Ziegler D, Haxhiu M A, Kaan E C, Papp J G, Ernsberger P
Research and Development, Solvay Pharma Deutschland, Hannover, Germany.
J Cardiovasc Pharmacol. 1996;27 Suppl 3:S26-37. doi: 10.1097/00005344-199627003-00005.
Moxonidine is a second-generation, centrally acting antihypertensive drug with a distinctive mode of action. Moxonidine activates I1-imidazoline receptors (I1-receptors) in the rostroventrolateral medulla (RVLM), thereby reducing the activity of the sympathetic nervous system. Moxonidine leads to a pronounced and long-lasting blood pressure reduction in different animal models of hypertension, e.g., spontaneously hypertensive rats, renal hypertensive rats, and renal hypertensive dogs. Blood pressure reduction with moxonidine is usually accompanied by a reduction in heart rate which, however, in most studies is of shorter duration and lesser magnitude than the fall in blood pressure. Chronic administration of moxonidine to SHRs with established hypertension causes normalization of myocardial fibrosis, capillarization, and regressive changes in myocytes, in parallel with the reduction of blood pressure. Left ventricular hypertrophy and renal glomerulosclerosis are also significantly reduced. After withdrawal of chronic moxonidine treatment, blood pressure gradually rises to pretreatment values. Direct injection of moxonidine into the vertebral artery of cats elicits a more pronounced fall in blood pressure compared with i.v. injection of an equivalent dose. This observation and others clearly indicate that moxonidine's antihypertensive activity is centrally mediated. The RVLM is the site of action within the CNS that mediates pronounced blood pressure reduction after direct administration of moxonidine into the RVLM of anesthetized SHRs. Selective I1-receptor antagonists introduced into this area abolish the action of systemic moxonidine. Receptor binding studies have shown high and selective affinity of moxonidine for I1-receptors vs. alpha(2)-adrenergic receptors. In vivo studies using a variety of selective I1 or alpha(2)-adrenergic agonists and antagonists have confirmed the primary role of I1-receptors in blood pressure regulation by moxonidine. In addition to lowering blood pressure, moxonidine possesses further properties that appear likely to be relevant in its therapeutic application in the hypertensive syndrome. Moxonidine increases urine flow rate and sodium excretion after central and direct intrarenal administration. It is active against ventricular arrhythmias in a variety of experimental settings. It lacks the respiratory depressant effect attributed to central alpha 2 activation. It exerts beneficial effects on glucose metabolism and blood lipids in genetically hypertensive obese rats. It exhibits anti-ulcer activity. And, finally, moxonidine lowers intraocular pressure, suggesting a possible benefit in glaucoma. Therefore, moxonidine, by its novel mode of action, represents a new therapeutic principle in the treatment of hypertension. Because of its unique profile, moxonidine may prove to be effective in slowing progression of the disease by providing protective effects beyond merely blood pressure reduction. Further studies are needed to verify this potential.
莫索尼定是一种第二代中枢性抗高血压药物，具有独特的作用方式。莫索尼定激活延髓头端腹外侧区（RVLM）的I1-咪唑啉受体（I1-受体），从而降低交感神经系统的活性。在不同的高血压动物模型中，如自发性高血压大鼠、肾性高血压大鼠和肾性高血压犬，莫索尼定可导致显著且持久的血压降低。使用莫索尼定降低血压时，通常会伴有心率降低，然而，在大多数研究中，心率降低的持续时间较短，幅度也小于血压下降幅度。对已患高血压的自发性高血压大鼠长期给予莫索尼定，可使心肌纤维化、毛细血管化以及心肌细胞的退行性变化恢复正常，同时血压降低。左心室肥厚和肾小球硬化也会显著减轻。长期莫索尼定治疗停药后，血压会逐渐回升至治疗前水平。与静脉注射等效剂量相比，将莫索尼定直接注入猫的椎动脉会引起更显著的血压下降。这一观察结果以及其他结果清楚地表明，莫索尼定的抗高血压活性是由中枢介导的。RVLM是中枢神经系统内的作用部位，在将莫索尼定直接注入麻醉的自发性高血压大鼠的RVLM后，可介导显著的血压降低。将选择性I1-受体拮抗剂引入该区域可消除全身性莫索尼定的作用。受体结合研究表明，莫索尼定对I1-受体的亲和力高且具有选择性，而对α2-肾上腺素能受体的亲和力较低。使用多种选择性I1或α2-肾上腺素能激动剂和拮抗剂的体内研究证实了I1-受体在莫索尼定调节血压中的主要作用。除了降低血压外，莫索尼定还具有其他一些特性，这些特性在其治疗高血压综合征的应用中似乎具有相关性。莫索尼定经中枢和直接肾内给药后可增加尿流率和钠排泄。在多种实验环境中，它对室性心律失常有效。它没有因中枢α2激活而产生的呼吸抑制作用。它对遗传性高血压肥胖大鼠的葡萄糖代谢和血脂有有益影响。它具有抗溃疡活性。最后，莫索尼定可降低眼压，提示可能对青光眼有益。因此，莫索尼定通过其新颖的作用方式，代表了治疗高血压的一种新的治疗原则。由于其独特的特性，莫索尼定可能不仅通过降低血压，还通过提供保护作用来有效减缓疾病进展。需要进一步研究来证实这一潜力。
