Discovery of vasodilatory effects of Na+/H+ exchanger 1 inhibitors to treat vasospastic angina
Xue-fei Dong1,2,3,4,5,
Xue-jiao Jing1,2,3,6,
Zhen-yu Tang7,
Sheng-lan Huang1,2,3,
Jia-ze Yin1,2,3,
Yuan Chen1,2,3,
Tao Guo1,2,3,
Bo Dong5,
Bin Li8,
Peng Li9,
Shuang-xi Wang1,2,3,9,
Wen-wu Bai1,2,3,10
1 State Key Laboratory for Innovation and Transformation of Luobing Theory
2 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences
3 Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China
4 Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
5 Department of Cardiology, Emergency Department, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
6 Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan 250012, China
7 Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan 250012, China
8 Department of Cardiology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, China
9 College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, Xinxiang 453003, China
10 Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan 250012, China
Correspondence to: Shuang-xi Wang: shuangxiwang@sdu.edu.cn, Wen-wu Bai: baiwenwu@sdu.edu.cn,
DOI: 10.1038/s41401-025-01734-0
Received: 6 August 2025
Accepted: 8 December 2025
Advance online: 20 February 2026
Abstract
The best way of treating vasospastic angina pharmacologically is to induce vasorelaxation under hypoxia only. We previously established a new method to quantify the contraction and relaxation of vascular smooth muscle cells (VSMCs) in real time. In the present study, we used this method to screen the effects of chemicals on VSMC dilation under normoxia, and we chose the chemicals with negative results as candidates. Next, we tested the effects of the candidates on VSMC dilation under hypoxia, and we found that cariporide and empagliflozin induced VSMC relaxation under hypoxia but not normoxia. Their effects on hypoxic VSMC relaxation were further confirmed in isolated carotid arteries. We demonstrated that treatment with cariporide (10 μM) or empagliflozin (5 μM) potently inhibited Na+/H+ exchanger 1, causing intracellular H+ accumulation that activated AMPK in VSMCs under hypoxia but not normoxia. KEGG analysis revealed that cariporide upregulated signaling related to AMPK, pH regulation, and Ca2+-linked proteins in VSMCs under hypoxia. In a swine model of vasopressin-induced coronary artery spasm, intravenous injection of cariporide or empagliflozin significantly increased coronary blood flow, limited infarct size, and improved heart function, and the protective effects on ischemic hearts were much stronger than those of the currently used vasodilator nifedipine. In conclusion, a novel approach was developed to screen vasodilators that function well under hypoxia but not normoxia. Using this approach, two Na+/H+ exchanger 1 inhibitors, namely, cariporide and empagliflozin, were identified to treat vasospastic angina as new coronary vasodilators.
