Effects of Zofenopril on Cardiac Sarcoplasmic Reticulum Calcium Handling

Frascarelli, Sabina; Carnicelli, Vittoria; Ghelardoni, Sandra; Chiellini, Grazia; Ronca, Francesca; Zucchi, Riccardo

doi:10.1097/fjc.0b013e3181be7597

Cited by 3 publications

(3 citation statements)

References 35 publications

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“…Another study, in which zofenopril effect on recovery of contractile function after a short period of ischemia in dogs was compared with a non–sulfhydryl‐containing ACEI, enalaprilat, revealed that enalaprilat attenuates postischemic dysfunction, at least in part by a prostaglandin‐mediated signaling, whereas beneficial effects of zofenopril are mainly associated to the antioxidant properties of its sulfhydryl moiety and preservation of protein thiols at the end of ischemia . However, it has also been reported that zofenopril stimulates active calcium uptake through sarcoplasmic reticulum cycling in the cardiomyocytes, which could account for improvements in myocardial contractility after I/R . In addition, improvement of postischemic LV function, increase in coronary blood flow, reduction of myocardial cell injury, creatine kinase release, lipid peroxidation and myocardial norepinephrine release all account for zofenopril‐mediated cardioprotection.…”

Section: Discussionmentioning

confidence: 99%

“…69 However, it has also been reported that zofenopril stimulates active calcium uptake through sarcoplasmic reticulum cycling in the cardiomyocytes, which could account for improvements in myocardial contractility after I/R. 70 In addition, improvement of postischemic LV function, increase in coronary blood flow, reduction of myocardial cell injury, creatine kinase release, lipid peroxidation, 71 and myocardial norepinephrine release 72 all account for zofenopril-mediated cardioprotection. Last but not least, it has also been demonstrated in a swine model of I/R that 2 days of zofenopril pretreatment significantly reduces the pressure-rate product, an index of myocardial oxygen demand, and decreases the peak efflux of epinephrine, norepinephrine, and adenosine catabolites in the coronary venous effluent.…”

Section: Discussionmentioning

confidence: 99%

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

Donnarumma

Ali

Rushing

et al. 2016

JAHA

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Donnarumma

Ali

Rushing

et al. 2016

JAHA

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“…ZOFE, due to its high lipophilicity, could potentially easily penetrate cardiac tissue and exert its antiremodeling effect regarding attenuation of LV hypertrophy, fibrosis, and LV functional improvement in SHR [27,42,43]. ZOFE was also reported to stimulate active Ca 2+ uptake via the sarcoplasmic reticulum cycle in cardiomyocytes, which could account for the improvement in myocardial contractility after ischemia-reperfusion damage [44] and improvement of diastolic relaxation in our experiment. Nevertheless, Donnarumma et al [45] confirmed that ZOFE-mediated cardioprotection in murine and swine models of myocardial ischemia/ reperfusion injury was associated with an increase in H 2 S levels, and Bucci et al [15] confirmed that the release of H 2 S from zofenopril, an active metabolite of S-zofenopril, represented an additional beneficial mechanism unrelated to ACE inhibition.…”

Section: Discussionmentioning

confidence: 52%

The effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats treated with the ACE2 inhibitor MLN-4760

Cacanyiova,

Cebova,

Simko

et al. 2023

Biol Res

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Background Angiotensin converting enzyme 2 (ACE2) plays a crucial role in the infection cycle of SARS-CoV-2 responsible for formation of COVID-19 pandemic. In the cardiovascular system, the virus enters the cells by binding to the transmembrane form of ACE2 causing detrimental effects especially in individuals with developed hypertension or heart disease. Zofenopril, a H2S-releasing angiotensin-converting enzyme inhibitor (ACEI), has been shown to be effective in the treatment of patients with essential hypertension; however, in conditions of ACE2 inhibition its potential beneficial effect has not been investigated yet. Therefore, the aim of the study was to determine the effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats, an animal model of human essential hypertension and heart failure, under conditions of ACE2 inhibition induced by the administration of the specific inhibitor MLN-4760 (MLN). Results Zofenopril reduced MLN-increased visceral fat to body weight ratio although no changes in systolic blood pressure were recorded. Zofenopril administration resulted in a favorable increase in left ventricle ejection fraction and improvement of diastolic function regardless of ACE2 inhibition, which was associated with increased H2S levels in plasma and heart tissue. Similarly, the acute hypotensive responses induced by acetylcholine, L-NAME (NOsynthase inhibitor) and captopril (ACEI) were comparable after zofenopril administration independently from ACE2 inhibition. Although simultaneous treatment with zofenopril and MLN led to increased thoracic aorta vasorelaxation, zofenopril increased the NO component equally regardless of MLN treatment, which was associated with increased NO-synthase activity in aorta and left ventricle. Moreover, unlike in control rats, the endogenous H2S participated in maintaining of aortic endothelial function in MLN-treated rats and the treatment with zofenopril had no impact on this effect. Conclusions Zofenopril treatment reduced MLN-induced adiposity and improved cardiac function regardless of ACE2 inhibition. Although the concomitant MLN and zofenopril treatment increased thoracic aorta vasorelaxation capacity, zofenopril increased the participation of H2S and NO in the maintenance of endothelial function independently from ACE2 inhibition. Our results confirmed that the beneficial effects of zofenopril were not affected by ACE2 inhibition, moreover, we assume that ACE2 inhibition itself can lead to the activation of cardiovascular compensatory mechanisms associated with Mas receptor, nitrous and sulfide signaling.

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Effect of acute and chronic zofenopril administration on cardiac gene expression

2011

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We investigated whether acute and chronic administration of zofenopril, an angiotensin converting enzyme inhibitor, may modulate the expression of genes which are involved in the pathophysiology of myocardial ischemia and heart failure. We used an acute and a chronic model. In the former isolated rat hearts were perfused for 120 min in the presence or in the absence of 10 μM zofenoprilat, the active metabolite of zofenopril. In the chronic model one group of rats was treated with zofenopril (15.2 mg/Kg die per os) for 15 days, while control rats were treated with the same diet, except that zofenopril was omitted. Total RNA was extracted from hearts, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to evaluate the expression of α myosin heavy chain, superoxide dismutase, heat shock protein 70 (HSP70), nitric oxide synthase 2 and 3 (NOS2, NOS3), heme oxygenase 1, atrial natriuretic peptide (ANP), muscle phosphofructokinase. Acute or chronic zofenopril administration did not produce any change in hemodynamic variables. qRT-PCR experiments showed that in the acute model ANP expression was slightly although not significantly increased. In the chronic model, significant changes in gene expression were detected: in particular, HSP70 was upregulated (1.06 ± 0.38 vs. 0.72 ± 0.20 arbitrary units, P = 0.025), while NOS3 was downregulated (0.66 ± 0.06 vs. 0.83 ± 0.18 arbitrary units, P = 0.007). In the chronic model, liver samples were also assayed, but no significant change in the expression of any gene was detected. We conclude that zofenopril can produce heart-specific effects on gene expression. Persistent changes were detected with regard to specific heat shock protein and nitric oxide synthase subtypes. This action might contribute to the therapeutical response, and particularly to the increased resistance to ischemia.

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Effects of Zofenopril on Cardiac Sarcoplasmic Reticulum Calcium Handling

Cited by 3 publications

References 35 publications

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

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

The effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats treated with the ACE2 inhibitor MLN-4760

Effect of acute and chronic zofenopril administration on cardiac gene expression

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