There are two main types of alpha-receptor: alpha-1 receptors and alpha-2 receptors.

• Alpha-1 (α)₁ receptors are found at the post-synaptic cleft where the sympathetic nervous system innervates vascular smooth muscle. Under normal conditions, stimulation of the alpha-1 receptor causes contraction of the smooth muscle and a functional vasoconstriction.
• In contrast, alpha-2 receptors are found both peripherally and centrally in neuronal tissue that regulates blood pressure, heart rate and blood vessel dilation.

Drugs that affect alpha-receptors are used for a range of conditions. They are not first line therapy for common conditions such as hypertension but are used for a range of conditions including:

• treatment of resistant hypertension and hypertension during pregnancy,
• phaeochromocytoma,
• menopausal flushing, and
• benign prostatic hyperplasia.

There are three useful examples of drugs that affect alpha-receptors in the body: clonidine, methyldopa and prazosin. They can be grouped into two main action groups:

1. Drugs that are agonists at central alpha₂ receptors in the central nervous system (clonidine and methyldopa), and
2. Drugs that are antagonists at the alpha₁ and alpha₂ receptors in the arteries and veins causing vasodilatation (prazosin).

Clonidine and methyldopa are examples of alpha-2₂ receptor agonists that act peripherally at the terminus of the sympathetic nerve terminal and centrally in the medulla oblongata to cause a reduction in blood pressure.

Peripheral action of alpha-2 receptor agonists at the end of the sympathetic nerve terminal on the alpha-2 receptor induces the negative feedback loop to reduce further release of noradrenaline (NA) as shown in Figure 1 (note NA is also known as norepinephrine (NE)).

_{Role of alpha-2 receptor on the down regulation of release of noradrenaline (NE) from the sympathetic nervous system and the mechanism of vascular smooth muscle contraction}

 

The central action alpha-2 agonists on the medulla oblongata (brain stem) reduces sympathetic outflow increasing the effect of the nucleus tractus solitarii (NTS) on inhibiting sympathetic outflow from the vasomotor centre (VMC) in the medulla oblongata in the brain stem (This will be explored in more detail later in the course).

📺 Watch this video about alpha-receptors and drugs that affect these receptors (6:20 min)

Both the peripheral and central actions achieve a similar outcome – to reduce sympathetic tone or directly block the effect of the sympathetic nervous system at the alpha- and beta-receptors in the cardiovascular system. Let’s look at these drugs in more detail.

Clonidine

Clonidine is a centrally acting alpha₂ receptor agonist. The central alpha₂ receptor is an example of a G-protein coupled receptor that targets the function of adenylyl cyclase and the cAMP system to alter the function of a transmembrane ion channel (in this case the calcium ion channel).

Clonidine binds with the alpha₂ receptor on the neuron in the central nervous system and peripheral neuron. This activates the G_I-protein which inactivates adenylyl cyclase. This causes a reduction in the production of cAMP and protein kinase (active) (PKA). This in turn leads to a reduced influx of calcium ions (Ca2+) into the neuron cell, allowing the neuron to restore it polarization status. This change in polarization reduces the release of noradrenaline from the presynaptic sympathetic neuron. The following video briefly describes this process.

📺 Watch Clonidine: Mechanism of action

Methyldopa

Methyldopa is another example of a centrally acting alpha₂ receptor agonist. Like clonidine, methyldopa stimulates the central alpha₂ receptor which results in a reduced sympathetic outflow to the heart, kidneys and peripheral vasculature.  Methyldopa has more central nervous system and hepatotoxic side effects compared with other antihypertensives which is why it is typically only used during pregnancy.

Prazosin

Prazosin is an alpha receptor antagonist.  It selectively blocks the alpha₁-adrenoreceptors in the peripheral vasculature. Under normal conditions, the stimulation of the alpha₁-adrenoreceptor on vascular smooth muscle causes an increase in inositol triphosphate (IP₃) causing the release of Ca²⁺ from the sarcoplasmic reticulum in the vascular smooth muscle cell. It also activates protein kinase-C (PK-C). Both cause contraction of the vascular smooth muscle as seen in Figure 2 below. Therefore prasozin inhibits catecholamine (noradrenaline and adrenaline) induced vasoconstriction and is used to treat hypertension and benign prostatic hyperplasia (BPH).

_{Mechanism of smooth muscle contraction mediated by alpha1 and alpha2 receptors on vascular smooth muscle adapted from Klabunde, R. CV Pharmacology. All rights reserved}

📺 Watch this video about drugs that affect the alpha-receptors – Pharmacology (5:36 min)