Imidazoline receptors: a challenge

The hypotensive effect of imidazoline-like drugs (IMs) directly injected into the rostroventrolateral part of the brainstem (NRL/RVLM) was shown to involve non-adrenergic imidazoline specific receptors (IRs). Some IMs caused hypotension when injected there, irrespective of their affinity and selectivity for any α-adrenoceptor subtype. Compounds, such as LNP 509, S 23515, S 23757 or benazoline with very high selectivities for IRs over α₂-adrenoceptors (A₂Rs), became available recently. Some of these compounds (LNP 509, S 23515) caused hypotension when injected alone into the NRL/RVLM region. Nevertheless, high selectivity for IRs will not predict by its own the capability of IMs to elicit hypotension as some of these substances behaved as antagonists towards the hypotensive effects of the latter. As far as hybrid drugs, i.e., with mixed binding profiles (I₁/α₂), were concerned, a significant correlation has been reported between their central hypotensive effect and their affinity for IRs. Imidazoline antagonists, such as idazoxan, were repeatedly shown to competitively prevent and reverse the centrally induced hypotensive effect of IMs. The sole stimulation of A₂Rs within the NRL/RVLM region was not sufficient to decrease blood pressure as much as IMs did, as shown by the lack of significant blood pressure lowering effect of α-methylnoradrenaline (α-MNA). No correlation was observed between affinity of IMs for A₂Rs and their central hypotensive effects. It is also noticeable that yohimbine, an A₂Rs antagonist, was repeatedly shown to abolish the hypotensive effect of hybrids but usually in a non-competitive manner. Mutation of A₂Rs was shown to prevent the hypotensive effects of centrally acting drugs. It is concluded that (i) drugs highly selective for I₁Rs over A₂Rs can reduce blood pressure by their own; (ii) the central hypotensive effect of IMs needs implication of IRs and appears to be facilitated by additional activation of A₂Rs; and (iii) this effect requires intact A₂Rs along the sympathetic pathways.