Tehrani Arash Y, Zhao Roy, Donen Graham, Bernatchez Pascal
Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada; Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada.
Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada; Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada.
Nitric Oxide. 2023 Feb 1;131:18-25. doi: 10.1016/j.niox.2022.12.002. Epub 2022 Dec 21.
Low basal nitric oxide (NO) production is associated with a dysfunctional endothelium and vascular diseases. We have shown that some angiotensin II (AngII) receptor type 1 (AT1R) blockers (ARBs), a group of clinic-approved blood pressure (BP)-lowering medications, are also capable of activating endothelial function acutely and chronically, both ex vivo and in vivo, in pleiotropic, AngII-independent fashions, which suggested that endothelial function enhancement with ARBs may be independent of their well-documented BP lowering properties. Herein, we attempt to identify the most potent ARB at activating endothelial function when administered at sub-BP-lowering doses and determine its anti-aortic root remodeling properties in a model of Marfan syndrome (MFS). Amongst the 8 clinically available ARBs tested, only telmisartan and azilsartan induced significant (70% and 49%, respectively) NO-dependent inhibition of aortic contractility when administered for 4 weeks at sub-BP lowering, EC doses. Low-dose telmisartan (0.47 mg/kg) attenuated MFS-associated aortic root widening, medial thickening, and elastic fiber fragmentation to the same degree as high-dose telmisartan (10 mg/kg) despite wide differences in BP lowering between the two doses. Our study suggests that telmisartan is the most potent ARB at promoting increased endothelial function at low sub-BP doses and that it retained major aortic root widening inhibition activities. ARBs may enhance endothelial function independently from BP-lowering pathways, which could lead to new therapeutic approaches.
基础一氧化氮（NO）生成量低与内皮功能障碍和血管疾病相关。我们已经表明，一些血管紧张素II（AngII）1型受体（AT1R）阻滞剂（ARBs），一类临床批准的降压药物，也能够在体外和体内以多效性、不依赖AngII的方式急性和慢性地激活内皮功能，这表明ARBs增强内皮功能可能与其广为人知的降压特性无关。在此，我们试图确定在给予低于降压剂量时激活内皮功能最有效的ARB，并在马凡综合征（MFS）模型中确定其抗主动脉根部重塑特性。在所测试的8种临床可用ARBs中，仅替米沙坦和阿齐沙坦在低于降压的有效浓度（EC）剂量下给药4周时，能诱导显著的（分别为70%和49%）依赖NO的主动脉收缩抑制。低剂量替米沙坦（0.47mg/kg）减轻MFS相关的主动脉根部增宽、中层增厚和弹性纤维断裂的程度与高剂量替米沙坦（10mg/kg）相同，尽管两剂量之间的降压幅度差异很大。我们的研究表明，替米沙坦是在低于降压剂量时促进内皮功能增强最有效的ARB，并且它保留了主要的主动脉根部增宽抑制活性。ARBs可能独立于降压途径增强内皮功能，这可能会带来新的治疗方法。
