Head G A, Chan C K, Burke S L
Neuropharmacology Laboratory, Baker Medical Research Institute, Prahran, Victoria, Australia.
J Auton Nerv Syst. 1998 Oct 15;72(2-3):163-9. doi: 10.1016/s0165-1838(98)00101-5.
Since the first suggestion of the existence of imidazoline receptors, there has been a continuing and yet unresolved debate as to their contribution to the antihypertensive actions of clonidine-like agents. In this review we bring together a number of studies from our laboratory which have examined the importance and interdependence of imidazoline receptors and alpha2-adrenoceptors in the mechanism of action of centrally acting antihypertensive drugs. Using conscious rabbits and a range of imidazoline and specific alpha2-adrenoceptor antagonists we have consistently found that second generation agents rilmenidine and moxonidine preferentially act via imidazoline receptors but that alpha2-adrenoceptors are important for the hypotension produced by clonidine and alpha-methyldopa. Despite this difference in receptor mechanism, the hypotension produced by all these drugs is dependent on central noradrenergic pathways. In other studies using anaesthetised rabbits and direct measures of sympathetic nerve activity we confirmed the generally held view that the major site of sympatho-inhibitory actions and sympathetic baroreflex effects of centrally acting antihypertensive agents is the rostral ventrolateral medulla (RVLM). We also found, using microinjection of specific antagonists, that alpha2-adrenoceptors in this nucleus appear to be activated as a consequence of imidazoline receptor activation. Thus, there appears to be a close relationship between imidazoline receptors and alpha2-adrenoceptors located in the RVLM in mediating the hypotension and inhibition of renal sympathetic nerve activity. Furthermore in recent studies using a noradrenergic neurotoxin microinjected into the RVLM we found that this treatment selectively blocked the actions of moxonidine but not clonidine, suggesting that I1-imidazoline receptors may be located on adrenergic terminals in situ. By contrast, clonidine acts predominantly via alpha2-adrenoceptors, perhaps located on cell bodies in the nucleus. We conclude that there is indeed a close nexus between 'presynaptic' imidazoline receptors on noradrenergic terminals and 'downstream' alpha2-adrenoceptors within the RVLM. Our hypothesis brings together opposing points of view that the mechanism for hypotension must involve either the imidazoline receptor or the alpha2-adrenoceptor. Clearly both are important.
自从首次有人提出存在咪唑啉受体以来，关于它们在可乐定类药物降压作用中的贡献，一直存在持续且未解决的争论。在这篇综述中，我们汇集了来自我们实验室的多项研究，这些研究探讨了咪唑啉受体和α2肾上腺素能受体在中枢性抗高血压药物作用机制中的重要性和相互依赖性。使用清醒家兔以及一系列咪唑啉和特异性α2肾上腺素能受体拮抗剂，我们一直发现第二代药物利美尼定和莫索尼定优先通过咪唑啉受体起作用，但α2肾上腺素能受体对于可乐定和α-甲基多巴产生的低血压很重要。尽管受体机制存在这种差异，但所有这些药物产生的低血压都依赖于中枢去甲肾上腺素能途径。在其他使用麻醉家兔并直接测量交感神经活动的研究中，我们证实了普遍的观点，即中枢性抗高血压药物的交感抑制作用和交感压力反射效应的主要部位是延髓头端腹外侧区（RVLM）。我们还发现，通过微量注射特异性拮抗剂，该核中的α2肾上腺素能受体似乎是咪唑啉受体激活的结果。因此，位于RVLM的咪唑啉受体和α2肾上腺素能受体之间似乎在介导低血压和抑制肾交感神经活动方面存在密切关系。此外，在最近使用微量注射到RVLM中的去甲肾上腺素能神经毒素的研究中，我们发现这种处理选择性地阻断了莫索尼定的作用，但不影响可乐定的作用，这表明I1-咪唑啉受体可能原位位于肾上腺素能神经末梢上。相比之下，可乐定主要通过α2肾上腺素能受体起作用，可能位于该核中的细胞体上。我们得出结论，去甲肾上腺素能神经末梢上的“突触前”咪唑啉受体与RVLM内的“下游”α2肾上腺素能受体之间确实存在紧密联系。我们的假设汇集了相反的观点，即低血压机制必须涉及咪唑啉受体或α2肾上腺素能受体。显然两者都很重要。
