The effects of oral pretreatment with zofenopril, an angiotensin-converting enzyme inhibitor, on early reperfusion and subsequent electrophysiologic stability in the pig

Tio, René A.; Langen, C. D. J. de; Graeff, Pieter A. de; Gilst, Wiek H. van; Bel, Kj; Wolters, K.; Mook, Ph; Wijngaarden, Jan van; Wesseling, H

doi:10.1007/bf01856557

Cited by 30 publications

(10 citation statements)

References 28 publications

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“…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. 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 . Therefore, zofenopril clearly exerts a number of beneficial effects beyond ACE inhibition whose precise mechanisms remain still under investigation.…”

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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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%

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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“…32,33 Furthermore, reperfusion of the acutely infarcted area (as obtained experimentally by removal of a coronary ligature and clinically by thrombolytic agents) produces a surge in reactive oxygen species, causing tissue damage beyond that inflicted by ischaemia 34 and partially attributed to activation of local humoral factors, including A II. Inhibition of ACE was shown to minimize the extent of this damage, 35,36 although it is unclear how much of this benefit should be attributed to A II suppression and how much to potentiation of bradykinin.…”

Section: Oxidative Stressmentioning

confidence: 99%

Angiotensin II as a cardiovascular risk factor

Gavras

2002

J Hum Hypertens

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A renin-angiotensin level that is inappropriately high for the systemic blood pressure and the state of sodium balance is now recognized to be one of the modifiable cardiovascular risk factors. Angiotensin acts both as a circulating hormone and as a locally acting paracrine/autocrine/intracrine factor. The adverse effects of angiotensin on the heart include the mechanical results of elevated resistance to the pumping function of the myocardium, as well as the effects of neurohumoral abnormalities on various cardiac structures. In addition, cardiac damage follows acute ischaemic injury or chronic energy starvation due to coronary artery disease, attributable to either mechanical obstruction Keywords: angiotensin II; renin-angiotensin system; cardiovascular disease; myocardial infarction Myocardial ischaemiaAngiotensin II (A II) is one of the major systemic pressor hormones (others include noradrenaline, vasopressin and endothelin). The idea that excessive levels of circulating A II can cause myocardial infarctions originated from an early experiment in which exogenous infusion of A II produced widespread areas of myocardial necrosis in rabbits. 1 Clinical observations in patients subjected to extreme stimulation of the renin-angiotensin system during haemodialysis revealed that these patients were prone to coronary death. This was attributed to intense coronary vasoconstriction, because focal myocardial necrosis was described in areas with no detectable coronary obstructive lesions. 2 These experiments were later replicated and amplified by other investigators. 3,4 It was found that an excess of endogenous or exogenous A II can damage the myocardium via several additional mechanisms, such as increased sarcolemmic permeability and death of cardiac myocytes, or increased permeability and destruction of coronary microvascular endothelial cells. All these eventually lead to the replacement of contractile myocardium by fibrotic tissue.Angiotensin II exerts a preferential pressor action on the coronary, renal, cerebral and adrenal vasculaCorrespondence: H Gavras, Department of Medicine, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA. E-mail: hgavrasȰbu.edu (atherosclerotic and/or thrombotic) or functional stenosis (vasospasm). Activation of the renin-angiotensin system has several haemodynamic and humoral consequences, all of which may damage the myocardium. These include acute myocardial ischaemia, left-ventricular hypertrophy, arrhythmias, alterations in the coagulation-fibrinolysis equilibrium, increased oxidative stress, and pro-inflammatory activity. A brief review of some of the mechanisms by which activation of the renin-angiotensin system can inflict damage on the heart is presented.

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“…A substantial reduction in mortality has been attributed to a significant decrease in sudden cardiac deaths possibly because of fewer episodes of complex arrhythmias (5, 6). The positive influence of inhibition of angiotensin-converting enzyme has been linked to bradykinin-mediated effects (7,8). However, the role of direct blockade of the AT1 receptor by losartan in episodes of sudden cardiac arrhythmias is still debated (9 -11).…”

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confidence: 99%

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Doronin

Potapova

et al. 2004

Journal of Biological Chemistry

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We report a novel signal transduction complex of the angiotensin receptor type 1. In this complex the angiotensin receptor type 1 associates with the potassium channel ␣-subunit Kv4.3 and regulates its intracellular distribution and gating properties. Electrophysiological remodeling in hypertrophy and heart failure predisposes the heart to lethal arrhythmias, which account for half of the mortality (1, 2). Experimental evidence derived from large scale clinical trials shows that inhibition of angiotensin II synthesis by inhibitors of angiotensin-converting enzyme or direct blockade of angiotensin receptor type 1 (AT1 1 receptor) with the antagonist losartan protects the heart from hypertensive complications (3, 4). A substantial reduction in mortality has been attributed to a significant decrease in sudden cardiac deaths possibly because of fewer episodes of complex arrhythmias (5, 6). The positive influence of inhibition of angiotensin-converting enzyme has been linked to bradykinin-mediated effects (7,8). However, the role of direct blockade of the AT1 receptor by losartan in episodes of sudden cardiac arrhythmias is still debated (9 -11). Electrophysiologic remodeling affects the entire spectrum of cardiac ion channels including the transient outward potassium current (I to ) whose density is often decreased in heart failure (2, 12, 13).The mechanism of I to down-regulation in heart failure is not completely understood and is likely to have multiple etiologies. In part it can be explained by the inhibitory effects of angiotensin II. Experiments with spontaneously hypertensive rats suggest that the AT1 receptor might be directly involved in the regulation of I to . In this animal model I to is inhibited and can be recovered by treatment with the AT1 receptor specific antagonist losartan (14). Experiments with isolated cardiomyocytes show that stimulation of the AT1 receptor results in the inhibition of I to in myocytes from rat or canine ventricle (15,16). In large mammals such as dogs or humans with substantial ventricular wall thickness, I to exhibits a transmural gradient that is vital for normal electrical activity (17,18). Distortion of the I to gradient leads to dispersion of repolarization across the ventricular wall, providing a substrate for ventricular arrhythmias (19). In both canine and human ventricle, I to density is higher in epicardial and midmyocardial than in the endocardial cells (17,18). The gradient of I to inversely correlates with the gradient of angiotensinogen across the ventricular wall whose expression is more prominent in the subendocardial than in either midmyocardium or epicardium regions (20). Evidence exists that cardiomyocytes, Purkinje fibers, and cardiac fibroblasts produce angiotensin II (21-23). Therefore, locally produced angiotensin II could act in a paracrine and/or autocrine manner to regulate I to . Experiments in vitro show that losartan stimulates I to in canine cardiomyocytes isolated from endocardium and converts the configuration of the action potential of endocar...

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The effects of oral pretreatment with zofenopril, an angiotensin-converting enzyme inhibitor, on early reperfusion and subsequent electrophysiologic stability in the pig

Cited by 30 publications

References 28 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

Angiotensin II as a cardiovascular risk factor

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

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