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

Abstract

BackgroundZofenopril, 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 ResultsZofenopril (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 synthase1177 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.ConclusionsZofenopril‐mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling.

Zofenopril exerts a cardiovascular protective effect on rats infused with angiotensin II beyond angiotensin-converting enzyme inhibition

“…The potential of sulphydryl angiotensin‐converting enzyme inhibitors in scavenging free radical oxygen species has been proposed as a contributing factor to the cardioprotection exerted by this type of compounds . A recent publication examined the effects of zofenopril on cardiac damage in murine and swine models of myocardial ischaemia reperfusion and suggested that zofenopril exerts cardioprotective by increasing nitric oxide and hydrogen sulphide bioavailability . This is consistent with previous results obtained in our laboratory and with the current results where the antihypertensive effect of zofenopril was accompanied by prevention of cardiac remodelling and improvement of redox status.…”

Combined Angiotensin Receptor–Neprilysin Inhibitors Improve Cardiac and Vascular Function Via Increased NO Bioavailability in Heart Failure

“…To further understand how sacubitril/valsartan treatment protects the failing heart, we measured NO bioavailability in circulation and in the myocardium. NO is both a key mediator and marker of endothelial function and a well‐established cardioprotective factor in acute myocardial infarction and HF . We did observe increased circulating nitrite levels, a storage form of NO, in both valsartan‐ and sacubitril/valsartan‐treated animals, which is likely attributable to reduced oxidative stress and reactive oxygen species and perhaps increased generation of NO via eNOS.…”

“…Despite the observed increases in plasma nitrite at 8 weeks after valsartan and sacubitril/valsartan treatment, only sacubitril/valsartan treatment increased myocardial nitrite at 12 weeks after reperfusion (Figure C and D). The increase in NO stores within the myocardium is especially important given the cardioprotective effects NO can exert and the decreases in NO known to occur in HF …”

“…The increase in NO stores within the myocardium is especially important given the cardioprotective effects NO can exert and the decreases in NO known to occur in HF. [35][36][37] Myocardial eNOS gene expression ( Figure 6E) and protein levels ( Figure 6F and 6G) of endogenous NO synthesizing enzymes were unchanged among groups. However, sacubitril/ valsartan therapy increased protein levels of PKG, a downstream effector of NO 34 (Figure 6H and 6I), providing further evidence of increased NO signaling after sacubitril/valsartan treatment in HF.…”

Nitric oxide and hydrogen sulfide: the gasotransmitter paradigm of the vascular system

“…Similarly, Monti and co‐authors have found that S‐zofenoprilat, in a CSE/H 2 S‐mediated manner, abolished all the inflammatory features induced by IL‐1β in human umbilical vein endothelial cells, especially the NF‐κB/COX‐2/prostanoid pathway (Monti et al, ). Again, pretreatment with S‐zofenopril significantly augmented both plasma and myocardial H 2 S and NO levels in mice and plasma H 2 S in pigs, as well as reducing myocardial infarct size and cardiac troponin I levels after I/R injury (Donnarumma et al, ). These findings taken together, suggest that it is indeed feasible to develop H 2 S‐releasing drugs, as therapeutic agents in IBVD.…”