Department of Pharmacology, Maastricht University, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
J Hypertens. 2012 Sep;30(9):1799-808. doi: 10.1097/HJH.0b013e3283569c7a.
Endothelin-1 (ET1) is a potent vasoconstrictor peptide with pro-mitogenic and pro-inflammatory properties and is therefore of interest in the development of endothelial dysfunction, endothelium-dependent flow-related remodeling, and hypertension-related remodeling. ET1 can be formed through cleavage of big ET1 by endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP).
We investigated whether the dual NEP/ECE inhibitor SOL1 improves resistance artery function and structure in 12 weeks old spontaneously hypertensive rats (SHRs) and whether arterial structural responses to decreased (-90%) or increased (+100%) blood flow are impaired in young SHRs. To this end two groups of SHRs received chronic 4-week treatment at two different time points (4-8 and 8-12 weeks) prior to the experiment. We compared in-vitro effects of cyclo-oxygenase inhibition (1 μmol/l indomethacine), nitric oxide synthase inhibition (100 μmol/l N(ω)-L-nitro arginine methyl ester), and stimulation of the endothelium by 0.001-10 μmol/l acetylcholine (ACh) in isolated third-order mesenteric arteries of SHRs and aged-matched Wistar-Kyoto (WKY) rats.
SOL1 had no effect on blood pressure in SHRs or WKY rats. ACh caused biphasic effects in mesenteric arteries of SHRs. The contractile component (endothelium-derived contractile factor) was absent in WKY and abolished by acute indomethacin administration or chronic SOL1 treatment. Endothelium-derived nitric oxide-type responses did not differ in both strains and were not influenced by SOL1 treatment. Endothelium-derived hyperpolarizing factor-type responses were severely impaired in SHRs as compared to WKY rats and were normalized by chronic SOL1 treatment. In first-order mesenteric arteries, outward flow-induced remodeling was impaired in SHRs. Chronic SOL1 treatment did not restore this response.
Thus chronic SOL1 treatment during the development of hypertension in SHRs has no effect on blood pressure but improves several aspects of endothelium-dependent vasomotor responses but not arterial remodeling.
内皮素-1（ET1）是一种有效的血管收缩肽，具有促有丝分裂和促炎作用，因此对内皮功能障碍、内皮依赖性血流相关重塑和高血压相关重塑的发展具有重要意义。ET1 可以通过内皮素转换酶（ECE）和中性内肽酶（NEP）对大 ET1 的裂解而形成。
我们研究了双重 NEP/ECE 抑制剂 SOL1 是否能改善 12 周龄自发性高血压大鼠（SHR）的阻力动脉功能和结构，以及年轻 SHR 对降低（-90%）或增加（+100%）血流的动脉结构反应是否受损。为此，我们在实验前，在两个不同的时间点（4-8 周和 8-12 周）对两组 SHR 进行了为期 4 周的慢性治疗。我们比较了 SHR 分离的第三级肠系膜动脉中 COX 抑制（1μmol/l 吲哚美辛）、NOS 抑制（100μmol/l N（ω）-L-硝基精氨酸甲酯）和 0.001-10μmol/l 乙酰胆碱（ACh）刺激内皮的体外效应，以及年龄匹配的 Wistar-Kyoto（WKY）大鼠。
SOL1 对 SHR 或 WKY 大鼠的血压没有影响。ACh 在 SHR 的肠系膜动脉中引起双相作用。WKY 大鼠的收缩成分（内皮衍生的收缩因子）缺失，并用急性吲哚美辛给药或慢性 SOL1 处理消除。两种菌株的内皮衍生的一氧化氮型反应没有差异，也不受 SOL1 处理的影响。与 WKY 大鼠相比，SHR 的内皮衍生的超极化因子型反应严重受损，经慢性 SOL1 治疗后得到纠正。在一级肠系膜动脉中，外向流诱导的重塑在 SHR 中受损。慢性 SOL1 治疗不能恢复这种反应。
因此，在 SHR 高血压发展过程中，慢性 SOL1 治疗对血压没有影响，但改善了几种内皮依赖性血管舒缩反应，但不能改善动脉重塑。
