Baranowska Iwona, Gawrys Olga, Roszkowska-Chojecka Malwina M, Badzynska Bozena, Tymecka Dagmara, Olszynski Krzysztof H, Kompanowska-Jezierska Elzbieta
Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
Faculty of Chemistry, University of Warsaw, Warsaw, Poland.
Front Pharmacol. 2021 May 17;12:658805. doi: 10.3389/fphar.2021.658805. eCollection 2021.
The contribution of chymase, one of the enzymes responsible for angiotensin II generation in non-ACE pathway, remains unclear in the development of hypertension. The aim of the study was to investigate chymase inhibition as potential antihypertensive therapy in spontaneously hypertensive rats (SHR). To block chymase we employed chymostatin, a commercial inhibitor, and new analogues of rapeseed-derived peptides, VWIS and RIY. These simple and easy to obtain peptides not only block chymase, but also possess weak activity to inhibit ACE. This is a first attempt to evaluate the impact of chronic administration of selected inhibitors on blood pressure of SHR in two phases of hypertension. Male SHR (6 or 16 weeks old) were treated daily for two weeks with chymostatin (CH; 2 mg/kg/day), the peptides VWIS (12.5 mg/kg/day) or RIY (7.5 mg/kg/day); control groups received chymostatin solvent (0.15% DMSO in saline) or peptide solvent (saline). The substances were administered intravenously to conscious animals a chronically cannulated femoral vein. Systolic blood pressure (SBP) was measured by telemetry. Metabolic parameters were measured weekly, and tissue samples were harvested after two weeks of treatment. None of the administered chymase inhibitors affected the development of hypertension in young rats. Only RIY exhibited beneficial properties when administered in the established phase of hypertension: SBP decreased from 165 ± 10 to 157 ± 7 mmHg while the excretion of nitric oxide metabolites increased significantly. The glomerulosclerosis index was lower after RIY treatment in both age groups (significant only in young rats 0.29 ± 0.05 vs 0.48 ± 0.04 in the control group; < 0.05). Hence, it seems that peptide RIY exhibits some positive effect on renal morphology. The results obtained suggest that the peptide RIY may be a useful tool in the treatment of hypertension, especially in cases when ACE inhibitors are not effective.
糜酶是在非ACE途径中负责生成血管紧张素II的酶之一，其在高血压发展中的作用仍不清楚。本研究的目的是探讨抑制糜酶作为自发性高血压大鼠（SHR）潜在抗高血压治疗方法的效果。为了阻断糜酶，我们使用了抑肽酶（一种商业抑制剂）以及油菜籽衍生肽的新类似物VWIS和RIY。这些简单且易于获得的肽不仅能阻断糜酶，还具有较弱的抑制ACE的活性。这是首次尝试评估在高血压两个阶段长期给予选定抑制剂对SHR血压的影响。雄性SHR（6周或16周龄）每天用抑肽酶（CH；2mg/kg/天）、肽VWIS（12.5mg/kg/天）或RIY（7.5mg/kg/天）治疗两周；对照组接受抑肽酶溶剂（0.15%二甲基亚砜溶于生理盐水）或肽溶剂（生理盐水）。通过慢性插管的股静脉将这些物质静脉注射给清醒动物。通过遥测测量收缩压（SBP）。每周测量代谢参数，并在治疗两周后采集组织样本。所给予的糜酶抑制剂均未影响幼龄大鼠高血压的发展。仅在高血压已确立阶段给予RIY时显示出有益作用：SBP从165±10降至157±7mmHg，同时一氧化氮代谢产物的排泄显著增加。两个年龄组在RIY治疗后肾小球硬化指数均较低（仅在幼龄大鼠中显著，对照组为0.48±0.04，RIY治疗组为0.29±0.05；P<0.05）。因此，肽RIY似乎对肾脏形态有一些积极影响。所得结果表明，肽RIY可能是治疗高血压的有用工具，尤其是在ACE抑制剂无效的情况下。
