Adrenoceptor Physiology

ADRENOCEPTOR PHYSIOLOGY

The term “adrenergic” originally referred to the effects of epinephrine (adrenaline), although nor-epinephrine (noradrenaline) is the primary neu-rotransmitter responsible for most of the adrenergic activity of the sympathetic nervous system. With the exception of eccrine sweat glands and some blood vessels, norepinephrine is released by post-ganglionic sympathetic fibers at end-organ tissues (Figure 14–1). In contrast, acetylcholine is released by preganglionic sympathetic fibers and all para-sympathetic fibers.

Norepinephrine is synthesized in the cyto-plasm of sympathetic postganglionic nerve end-ings and stored in the vesicles (Figure 14–2). After release by a process of exocytosis, the action of norepinephrine is primarily terminated by reup-take into the postganglionic nerve ending (inhib-ited by tricyclic antidepressants), but also by diffusion from receptor sites, or via metabolism by monoamine oxidase (inhibited by monoamine oxidase inhibitors) and catechol-O-methyltransfer-ase (Figure 14–3). Prolonged adrenergic activation leads to desensitization and hyporesponsiveness to further stimulation.

Adrenergic receptors are divided into two gen-eral categories: α and β. Each of these has been fur-ther subdivided into at least two subtypes: α₁ and α₂, and β₁, β₂, and β₃. The α-receptors have beenfurther divided using molecular cloning techniques into α_1A, α_1B, α_1D, α_2A, α_2B, and α_2C. These receptors are linked to G proteins ( Figure 14–4; Drs. Rodbell and Gilman received the Nobel Prize in physiology or medicine in 1994 for their discovery)—heterotri-meric receptors with α, β, and γ subunits. The differ-ent adrenoceptors are linked to specific G proteins, each with a unique effector, but each using guano-sine triphosphate (GTP) as a cofactor. α₁ is linked to G_q, which activates phospholipases; α₂ is linked to G_i, which inhibits adenylate cyclase, and β is linked to G_s, which activates adenylate cyclase.

α₁-Receptors

α₁-Receptors are postsynaptic adrenoceptorslocated in smooth muscle throughout the body (in the eye, lung, blood vessels, uterus, gut, and geni-tourinary system). Activation of these receptors increases intracellular calcium ion concentration, which leads to contraction of smooth muscles. Thus, α₁-agonists are associated with mydriasis (pupil-lary dilation due to contraction of the radial eye muscles), bronchoconstriction, vasoconstriction, uterine contraction, and constriction of sphincters in the gastrointestinal and genitourinary tracts. α₁-stimulation also inhibits insulin secretion andlipolysis. The myocardium possesses α₁-receptors that have a positive inotropic effect, which might play a role in catecholamine-induced arrhythmia. During myocardial ischemia, enhanced α₁-receptor coupling with agonists is observed. Nonetheless, the most important cardiovascular effect of α₁-stimulation is vasoconstriction, which increases peripheral vascular resistance, left ventricular after-load, and arterial blood pressure.

α₂-Receptors

In contrast to α₁-receptors, α₂-receptors are located primarily on the presynaptic nerve termi-nals. Activation of these adrenoceptors inhibits adenylate cyclase activity. This decreases the entry of calcium ions into the neuronal terminal, which limits subsequent exocytosis of storage vesicles containing norepinephrine. Thus, α₂-receptors cre-ate a negative feedback loop that inhibits further norepinephrine release from the neuron. In addi-tion, vascular smooth muscle contains postsyn-aptic α₂-receptors that produce vasoconstriction. More importantly, stimulation of postsynaptic α₂-receptors in the central nervous system causessedation and reduces sympathetic outflow, which leads to peripheral vasodilation and lower blood pressure.

β₁-Receptors

β-Adrenergic receptors are classified into β₁, β₂, and β₃receptors. The catecholamines, norepinephrine, and epinephrine are equipotent on β₁ receptors, but epinephrine is significantly more potent than nor-epinephrine on β₂ receptors.The most important β₁-receptors are located on the postsynaptic membranes in the heart. Stimulation of these receptors activates adenyl-ate cyclase, which converts adenosine triphosphate to cyclic adenosine monophosphate and initiates a kinase phosphorylation cascade. Initiation of the cascade has positive chronotropic (increased heart rate), dromotropic (increased conduction), and ino-tropic (increased contractility) effects.

β₂-Receptors

β₂-Receptors are primarily postsynaptic adreno-ceptors located in smooth muscle and gland cells. They share a common mechanism of action with β₁-receptors: adenylate cyclase activation. Despitethis commonality, β₂ stimulation relaxes smooth muscle, resulting in bronchodilation, vasodilation, and relaxation of the uterus (tocolysis), bladder, and gut. Glycogenolysis, lipolysis, gluconeogenesis, and insulin release are stimulated by β₂-receptor activa-tion. β₂-agonists also activate the sodium–potassium pump, which drives potassium intracellularly and can induce hypokalemia and dysrhythmias.

β₃-Receptors

β₃-Receptors are found in the gallbladder and brainadipose tissue. Their role in gallbladder physiology is unknown, but they are thought to play a role in lipolysis and thermogenesis in brown fat.

Dopaminergic Receptors

Dopamine (DA) receptors are a group of adrener-gic receptors that are activated by dopamine; these receptors are classified as D₁ and D₂ receptors. Acti-vation of D₁ receptors mediates vasodilation in the kidney, intestine, and heart. D₂ receptors are believed to play a role in the antiemetic action of droperidol.