Zofenopril Protects Against Myocardial Ischemia–Reperfusion Injury by Increasing Nitric Oxide and Hydrogen Sulfide Bioavailability

Abstract

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 (H ₂S) bioavailability and nitric oxide ( NO) levels via bradykinin‐dependent signaling. Both H ₂S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H ₂S 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 H ₂S and NO levels were measured along with the levels of H ₂S and NO enzymes (cystathionine β‐synthase, cystathionine γ‐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 H ₂S and NO levels in mice and plasma H ₂S (sulfane sulfur) in pigs. Cystathionine β‐synthase, cystathionine γ‐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 H ₂S and NO signaling.