Ernsberger P, Friedman J E, Koletsky R J
Department of Medicine, Case Western Reserve School of Medicine, Cleveland, Ohio 44106-4982, USA.
J Hypertens Suppl. 1997 Jan;15(1):S9-23. doi: 10.1097/00004872-199715011-00002.
To review previous work and present additional evidence characterizing the I1-imidazoline receptor and its role in cellular signaling, central cardiovascular control, and the treatment of metabolic syndromes. Second-generation centrally-acting antihypertensives inhibit sympathetic activity mainly via imidazoline receptors, whereas first-generation agents act via alpha2-adrenergic receptors. The I1 subtype of imidazoline receptor resides in the plasma membrane and binds central antihypertensives with high affinity.
Radioligand binding assays have characterized I1-imidazoline sites in the brainstem site of action for these agents in the rostral ventrolateral medulla. Binding affinity at I1-imidazoline sites, but not at other classes of imidazoline binding sites, correlates closely with the potency of central antihypertensive agents in animals and in human clinical trials. The antihypertensive action of systemic moxonidine is eliminated by the I1/alpha2-antagonist efaroxan, but not by selective blockade of alpha2-adrenergic receptors. Until now, the cell signaling pathway coupled to I1-imidazoline receptors was unknown. Using a model system lacking alpha2-adrenergic receptors (PC12 pheochromocytoma cells) we have found that moxonidine acts as an agonist at the cell level and I1-imidazoline receptor activation leads to the production of the second messenger diacylglycerol, most likely through direct activation of phosphatidylcholine-selective phospholipase C. The obese spontaneously hypertensive rat (SHR; SHROB strain) shows many of the abnormalities that cluster in human syndrome X, including elevations in blood pressure, serum lipids and insulin. SHROB and their lean SHR littermates were treated with moxonidine at 8 mg/kg per day. SHROB and SHR treated with moxonidine showed not only lowered blood pressure but also improved glucose tolerance and facilitated insulin secretion in response to a glucose load. Because alpha2-adrenergic agonists impair glucose tolerance, I1-imidazoline receptors may contribute to the multiple beneficial effects of moxonidine treatment.
The I1-imidazoline receptor is a specific high-affinity binding site corresponding to a functional cell-surface receptor mediating the antihypertensive actions of moxonidine and other second-generation centrally-acting agents, and may play a role in countering insulin resistance in an animal model of metabolic syndrome X.
回顾以往的研究工作，并提供更多证据来描述 I1 - 咪唑啉受体及其在细胞信号传导、中枢心血管控制和代谢综合征治疗中的作用。第二代中枢性抗高血压药物主要通过咪唑啉受体抑制交感神经活动，而第一代药物则通过α2 - 肾上腺素能受体起作用。咪唑啉受体的 I1 亚型位于质膜上，与中枢性抗高血压药物具有高亲和力。
放射性配体结合试验已对这些药物在延髓头端腹外侧的脑干作用部位的 I1 - 咪唑啉位点进行了表征。I1 - 咪唑啉位点的结合亲和力，而非其他类型的咪唑啉结合位点的亲和力，与动物和人类临床试验中中枢性抗高血压药物的效力密切相关。全身性莫索尼定的抗高血压作用可被 I1/α2 - 拮抗剂依酚氯铵消除，但不能被α2 - 肾上腺素能受体的选择性阻断所消除。到目前为止，与 I1 - 咪唑啉受体偶联的细胞信号通路尚不清楚。使用缺乏α2 - 肾上腺素能受体的模型系统（PC12 嗜铬细胞瘤细胞），我们发现莫索尼定在细胞水平上作为激动剂起作用，I1 - 咪唑啉受体激活导致第二信使二酰基甘油的产生，很可能是通过直接激活磷脂酰胆碱选择性磷脂酶 C。肥胖自发性高血压大鼠（SHR；SHROB 品系）表现出许多聚集在人类 X 综合征中的异常，包括血压升高、血脂和胰岛素升高。SHROB 及其瘦的 SHR 同窝仔每天接受 8 mg/kg 的莫索尼定治疗。接受莫索尼定治疗的 SHROB 和 SHR 不仅血压降低，而且葡萄糖耐量改善，对葡萄糖负荷的胰岛素分泌增加。由于α2 - 肾上腺素能激动剂会损害葡萄糖耐量，I1 - 咪唑啉受体可能有助于莫索尼定治疗的多种有益作用。
I1 - 咪唑啉受体是一个特定的高亲和力结合位点，对应于一个功能性细胞表面受体，介导莫索尼定和其他第二代中枢性作用药物的抗高血压作用，并可能在代谢综合征 X 的动物模型中对抗胰岛素抵抗方面发挥作用。
