Glucocorticoid receptor-knockout mice exhibit an enlarged cortex, but the size of the medulla decreases, and PNMT activity becomes undetectable (Fig. 43.4). After release, epinephrine is transported back into the granule for storage and regulated exocytosis. The secretion of epinephrine and norepinephrine from the adrenal medulla is mainly regulated by descending sympathetic signals in response to different forms of stress, such as exercise, hypoglycemia, and hemorrhagic hypovolemia (Fig. 43.2). The adrenal gland histology consists of an outer cortex (C) and an inner medulla (M), with the central vein (V) present (Fig. 43.2). The cortex exhibits zonation, and each zone corresponds to a specific endocrine function (Fig. 43.2). The primary autonomic centers responsible for initiating sympathetic responses are located in the hypothalamus and brainstem, receiving inputs from the cerebral cortex, limbic system, hypothalamus, and brainstem (Fig. 43.5). The chemical signal for catecholamine secretion from the adrenal medulla is acetylcholine (ACh), which is released from preganglionic sympathetic neurons and binds to nicotinic receptors on chromaffin cells (Fig. 43.5). ACh enhances the activity of tyrosine hydroxylase, dopamine β-hydroxylase, and promotes exocytosis of chromaffin granules (Fig. 43.4). The synthesis of epinephrine and norepinephrine is closely associated with secretion, maintaining relatively constant levels of intracellular catecholamines despite changing sympathetic activity. Catecholamines exert their effects through α and β-adrenergic receptors, which are further divided into α1, α2, β1, β2, and β3 receptors (Table 43.1). The potency of endogenous and pharmacological agonists and antagonists varies among these receptors, with epinephrine and norepinephrine being potent agonists for α receptors, β1, and β3 receptors, and epinephrine being more potent than norepinephrine for β2 receptors. Multiple synthetic adrenergic agonists and antagonists are available with selective or nonselective action (Table 43.1). The downstream signaling pathways associated with these receptors depend on the duration of agonist exposure and the cell type (Table 43.1).
Fig. 43.4 ). Glucocorticoid receptor–knockout mice have an enlarged cortex, but the size of the medulla is decreased and PNMT activity is undetectable.
Epinephrine is then transported back into the granule for storage and to undergo regulated exocytosis.
Secretion of epinephrine and norepinephrine from the adrenal medulla is regulated primarily by descending sympathetic signals in response to various forms of stress, including exercise, hypoglycemia, and hemorrhagic hypovolemia •Fig. 43.2 Histologyoftheadrenalgland.A,Lowmagnificationillustratingtheoutercortex(C)andinnermedulla(M;notethecentralvein[V]).B,Highermagnificationclearlyillustratingthezonationofthecortex.Thecorrespondingendocrinefunctionandthedifferentzonesofthecortexandthemedullaarenoted.(FromYoungBetal.Wheater’s Functional Histology. 5thed.Philadelphia:ChurchillLivingstone;2006.)
Fig. 43.5 ). The primary autonomic centers that initiate sympathetic responses reside in the hypothalamus and brainstem, and they receive input from the cerebral cortex, the limbic system, and other regions of the hypothalamus and brainstem.
The chemical signal for secretion of catecholamine from the adrenal medulla is acetylcholine (ACh), which is secreted from preganglionic sympathetic neurons and binds to nicotinic receptors on chromaffin cells (see
Fig.
43.5 ). ACh increases the activity of the rate-limiting enzyme tyrosine hydroxylase in chromaffin cells (see
Fig. 43.4 ). It also increases the activity of dopamine β-hydroxylase and stimulates exocytosis of the chromaffin granules. Synthesis of epinephrine and norepinephrine is closely coupled to secretion so that levels of intracellular catecholamines do not change significantly even in the face of changing sympathetic activity.
Mechanism of Action of Catecholamines
Adrenergic receptors are generally classified as α-and β-adrenergic receptors, with the α-adrenergic receptors • Fig. 43.3 Blood flow through the adrenal gland. Capsular arteries give rise to sinusoidal vessels that carry blood centripetally through the cortex to the medulla. (Modified from Young B et al. Wheater’s Functional Histology. 5th ed. Philadelphia: Churchill Livingstone; 2006.) further divided into α1 and α2 receptors and the β-adrenergic receptors divided into β1, β2, and β3 receptors (
Table 43.1 ). These receptors can be characterized according to: 1.
Relative potency of endogenous and pharmacological agonists and antagonists. Epinephrine and norepinephrine are potent agonists for α receptors and for β1 and β3 receptors, whereas epinephrine is more potent than norepinephrine for β2 receptors. A large number of synthetic selective and nonselective adrenergic agonists and antagonists now exist.
2.
Downstream signaling pathways.
Table 43.1 shows the primary pathways that are coupled to the different adrenergic receptors. This is an oversimplification, because differences in signaling pathways for a given receptor have been linked to the duration of agonist exposure and cell type.
3.