Feldman J, Greney H, Monassier L, Vonthron C, Bruban V, Dontenwill M, Bousquet P
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, CNRS-Université Louis Pasteur, Strasbourg, France.
J Auton Nerv Syst. 1998 Oct 15;72(2-3):94-7. doi: 10.1016/s0165-1838(98)00093-9.
The site of the hypotensive action of imidazoline compounds, such as clonidine, was first identified within the rostroventrolateral part of the brainstem: the nucleus reticularis lateralis. After that, it was shown that imidazolines and related substances reduced blood pressure when applied in this area whereas catecholamines were not capable of producing such an effect. These data led us to suggest the existence of receptors specific for imidazoline-like compounds different from the alpha2-adrenoceptors. Soon after, the existence of imidazoline binding sites was reported in the brain and in a variety of peripheral tissues including the human kidney. As expected, these specific binding sites do not bind the catecholamines. The imidazoline binding sites are already subclassified in two groups: the I1-subtype sensitive to clonidine and idazoxan, and the I2-subtype, sensitive to idazoxan and nearly insensitive to clonidine. Functional studies confirmed that the hypotensive effects of clonidine-like drugs involved imidazoline receptors while their most frequent side effects only involved alpha2-adrenoceptors. However, recent functional evidence suggests that a cross talk between imidazoline receptors and alpha2-adrenoceptors is necessary to trigger a hypotensive effect within the ventral brainstem. Rilmenidine and Moxonidine are the leader compounds of a new class of antihypertensive drugs selective for imidazoline receptors. At hypotensive doses, these drugs are devoid of significant sedative effect. Rilmenidine evoked hypotension when injected within the nucleus reticularis lateralis region; it competed for [3H]-clonidine bound to specific imidazoline binding sites in human medullary membrane preparations but proved more selective for cerebral imidazoline receptors than clonidine. It is suggested that this selectivity might explain the low incidence of their side effects. Additional potentially beneficial actions on cardiac arrhythmias or congestive heart failure enlarge the therapeutic interest of imidazoline-related drugs. Recent binding and functional data throw a new light on the optimal pharmacological profile of this second generation of centrally acting antihypertensive drugs.
咪唑啉化合物（如可乐定）的降压作用部位最初是在脑干的嘴端腹外侧部分被确定的，即外侧网状核。此后，研究表明，咪唑啉及相关物质应用于该区域时可降低血压，而儿茶酚胺则无法产生这种效果。这些数据使我们推测存在不同于α2肾上腺素能受体的咪唑啉样化合物特异性受体。不久之后，在大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的存在。不出所料，这些特异性结合位点不与儿茶酚胺结合。咪唑啉结合位点已被分为两组：对可乐定和吲哚唑烷敏感的I1亚型，以及对吲哚唑烷敏感且对可乐定几乎不敏感的I2亚型。功能研究证实，可乐定类药物的降压作用涉及咪唑啉受体，而其最常见的副作用仅涉及α2肾上腺素能受体。然而，最近的功能证据表明，咪唑啉受体与α2肾上腺素能受体之间的相互作用对于触发腹侧脑干内的降压作用是必要的。利美尼定和莫索尼定是一类新型的对咪唑啉受体有选择性的抗高血压药物的先导化合物。在降压剂量下，这些药物没有明显的镇静作用。利美尼定注射到外侧网状核区域时会引起低血压；它能竞争与人类髓质膜制剂中特异性咪唑啉结合位点结合的[3H] - 可乐定，但事实证明它对脑内咪唑啉受体的选择性比对可乐定更高。有人认为这种选择性可能解释了它们副作用发生率较低的原因。对心律失常或充血性心力衰竭的其他潜在有益作用增加了咪唑啉相关药物的治疗价值。最近的结合和功能数据为这类第二代中枢性抗高血压药物的最佳药理学特性提供了新的线索。
