期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 5, 期 7, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.116.003531
关键词
antihypertensive agent; hydrogen sulfide; myocardial ischemia; nitric oxide; oxidant stress; troponin
资金
- Menarini Industrie Farmaceutiche Riunite grant
- National Heart, Lung, and Blood Institute (National Institutes of Health) [1R01 HL092141, 1R01 HL093579, 1U24 HL 094373, 1P20 HL113452]
- Ochsner Translational Medical Research Institute Grant
- Louisiana State University Medical School Alumni Association
Background-Zofenopril, a sulfhydrylated angiotensin-converting enzyme inhibitor (ACEI), reduces mortality and morbidity in infarcted patients to a greater extent than do other ACEIs. Zofenopril is a unique ACEI that has been shown to increase hydrogen sulfide (H2S) bioavailability and nitric oxide (NO) levels via bradykinin-dependent signaling. Both H2S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H2S and NO bioavailability and cardiac damage in murine and swine models of myocardial ischemia/reperfusion (I/R) injury. Methods and Results-Zofenopril (10 mg/kg PO) was administered for 1, 8, and 24 hours to establish optimal dosing in mice. Myocardial and plasma H2S and NO levels were measured along with the levels of H2S and NO enzymes (cystathionine beta-synthase, cystathionine gamma-lyase, 3-mercaptopyruvate sulfur transferase, and endothelial nitric oxide synthase). Mice received 8 hours of zofenopril or vehicle pretreatment followed by 45 minutes of ischemia and 24 hours of reperfusion. Pigs received placebo or zofenopril (30 mg/daily orally) 7 days before 75 minutes of ischemia and 48 hours of reperfusion. Zofenopril significantly augmented both plasma and myocardial H2S and NO levels in mice and plasma H2S (sulfane sulfur) in pigs. Cystathionine b-synthase, cystathionine gamma-lyase, 3-mercaptopyruvate sulfur transferase, and total endothelial nitric oxide synthase levels were unaltered, while phospho-endothelial nitric oxide synthase(1177) was significantly increased in mice. Pretreatment with zofenopril significantly reduced myocardial infarct size and cardiac troponin I levels after I/R injury in both mice and swine. Zofenopril also significantly preserved ischemic zone endocardial blood flow at reperfusion in pigs after I/R. Conclusions-Zofenopril-mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling.
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