Bousquet P, Dontenwill M, Greney H, Feldman J
Laboratoire de Pharmacologie Cardiovasculaire et Rénale, CNRS ERS 109, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.
J Hypertens Suppl. 1998 Aug;16(3):S1-5.
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.
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.
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.
咪唑啉化合物（如可乐定）的降压作用位点最初在延髓嘴端腹外侧部的外侧网状核（NRL/RVLM）中被确定。研究表明，咪唑啉及其相关物质作用于该区域时可降低血压，而儿茶酚胺则无此作用。
我们之前曾提出存在与α-肾上腺素能受体不同的咪唑啉样化合物特异性受体。随后在脑以及包括人肾在内的多种外周组织中报道了咪唑啉结合位点，正如预期的那样，这些特异性结合位点不与儿茶酚胺结合。咪唑啉结合位点分为两个亚组：对可乐定和异喹胍敏感的I1型，以及对异喹胍敏感且对可乐定基本不敏感的I2型。大量研究已证实这些受体参与各种调节和病理过程，其中高血压最为显著。
功能研究已证实，可乐定类药物的降压作用涉及I1-咪唑啉受体，而其最常见的副作用仅涉及α2-肾上腺素能受体。最近的研究表明，两种受体类型可能都有必要参与引发中枢性降压作用。利美尼定是一种与咪唑啉结构类似的恶唑啉化合物，已被提议作为一类对I1-咪唑啉受体具有选择性的新型抗高血压药物的原型。在降压剂量下，该药物无任何明显的镇静作用。与可乐定一样，将其注入NRL区域时会引起低血压，并且它能完全取代人髓质膜制剂中与特异性咪唑啉结合位点结合的[3H]可乐定，但已证明它对脑咪唑啉受体的选择性高于可乐定。这种选择性可能解释了利美尼定引起副作用的发生率较低的原因。
利美尼定是第一种在I1-咪唑啉受体和α2-肾上腺素能受体之间表现出良好选择性的药物，例如可降低血压但避免镇静和口干。
