Arnoux Alizée, Aubertin Gaëlle, Da Silva Sylvia, Weiss Maud, Bousquet Pascal, Monassier Laurent, Niederhoffer Nathalie
Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire-UR7296, CRBS, Faculté de Médecine, Université de Strasbourg, France .
J Cardiovasc Pharmacol. 2022 Feb 1;79(2):229-234. doi: 10.1097/FJC.0000000000001128.
Imidazoline receptor antisera selected/Nischarin was proposed several years ago as the functional entity for the I1 medullary receptors (I1Rs) targeted, together with α2-adrenoceptors, by the centrally acting antihypertensive drugs, such as clonidine. The objective of this study was to test this assumption using a pyrroline analog of clonidine, LNP599, which, unlike clonidine and related compounds, displays high selectivity toward I1Rs. Cardiovascular effects of LNP599 (3 mg/kg intravenous) were evaluated in anesthetized, artificially ventilated nischarin mutant rats expressing a truncated form of nischarin lacking the putative imidazoline binding site. LNP599 induced a rapid and pronounced fall in arterial blood pressure in wild-type animals (-42.7% ± 11.0% after 15 minutes), associated with a ≈30% heart rate reduction. Similar effects were obtained in homozygous and heterozygous nischarin mutant rats. The observation that the hypotensive response to I1R activation is not affected by the absence of the putative imidazoline binding site on nischarin strongly suggests that nischarin cannot be regarded as the functional I1R. Carbohydrate regulation was improved in nischarin mutant rats, further supporting the conclusion that nischarin and I1R are 2 distinct molecular entities.
几年前有人提出，咪唑啉受体抗血清/尼沙林是中枢性降压药（如可乐定）靶向的I1髓质受体（I1Rs）的功能实体，这些药物还靶向α2肾上腺素能受体。本研究的目的是使用可乐定的脯氨酸类似物LNP599来验证这一假设，与可乐定及相关化合物不同，LNP599对I1Rs具有高选择性。在麻醉、人工通气的表达截短形式尼沙林（缺乏假定的咪唑啉结合位点）的尼沙林突变大鼠中评估了LNP599（3mg/kg静脉注射）的心血管效应。LNP599使野生型动物的动脉血压迅速且显著下降（15分钟后下降42.7%±11.0%），同时心率降低约30%。在纯合和杂合尼沙林突变大鼠中也获得了类似的效果。对I1R激活的降压反应不受尼沙林上假定的咪唑啉结合位点缺失影响这一观察结果强烈表明，尼沙林不能被视为功能性I1R。尼沙林突变大鼠的碳水化合物调节得到改善，进一步支持了尼沙林和I1R是两个不同分子实体的结论。
