If you need a refresher on the process of synaptic transmission, please review the following Neurophysiology Modules you completed in the spring:
|Norepinephrine is synthesized from the amino acid tyrosine through by a series of enzymatic steps in particular cells in the central nervous system, as well as by most postganglionic neurons of the sympathetic nervous system. Norepinephrine is released like most neurotransmitters: when an action potential invades a nerve terminal, voltage-gated calcium channels (typically N-type) open, and the entry of calcium causes fusion of the norepinephrine-containing vesicles with the membrane, thereby releasing norepinephrine into the synaptic cleft.|
Norepinephrine is converted to epinephrine by the enzyme phenylethanolamine N-methyltransferase (PNMT). This enzyme is abundant in the cytoplasm of most chromaffin cells located in the adrenal medulla. Chromaffin cells are innervated by preganglionic neurons of the sympathetic nervous system. Acetylcholine released from nerve terminals of sympathetic preganglionic neurons binds to nicotinic receptors on the chromaffin cells, causing the release of epinephrine (or norepinephrine for cells lacking PNMT) into the bloodstream. Typically, epinephrine constitutes about 80% of the hormones released into the bloodstream from the adrenal medulla.
|A few neurons in the central nervous system also contain PNMT. Interestingly, many of these neurons are located in the rostral ventrolateral medulla (RVLM), the brainstem area that plays a primary role in controlling blood pressure by regulating the activity of sympathetic preganglionic neurons. The axons of RVLM neurons project to the thoracic and lumbar spinal cord, and make synaptic connections with sympathetic preganglionic neurons. This diagram shows the locations of PNMT-containing neurons in a section through the human brainstem. Presumably the stained neurons are located in the RVLM.|
Norepinephrine and epinephrine bind to two main subtypes of metabotropic receptors: α and β. The α subtype can be divided into the α-1 and α-2 subtypes. The β subtype can be divided into β-1, β-2 and β-3 receptors, although β-3 receptors are less important than the other subclasses.
The effects of norepinephrine/epinephrine binding to these receptors are summarized in the table below:
|Receptor||Effects of binding to the receptor|
|α1||Activates phospholipase C, resulting in an increase in intracellular Ca2+|
|α2||Decreases cAMP by inhibiting adenylate cyclase|
|β (all subtypes)||Increases cAMP by activating adenylate cyclase|
Based on this information, it appears that binding of ligand to α2 and β receptors would have opposite effects. However, there is a complication. α2 receptors are mostly presynaptic autoreceptors, such that ligand binding to the receptor reduces norepinephrine release from the nerve terminal. In contrast, α1 and β receptors are usually postsynaptic.
The adrenergic receptors of most importance in regulating the cardiovascular system are indicated in the following table:
(for cardiovascular control)
|Effect of Agonist||Effect of Antagonist|
|α1||Vascular smooth muscle (most tissues)||Increased blood pressure (due to vasoconstricton and increased peripheral resistance)||Decreased blood pressure (due to vasodilation and decreased peripheral resistance)|
|α2||Brainstem (including terminals of neurons projecting to the RVLM) and terminals of sympathetic efferent fibers||Decreased blood pressure (due to decreased RVLM activity)||Not in common use|
|β1||Heart (pacemaker cells, conduction system, cardiac muscle)||Increased heart rate and contractility||Decreased heart rate and contractility|
|β2||Vascular smooth muscle (skeletal muscle arterioles, coronary arterioles, hepatic arterioles)||Decreased blood pressure (mainly due to dilation of skeletal muscle arterioles)||Not in common use|
Drugs acting on α and β receptors have a variety effects on targets outside the cardiovascular system. Thus, the use of these drugs elicits many physiological effects in addition to those listed in the table above.
The table below shows the efficacy of norepinephrine and epinephrine in binding to α and β receptors. Norepinephrine released from sympathetic nerve terminals binds well to α receptors, as well as to β-1 receptors in the heart. However, norepinephrine binds very poorly to β-2 receptors.
In contrast, epinephrine binds well to β-1 and β-2 receptors, and with much less efficacy to α-receptors. However, in very high concentrations (e.g., use of the EPI-pen), epinephrine activates α-1 receptors.
Hence, the effects of epinephrine on the cardiovascular system are highly dose-dependent. At normal physiological concentrations, epinephrine activates β-1 and β-2 receptors, resulting in an increase in heart rate and contractility and dilation of muscle arterioles. At high concentrations, epinephrine causes vasoconstricton due to its effects on α-1 receptors.
|Receptor||Affinity for Norepinephrine and Epinephrine|
|α||Norepinephrine > Epinephrine
(although Epi binds at high concentrations)
|β1||Norepinephrine = Epinephrine|
|β2||Epinephrine >>> Norepinephrine
(in effect, norepinephrine does not bind to these receptors)
As noted in the neural control of blood pressure lecture, stretch receptors in the large arteries called baroreceptors signal changes in blood pressure to the central nervous system. These inputs trigger the baroreceptor reflex, which attempts to return blood pressure to the previous level by altering sympathetic and parasympathetic nervous system activity. These actions are summarized in the table below:
|Change in Blood Pressure||Change in Baroreceptor Afferent Activity||Change in Activity of Sympathetic Efferents to Heart and Blood Vessels||Change in Activity of Parasympathetic Efferents to Heart|
As a consequence of the baroreceptor reflex, a drug that acts on adrenergic receptors can precipitate changes in sympathetic and parasympathetic nervous system activity that tends to offset the effects of the drug. Take, for example, the case of an α1 receptor antagonist. Although such a drug would decrease total peripheral resistance and lower blood pressure, its administration also results in reflex-mediated increases in heart rate and contractility, as shown below.
|The baroreceptor reflex-mediated increases in heart rate and contractility precipitated by an α1 receptor antagonist result in increased myocardial oxygen demand, despite the fact that blood pressure (and afterload) have dropped. Hence, such a drug would not be ideal to reduce blood pressure in a patient with coronary vascular disease and impaired ability to supply the myocardium with oxygen.|
To review the synthesis, release, and actions of norepinephrine and epinephrine, watch this movie.
If the movie does not play in this window, or you would like to see it in a window of alternate size, download it from this link.