Parkin Monique L, Godwin Shirley J, Head Geoffrey A
Neuropharmacology Laboratory, Baker Heart Research Institute, Commercial Road Prahran, St Kilda Road Central, Melbourne, Victoria 8008, Australia.
J Hypertens. 2003 Jan;21(1):167-78. doi: 10.1097/00004872-200301000-00027.
To determine the involvement of central imidazoline receptors in the cardiovascular actions of the chronically administered antihypertensive agents moxonidine, rilmenidine and clonidine.
In 21 rabbits with implanted fourth-ventricular catheters, we investigated the central effects of three cumulative doses of an I(1)-imidazoline/alpha(2)-adrenoceptor antagonist, efaroxan, and of an alpha(2)-adrenoceptor antagonist, 2-methoxyidazoxan (2-MI), on the changes in blood pressure and heart rate (HR) elicited by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine, after 1 and 3 weeks of treatment. A low, medium and high dose of 2-MI was matched to three doses of efaroxan, such that each produced equal reversal of the hypotension induced by fourth-ventricular alpha-methyldopa and hence produced a similar degree of alpha(2)-adrenoceptor blockade.
Clonidine and moxonidine, at doses of 1 mg/kg per day, and rilmenidine at 5 mg/kg per day, produced sustained reductions in mean arterial pressure of 13 +/- 3, 15 +/- 2 and 13 +/- 2 mmHg, respectively over the 3-week treatment period, but did not alter HR. Central administration of efaroxan on day 9 and day 23 of treatment produced a greater increase in blood pressure than did 2-MI with all three antihypertensive agents. Blood pressure reached levels that were significantly above the original control values. By contrast, the alpha(2)-adrenoceptor antagonist 2-MI only induced a rebound blood pressure effect in clonidine- and to a lesser extent in rilmenidine-treated rabbits. Both efaroxan and 2-MI produced a similar degree of tachycardia in moxonidine-, rilmenidine- and clonidine-treated animals.(2)
The greater effect of efaroxan compared to the alpha(2)-adrenoceptor antagonist 2-MI suggests that the hypotension induced by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine is mediated predominantly via an action on central imidazoline receptors. Furthermore, all agents showed a propensity to produce rebound hypertension with imidazoline receptor blockade. However, only clonidine showed a rebound phenomenon when challenged by acute central alpha(2)-adrenoceptor blockade
确定中枢咪唑啉受体在长期给予的抗高血压药物莫索尼定、利美尼定和可乐定的心血管作用中的参与情况。
在21只植入第四脑室导管的家兔中，我们研究了I(1) -咪唑啉/α(2) -肾上腺素能受体拮抗剂依酚氯铵和α(2) -肾上腺素能受体拮抗剂2 -甲氧基咪唑克生（2 - MI）的三个累积剂量对慢性皮下给予莫索尼定、利美尼定和可乐定1周和3周后引起的血压和心率（HR）变化的中枢效应。将低、中、高剂量的2 - MI与三个剂量的依酚氯铵相匹配，使得每种药物对第四脑室注射α -甲基多巴引起的低血压产生相同程度的逆转，从而产生相似程度的α(2) -肾上腺素能受体阻断。
在为期3周的治疗期间，每天1 mg/kg剂量的可乐定和莫索尼定以及每天5 mg/kg剂量的利美尼定分别使平均动脉压持续降低13±3、15±2和13±2 mmHg，但未改变心率。在治疗的第9天和第23天，中枢给予依酚氯铵比给予2 - MI时，三种抗高血压药物引起的血压升高幅度更大。血压达到显著高于原始对照值的水平。相比之下，α(2) -肾上腺素能受体拮抗剂2 - MI仅在可乐定治疗的家兔中诱导血压反跳效应，在利美尼定治疗的家兔中程度较轻。依酚氯铵和2 - MI在莫索尼定、利美尼定和可乐定治疗的动物中产生的心动过速程度相似。
与α(2) -肾上腺素能受体拮抗剂2 - MI相比，依酚氯铵的作用更强，这表明慢性皮下给予莫索尼定、利美尼定和可乐定引起的低血压主要是通过对中枢咪唑啉受体的作用介导的。此外，所有药物在咪唑啉受体阻断时都有产生反跳性高血压的倾向。然而，只有可乐定在受到急性中枢α(2) -肾上腺素能受体阻断挑战时出现反跳现象
