Is the hypotensive effect of clonidine and related drugs due to imidazoline binding sites?

Clonidine and related alpha(2)-adrenergic receptor (alpha(2)AR) agonists lower arterial pressure primarily bg an action within the central nervous system. These drugs also have varying degrees of affinity for other cellular components called nonadrenergic imidazoline binding sites (NAIBS). For over 20 years, the alpha(2)AR agonist activity of clonidine-like drugs was thought to account for their therapeutic effects (alpha(2) theory). However, several groups have recently proposed a competing ''imidazoline theory'' according to which the hypotensive effect of clonidine-like drugs would in fact owe more to their affinity for one type of NAIBS, called I-1 receptors. The alpha(2)-theory is strongly supported by four main types of congruent data. First, the hypotensive effect of systemically administered clonidine is blocked by alpha(2)AR antagonists that are without affinity for I-1 NAIBs. Second, the hypotensive effect of intravenous clonidine is absent in genetically engineered mice in which a defective alpha(2A)AR has been substituted for the normal one. Third, the sympatholytic effect of clonidine is consistent with the presence of conventional inhibitory alpha(2A)ARs on sympathetic preganglionic neurons and on their main excitatory inputs in the medulla oblongata. Fourth, the first I-1 ligand without affinity for alpha(2)ARs was found to be biologically inactive. The imidazoline theory is supported by a limited repertoire of whole animal ''in vivo'' pharmacological experiments that remain open to a wide range of interpretations. In conclusion, the bulk of the evidence strongly support:; a largely predominant role of alpha(2)AR mechanisms in the action of most clonidine-like agents at therapeutically relevant closes or concentrations. Even the small pharmacological differences between these agents cannot yet be linked with certainty to their relative affinity for I-1 NAIBS.