title: Zofenopril Protects Against Myocardial Ischemia-Reperfusion Injury by Increasing Nitric Oxide and Hydrogen Sulfide Bioavailability.
abstract: 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.
  
  
  
  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 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 H2S and NO levels in mice and plasma H2S (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.
  
  
  
  Zofenopril-mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling.
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Erminia
authors.initials: E
authors.lastname: Donnarumma
authors.affiliation: Department of Cardiology, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Murtuza J
authors.initials: MJ
authors.lastname: Ali
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Rushing
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Scarborough
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Bradley
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Chelsea L
authors.initials: CL
authors.lastname: Organ
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Kazi N
authors.initials: KN
authors.lastname: Islam
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Polhemus
authors.affiliation: Menarini Ricerche S.p.a., Preclinical Development, Florence, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Evangelista
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.affiliation: Ochsner Medical Center, New Orleans, LA.
authors.forename: J Stephen
authors.initials: JS
authors.lastname: Jenkins
authors.affiliation: Ochsner Medical Center, New Orleans, LA.
authors.forename: Rajan A G
authors.initials: RA
authors.lastname: Patel
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA tgoodc@lsuhsc.edu.
authors.forename: Traci T
authors.initials: TT
authors.lastname: Goodchild
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001682:Biological Availability; D015153:Blotting, Western; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology; D003541:Cystathionine beta-Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology; D011897:Random Allocation; D012039:Regional Blood Flow; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013466:Sulfurtransferases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D019210:Troponin I / Q000187:drug effects / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D019210:Troponin I; C044958:zofenopril; D009569:Nitric Oxide; D002216:Captopril; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D013466:Sulfurtransferases; C021550:3-mercaptopyruvate sulphurtransferase; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D017257:Ramipril; D006862:Hydrogen Sulfide
keywords: antihypertensive agent; hydrogen sulfide; myocardial ischemia; nitric oxide; oxidant stress; troponin