Background: The site of the hypotensive action of imidazoline compounds, such as clonidine, was first identified within the nucleus reticularis lateralis of the rostroventrolateral part of the medulla (NRL/RVLM). It was shown that imidazolines and related substances reduced blood pressure when applied in this area whereas no catecholamine was capable of such an effect. IMIDAZOLINE-SPECIFIC BINDING: We previously suggested the existence of receptors specific for imidazoline-like compounds that differed from the alpha-adrenergic receptors. Imidazoline-binding sites were subsequently reported in the brain and in a variety of peripheral tissues, including the human kidney, and as expected these specific binding sites do not bind the catecholamines. The imidazoline-binding sites are classified into two subgroups: the I1-type, which is sensitive to clonidine and idazoxan, and the I2-type, sensitive to idazoxan and largely insensitive to clonidine. Numerous studies have confirmed the involvement of these receptors in various regulations and pathological processes, hypertension being the most notable.
Drugs: Functional studies have confirmed that the hypotensive effects of clonidine-like drugs involve I1-imidazoline receptors while their most frequent side effects only involve alpha2-adrenergic receptors. Recent studies have shown that a contribution of both receptor types might be necessary to trigger the hypotensive effect of central origin. Rilmenidine, an oxazoline analogue to the imidazolines, has been proposed as the prototype of a new class of antihypertensive drugs selective for I1-imidazoline receptors. At hypotensive doses, this drug is devoid of any significant sedative effect. As with clonidine, it evokes hypotension when injected into the NRL region and it completely displaces the [3H]clonidine bound to specific imidazoline-binding sites in human medullary membrane preparations, but it has proved more selective for cerebral imidazoline receptors than clonidine. This selectivity might explain the low incidence of side effects evoked by rilmenidine.
Conclusion: Rilmenidine is the first example of a drug exhibiting a favourable selectivity between I1-imidazoline receptors and alpha2-adrenergic receptors, for example reducing blood pressure but avoiding sedation and mouth dryness.