Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands.
Hypertens Res. 2017 Aug;40(8):738-745. doi: 10.1038/hr.2017.38. Epub 2017 Mar 16.
Endothelin 1 (ET-1), a potent vasoconstrictor, pro-mitogenic and pro-inflammatory peptide, may promote development of endothelial dysfunction and arterial remodeling. ET-1 can be formed through cleavage of big-ET-1 by endothelin-converting enzyme (ECE) or neutral endopeptidase (NEP). We investigated whether chronic treatment with the novel dual NEP/ECE inhibitor SOL1 improves functional and structural properties of resistance-sized arteries of 32-week-old male spontaneously hypertensive rats (SHR). SHR received a chronic 4-week treatment with SOL1, losartan or hydralazine. We then compared effects of inhibition of NO synthase (NOS) (100 μM l-NAME), blockade of ET- and ET-receptors (10 μM bosentan) and stimulation of the endothelium with 0.001-10 μM acetylcholine (ACh) in isolated third-order mesenteric resistance arteries. Losartan and hydralazine significantly lowered blood pressure. Losartan decreased the media-to-lumen ratio of resistance arteries. l-NAME (1) increased arterial contractile responses to K (5.9-40 mM) in the losartan, SOL1 and vehicle group and (2) increased the sensitivity to phenylephrine (PHE; 0.16-20 μM) in the SOL1 group but not in the losartan, hydralazine and vehicle group. Relaxing responses to ACh in the absence or presence of l-NAME during contractions induced by either 10 μM PHE or 40 mM K were not altered by any in vivo treatment. Acute treatment with bosentan did, however, significantly improve maximal relaxing responses involving endothelium-derived nitric oxide and -hyperpolarizing factors in the SOL1 group but not in the losartan, hydralazine or vehicle group. Thus, chronic inhibition of NEP/ECE improved basal endothelial function but did not alter blood pressure, resistance artery structure and stimulated endothelium-dependent relaxing responses in 32-week-old SHR.
内皮素 1（ET-1）是一种强效的血管收缩肽，具有促有丝分裂和促炎作用，可能促进内皮功能障碍和动脉重塑的发展。ET-1 可通过内皮素转换酶（ECE）或中性内肽酶（NEP）切割 big-ET-1 形成。我们研究了新型双重 NEP/ECE 抑制剂 SOL1 慢性治疗是否改善 32 周龄雄性自发性高血压大鼠（SHR）阻力型动脉的功能和结构特性。SHR 接受 SOL1、氯沙坦或肼屈嗪的慢性 4 周治疗。然后，我们比较了抑制一氧化氮合酶（NOS）（100μM l-NAME）、阻断内皮素和内皮素受体（10μM bosentan）以及用 0.001-10μM 乙酰胆碱（ACh）刺激内皮对分离的第三级肠系膜阻力动脉的影响。氯沙坦和肼屈嗪显著降低血压。氯沙坦降低了阻力动脉的中膜与内腔比。l-NAME（1）增加了洛沙坦、SOL1 和载体组中动脉对 K（5.9-40mM）的收缩反应，（2）增加了 SOL1 组对苯肾上腺素（PHE；0.16-20μM）的敏感性，但洛沙坦、肼屈嗪和载体组则没有。在由 10μM PHE 或 40mM K 诱导的收缩期间，在不存在或存在 l-NAME 的情况下，ACh 的舒张反应不受任何体内治疗的影响。然而，急性给予 bosentan 确实显著改善了 SOL1 组涉及内皮衍生的一氧化氮和 -超极化因子的最大舒张反应，但洛沙坦、肼屈嗪或载体组则没有。因此，慢性抑制 NEP/ECE 改善了基础内皮功能，但未改变 32 周龄 SHR 的血压、阻力动脉结构和刺激内皮依赖性舒张反应。
