Hexamethonium bromide

Acetylcholine, released by cholinergic neurons, activates two groups of acetylcholine receptors (AChRs); muscarinic AChRs (mAChRs) which belong to the superfamily of G-protein coupled receptors (GPCRs) and nicotinic AChRs (nAChRs) which belong to the ligand-gated ion channel superfamily. nAChRs also respond to nicotine, hence their name¹.

To date, 17 different but related subunits of nAChRs have been identified and cloned. They consist of α subunits (α1-10), which is responsible for the binding of ligands. In fact, this subunit includes a Cys-loop in the first extracellular domain that is required for agonist binding². The other subunits responsible for making up the active receptor are the β (β1-4), γ, δ and ε subunits³. Structurally, all subunits have the following: a conserved large extracellular N-terminal domain, 3 conserved transmembrane domains, a variable cytoplasmic loop and a fourth transmembrane domain with a short extracellular C-terminal domain. An active nAChR is generally a heteropentamer of these various subunits organized around a central pore¹.

All α subunits are expressed in neuronal cells except for the α1 subunit which is specifically expressed in the muscle³. In the peripheral autonomic nervous system, nicotinic receptors are prominent and are responsible mediating fast synaptic transmission in all peripheral autonomic ganglia⁴. In this system, these channel receptors are mostly made up of two α3 subunits heteromerized with three other subunits. The α3 subunit plays a most important role in this system as knockout mice suffer from severe autonomic failure accompanied by gastrointestinal and bladder malfunctions⁵.

Hexamethonium is a depolarising ganglionic blocker of nicotinic nACh (N_N) receptor that acts in autonomic ganglia by binding mostly in or on the N_N receptor, and not the acetylcholine binding site itself. It does not have any effect on mAChR located on target organs of the parasympathetic nervous system⁶.