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 mu M) or empagliflozin (5 mu M) 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.
[1]Shandong Univ, Chinese Minist Educ,Chinese Nat Hlth Commiss, Key Lab Cardiovasc Remodeling & Func Res, State Key Lab Innovat & Transformat Luobing Theory, Jinan 250012, Peoples R China.
[2]Shandong Univ, Chinese Acad Med Sci, Qilu Hosp, Dept Cardiol, Jinan 250012, Peoples R China.
[3]Cardiff Univ, Sch Med, Heath Pk, Cardiff CF14 4XN, Wales.
[4]Shandong First Med Univ, Dept Cardiol, Emergency Dept, Shandong Prov Hosp, Jinan 250021, Peoples R China.
[5]Shandong Univ, Dept Geriatr Med, Qilu Hosp, Jinan 250012, Peoples R China.
[6]Shandong Univ, Dept Crit Care Med, Qilu Hosp, Jinan 250012, Peoples R China.
[7]Shandong First Med Univ, Dept Cardiol, Cent Hosp, Jinan 250013, Peoples R China.
[8]Xinxiang Med Univ, Coll Pharm, Henan Int Joint Lab Cardiovasc Remodeling & Drug, Xinxiang Key Lab Vasc Remodeling Intervent & Mol, Xinxiang 453003, Peoples R China.
[9]Shandong Univ, Dept Tradit Chinese Med, Qilu Hosp, Jinan 250012, Peoples R China.
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