Agonists of alpha and beta adrenergic receptors

Content

Introduction

The autonomic nervous system (ANS) contributes to maintaining the balance of the organism by regulating, with independent self-control actions, the functions of the internal organs.

It is made up of distinct portions by structure and functions but which work together:

  • sympathetic nervous system (or orthosympathetic)
  • parasympathetic nervous system
  • enteric nervous system (or metasympathetic), consisting of nerve fibers that innervate internal organs

The nervous system receives stimuli of various kinds coming from the inside and from the outside of the body. The effects of the stimulation of the sympathetic and parasympathetic autonomic nervous system are mediated by the release of certain substances, neurotransmitters, belonging to the catecholamine family (adrenaline, noradrenaline and dopamine). The dopamine receptors are said dopaminergics, while the adrenaline and noradrenaline receptors are called adrenergic. These are membrane receptors metabotropic, that is coupled to G proteins and, based on the distribution in the tissues and the structural characteristics, are distinguished into α (alpha) and β (beta) receptors.

The α-adrenergic receptors are further divided into:

  • α1 receptors, which include the subtypes α1A, α1B and α1C
  • α2 receptors, which include the α2A, α2B and α2C subtypes

The β-adrenergic receptors are divided into:

  • β1 receptors
  • β2 receptors
  • β3 receptors

The drugs that enhance the action (agonists) of the adrenergic receptors are called sympathomimetics, as they mimic the effects of catecholamines, acting directly and / or indirectly on the receptors. Furthermore, agonist drugs that act through direct action are divided into selective And not selective.

alpha receptors

The α1 receptors are mainly located after the synapses, i.e. after the contact areas between nerve cells. These receptors are coupled to a Gq / 11 protein (excitatory type G protein) which promotes the activation of phospholipase C (PLC), resulting in an increase in the concentration of calcium within the cells. These receptors are mainly located in the smooth muscles of the bronchi and blood vessels, in the sphincters and in the radial muscles of the iris (part of the eye). They are important in controlling the functions of the cardiovascular system, given their presence in the vessels and in the heart; in the regulation of the functions of the genitourinary tract, due to their localization in the smooth muscles of the bladder and prostate; in the regulation of the gastrointestinal tract, due to their presence in the walls and sphincters of the intestine. The stimulation of these receptors causes the contraction of the muscles, with a consequent increase in peripheral resistance and, ultimately, in blood pressure; they are also responsible for pupil dilation in the absence of light (mydriasis) and for the contraction of the bladder sphincter with subsequent water retention.

The selective agonists of the α1 receptors are:

  • phenylephrine and metaraminol, mainly used as decongestants, as substances to dilate the pupils (mydriatics) and to increase blood pressure
  • oxymetazoline, used to relieve nasal congestion caused by colds, allergies and sinus infections

The α2 receptors are located both before and after the nerve synapses. They are highly expressed on noradrenergic neurons, in which they are able to determine the hyperpolarization of the cell membrane. They are receptors coupled to a Gi protein (inhibitory G protein), whose activation promotes the inhibition ofadenylate cyclase (an enzyme of the class of lyase which favors the breakdown of various chemical bonds) and the formation of a compound, cAMP (cyclic AMP), thus blocking the passage of calcium inside the cell. The α2-adrenergic receptors are generally responsible for a reduction in the release of noradrenaline (effects mediated by receptors, called self-receptors, located in the terminal part of the nerve cell that regulate the activity of the cell itself) but also for acetylcholine in the ganglia nerves present in the stomach wall (effect mediated by presynaptic heteroreceptors).

Their activation induces:

  • increased secretion of growth hormone (or somatotropin, GH) and stimulation of food intake
  • inhibition of insulin release by β-pancreatic cells
  • inhibition of lipase activity in adipocytes
  • platelet aggregation
  • arterial contraction
  • smooth muscle relaxation
  • reduction in the excretion of sodium, potassium and chlorine in the kidney

The selective agonists of the α2 receptors are the clonidine and α-methylnoradrenaline. Clonidine is a blood pressure lowering drug (antihypertensive), acts on the central nervous system by reducing the activation of the sympathetic system, heart rhythm and blood pressure. Α-methylnoradrenaline reduces pressure by relaxing and dilating blood vessels. Two other drugs are selective α2 receptor agonists guanfacine and guanabenz, also used as antihypertensive agents.

beta receptors

The β-adrenergic receptors are located after the synapses and are connected to a Gs protein (stimulatory G protein) that promotes the raising of cAMP levels, resulting in the activation of an enzyme, protein kinase A (PKA), which modifies the structure of different intracellular proteins by adding phosphoric acid to their structure (phosphorylation), responsible for numerous functional responses.

The β1 receptors are mainly located in the myocardium, where the rate and strength of contraction of the heart increase (positive inotropic, dromotropic and chronotropic effect).

Their activation in the heart, in fact, induces:

  • increased contractility of the myocardium, muscle tissue of the heart (positive inotropic effect)
  • increased heart rate (positive chronotropic effect)
  • increased conduction speed of electrical impulses in the heart (positive dromotropic effect)
  • increased excitability (positive bathmotropic effect)

They are also found in the kidney (in the juxtaglomerular apparatus), where they determine the release of renin, and at the level of adipocytes, where they are responsible for lipolysis, that is, the breakdown of triglycerides into fatty acids and glycerol.
A selective β1 receptor agonist is the dobutamine, drug with a positive inotropic action, used to counteract heart failure that occurs in adults as a consequence of reduced myocardial contractility, caused by heart surgery or organic heart disease.

The β2 receptors are present in the smooth muscle of blood vessels, bronchi and uterus.The activation mechanism of these receptors is the same as that described for the β1 receptors but, in this case, PKA modifies the structure (phosphorylating) of the myosin light chain kinase (MLCK) inactivating it and thus inhibiting the phosphorylation of myosin, resulting in muscle relaxation. Their activation, therefore, determines:

  • bronchodilation
  • relaxation of visceral smooth muscle and urogenital tract and uterine smooth muscle
  • increased muscle and hepatic glycogenolysis
  • increased gluconeogenesis

Among the selective agonists there are:

  • salbutamol
  • salmeterol
  • terbutaline

mainly used in the treatment of asthma, for their bronchodilator action. Furthermore, some β2 receptor agonists inhibit uterine contractions and are, therefore, used as antiabortives.

Finally, β3-adrenergic receptors are mainly located in adipose tissue. They promote the breakdown of fats (lipolysis) by activating the enzyme lipase which breaks down triglycerides into fatty acids. A selective β3 agonist is the mirabegron, drug used to treat overactive bladder.

Bibliography

Kuhar MJ, Couceyro PR, Lambert PD. α- and β-Adrenergic Receptors. In: Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Lippincott-Raven: Philadelphia, 1999

Small KM, McGraw DW, Liggett SB. Pharmacology and physiology of human adrenergic receptor polymorphisms [Summary]. Annual review of pharmacology and toxicology. 2003; 43: 381‐411

Further links

Strosberg AD. Structure, function, and regulation of adrenergic receptors. Protein Science. 1993; 2: 1198-209

Mayo Clinic. Albuterol - Inhalation Route (English)

Humanitas Research Hospital. Oxymetazoline

Humanitas Research Hospital. Clonidine

Humanitas Research Hospital. Methyldopa

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