Haxhiu M A, Dreshaj I, Schäfer S G, Ernsberger P
Department of Medicine and Neuroscience, Case Western Reserve University, Cleveland, Ohio 44106.
J Cardiovasc Pharmacol. 1994;24 Suppl 1:S1-8. doi: 10.1097/00005344-199424001-00002.
The rostral ventrolateral medulla (RVLM) is the primary region maintaining vasomotor tone, and a site of action for central antihypertensive agents. In vitro [125I]p-iodoclonidine binding studies showed that moxonidine was selective for I1-imidazoline over alpha 2-adrenergic receptors in the RVLM. We identified efaroxan and SK&F 86466 as selective I1- and alpha 2-antagonists, respectively. We tested moxonidine's action within the RVLM of spontaneously hypertensive rats (SHRs) on I1-imidazoline or alpha 2-adrenergic receptors, and determined whether the RVLM mediates the action of systemic moxonidine. SHRs were anesthetized, paralyzed, and ventilated and the RVLM was localized by testing for a pressor response to 2 nmol glutamate. To test whether I1 or alpha 2 mediates hypotensive effects of moxonidine, the I1/alpha 2 antagonist efaroxan (4 nmol) or the alpha 2-blocker SK&F 86466 (10 nmol) was administered 15 min before 4 nmol moxonidine. Efaroxan elevated blood pressure and abolished the action of moxonidine, whereas alpha 2-blockade with SK&F 86466 slightly lowered blood pressure and only partially attenuated moxonidine's effect. The depressor effect of intravenous moxonidine (40 micrograms/kg) was reversed within 10 min by microinjection of 10 nmol efaroxan into the RVLM. Prior bilateral microinjections of efaroxan (10 nmol in 80 nl/site) into the RVLM prevented the hypotensive action of moxonidine given i.v. (40 micrograms/kg). Pharmacokinetic studies showed that at the peak vasodepressor response (8 min post-injection), [3H]moxonidine spread less than 1 mm from the injection site. Moxonidine is a centrally acting antihypertensive with a selective action on I1-imidazoline receptors in RVLM.
延髓头端腹外侧区（RVLM）是维持血管运动张力的主要区域，也是中枢性抗高血压药物的作用部位。体外[125I]对碘氯苯胍结合研究表明，莫索尼定对RVLM中I1-咪唑啉受体的选择性高于α2-肾上腺素能受体。我们分别确定依酚氯铵和SK&F 86466为选择性I1-和α2-拮抗剂。我们测试了莫索尼定在自发性高血压大鼠（SHR）的RVLM内对I1-咪唑啉或α2-肾上腺素能受体的作用，并确定RVLM是否介导全身给予莫索尼定的作用。将SHR麻醉、麻痹并进行通气，通过测试对2 nmol谷氨酸的升压反应来定位RVLM。为了测试I1或α2是否介导莫索尼定的降压作用，在给予4 nmol莫索尼定前15分钟给予I1/α2拮抗剂依酚氯铵（4 nmol）或α2-阻滞剂SK&F 86466（10 nmol）。依酚氯铵使血压升高并消除了莫索尼定的作用，而用SK&F 86466进行α2-阻断则使血压略有降低，且仅部分减弱了莫索尼定的作用。通过向RVLM内微量注射10 nmol依酚氯铵，静脉注射莫索尼定（40微克/千克）的降压作用在10分钟内被逆转。事先向RVLM内双侧微量注射依酚氯铵（80纳升/部位，10 nmol）可防止静脉注射（40微克/千克）莫索尼定的降压作用。药代动力学研究表明，在血管舒张降压反应峰值（注射后8分钟）时，[3H]莫索尼定从注射部位扩散的距离小于1毫米。莫索尼定是一种中枢性抗高血压药物，对RVLM中的I1-咪唑啉受体具有选择性作用。
