Brochu I, Houde M, Desbiens L, Simard E, Gobeil F, Semaan W, Bkaily G, D'Orléans-Juste P
Department of Pharmacology, Medical School, Université de Sherbrooke, Sherbrooke, QC, Canada.
Br J Pharmacol. 2013 Sep;170(2):266-77. doi: 10.1111/bph.12259.
The contribution of endothelin-1 (ET-1) in a B2KO mouse model of a high salt-induced arterial hypertension was investigated.
Wild-type (WT) or B2KO mice receiving a normal diet (ND) or a high-salt diet (HSD) were monitored by radiotelemetry up to a maximum of 18 weeks. At the 12th week of diet, subgroups under ND or HSD received by gavage the ETA antagonist A127722 during 5 days. In addition, blood samples were collected and, following euthanasia, the lungs, heart and kidneys were extracted, homogenized and assayed for ET-1 by RIA. In a separate series of experiments, the ETA antagonist, BQ123 was tested against the pressor responses to a NOS inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) in anaesthetized WT and B2KO mice.
In B2KO, but not WT mice, 12 weeks of HSD triggered a maximal increase of the mean arterial pressure (MAP) of 19.1 ± 2.8 mmHg, which was corrected by A127722 to MAP levels found in B2KO mice under ND. Significant increases in immunoreactive ET-1 were detected only in the lungs of B2KO mice under HSD. On the other hand, metabolic studies showed that sodium urinary excretion was markedly reduced in B2KO compared with WT mice under ND. Finally, BQ123 (2 mg·kg(-1)) reduced by 50% the pressor response to L-NAME (2 mg·kg(-1)) in B2KO, but not WT mice under anaesthesia.
Our results support the concept that functional B2 receptors oppose high salt-induced increments in MAP, which are corrected by an ETA receptor antagonist in this mouse model of experimental hypertension.
研究内皮素-1（ET-1）在高盐诱导的动脉高血压B2KO小鼠模型中的作用。
通过无线电遥测技术对接受正常饮食（ND）或高盐饮食（HSD）的野生型（WT）或B2KO小鼠进行长达18周的监测。在饮食第12周时，ND或HSD组的亚组小鼠通过灌胃给予ETA拮抗剂A127722，持续5天。此外，采集血样，在安乐死后，取出肺、心脏和肾脏，匀浆并通过放射免疫分析法测定ET-1。在另一系列实验中，在麻醉的WT和B2KO小鼠中测试ETA拮抗剂BQ123对一氧化氮合酶抑制剂L-N(G)-硝基精氨酸甲酯（L-NAME）升压反应的影响。
在B2KO小鼠而非WT小鼠中，12周的HSD引发平均动脉压（MAP）最大升高19.1±2.8 mmHg，A127722将其校正至ND条件下B2KO小鼠的MAP水平。仅在HSD条件下的B2KO小鼠肺中检测到免疫反应性ET-1显著增加。另一方面，代谢研究表明，与ND条件下的WT小鼠相比，B2KO小鼠的尿钠排泄明显减少。最后，BQ123（剂量为2 mg·kg(-1)）使麻醉状态下B2KO小鼠而非WT小鼠对L-NAME（剂量为2 mg·kg(-1)）的升压反应降低50%。
我们的结果支持以下观点，即功能性B2受体可对抗高盐诱导的MAP升高，在该实验性高血压小鼠模型中，ETA受体拮抗剂可纠正这种升高。
