D. (2004). "Parameterization of connectionist models". Behavior Research Methods, Instruments, & Computers 36 (4): 732. doi:10.3758/BF03206554.
  26. ↑ Nieuwenhuis, Sander; Aston-Jones, Gary; Cohen, Jonathan D. (2005). "Decision making, the P3, and the locus coeruleus--norepinephrine system". Psychological Bulletin 131 (4): 510–32. doi:10.1037/0033-2909.131.4.510. PMID 16060800.
  27. ↑ Brown, Eric T.; Gilzenrat, Mark S.; Cohen, Jonathan D. "The locus coeruleus, adaptive gain, and the optimization of simple decision tasks" (PDF). Princeton University.
  28. ↑ Zauner, C; Schneeweiss, B; Kranz, A; Madl, C; Ratheiser, K; Kramer, L; Roth, E; Schneider, B; Lenz, K (2000). "Resting energy expenditure in short-term starvation is increased as a result of an increase in serum norepinephrine". The American Journal of Clinical nutrition 71 (6): 1511–5. PMID 10837292.
  29. ↑ Welle, Stephen; Lilavivat, Usah; Campbell, Robert G. (1981). "Thermic effect of feeding in man: Increased plasma norepinephrine levels following glucose but not protein or fat consumption". Metabolism 30 (10): 953–8. doi:10.1016/0026-0495(81)90092-5. PMID 7024722.
  30. ↑ 30.0 30.1 30.2 30.3 30.4 Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167
  31. ↑ 31.0 31.1 31.2 31.3 Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.Page 129
  32. ↑ 32.0 32.1 Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP. (2010). Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A. 17:6058–6063 doi:10.1073/pnas.0909586107 PMID 20231476
  33. ↑ Sharma B, Satish A, Kumar R (1999). Dictionary of Drugs. Anmol Publications. ISBN 81-261-1820-2.
  34. ↑ Gaddum JH (June 1956). "The Prefix 'Nor' in Chemical Nomenclature". Nature 177 (1046): 1046–1046. Bibcode:1956Natur.177.1046G. doi:10.1038/1771046b0.
  35. ↑ Matthiessen A, Foster GC (1868). "Researches into the chemical constitution of narcotine and of its products of decomposition". Journal of the Chemical Society 358.
  36. ↑ 36.0 36.1 These values are from rat heart. Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167
  37. ↑ 37.0 37.1 Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167
  38. ↑ 38.0 38.1 38.2 38.3 38.4 38.5 38.6 38.7 38.8 38.9 38.10 38.11 Unless else specified in boxes, then ref is: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.
  39. ↑ Figure 11-4 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.
  40. ↑ "Endokrynologia Kliniczna" ISBN 83-200-0815-8, page 502
  41. ↑ Chapter 11 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.

External links