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Antioxidant cardiovascular drugs and free radical-mediated injury
J Mol Cell Cardiol
23 (Supplement
III) (1991)
B-4-4 ~~XL’N4ANUO”ISTS,
NNUTNOPHILS AND REPEWUSION IHJURY Latour, Nontreal Heart Institute and Department of Pathology, University of Hontreal, Hontreai, Canada HlT X8. Preservation of the mitochondrial function and adenosine triphosphate stores of the cardiac work, increases in coronary and collateral blood (ATP), reduction flows, slowing of cellular calcium uptake, and cell membrane stabilization, are the mechanisms commonly held responsible for the observed cardioprotectfve effects of calcium antagonists during ischemia. However, these agents demonstrated little or no benefit in isolated heart preparations at reperfusion. In the recent years, a role for neutrophils has been recognized in reperfusion injury, and calcium antagonists, known to interfere with neutrophil activation, production of free oxygen radicals, release of proteolytic enzymes, phospholipase A2 activation, synthesis of vasoactive and chemotactic agents, and with platelet have been tested in ischemia/reperfusion models. Agents such as aggregation, diltiazem were found to limit infarct size when administered during reperfusion. An interaction with neutrophil mobilization, activation and distribution in the reperfused myocardium. and a prevention of the no-reflow were associated with the observed protection. These results may provide bases for new therapeutic approaches to limit myocardial injury in the clinical set up of coronary thrombolytic therapy.
B-4-5 Tli3 POLE OF SODIUl44ROTON EXCNANGEIN ISC~C/ENPEi!?USXOar
DAMAGE IN TNB NBAET. Grant N. Pierce, Beping Meng. Division of Cardiovascular Sciences, St. Boniface Research Cent-Fe an@ Dept. of Physiology, University of Manitoba, Winnipeg. Canada. During no flow ischemia, myocardial pH drops. Upon reperfusion, the extracellular space is washed out and a transsarcolennaal Ii+ gradient is exchange to remove Ht established which favors the stimulation of Nat-Et from the cell. The resultant influx of Nat will stimulate Nat-CaPt exchange which will elevate [Ca'+]i. If severe enough, this will ultimately result in contractile dysfunction and damage. If this cascade of events is correct, an agent which inhibits Nat -H ’ exchange should block this process and protect the heart. Dimethylamiloride (DMA) is a selective inhibitor of Nat-H+ exchange. We have found that it protects the heart from severe ischemic/reperfusion induced contractile dysfunction and damage. It protects if present only during reperfusion and at a relatively low [DMA] (20 uM). DMA blocks the rise in during reperfusion. Modifying [Na+]i and pH will lNa+li and [Ca’+]i alter reperfusion'damage. We conclude Nat-H+ exchange is an important pathway involved in ischem.ic/reperfusion damage in the heart. Supported by the Heart and Stroke Foundation of Manitoba.
B-4-6 ANTIO$l?ANT
(IWWOVASCULAR DRUG6 AND PItEE IUjDICAL~‘IXD eJNBy William B We&&, Beqjamin F h&ens, Anthony M tied&an, Jay H Kramer, I Tong Mak. Division of Experimental Medicine, The George Washington University Medical Center, Washington, DC 20037. Racently we have analysed several classes of eardiovaseular dti& for a&oxidant properties. Among the beta-blockers, propranold is a very hydrophobic drug wit& sign&ant antioxidant potency in preventing peroxidative illjury of sarc$emmal membranes and ctitiocytes (1). Both D- and Lpropranolol were shown to be equally effective aa antioxidants. Among t& Ca-channel blockers, the dihydropyridines, nifedipine and nicardipine, are highly potent (2) and this may be related to their great solubility in biological membranes. Both captopril, a SIX-ACE inhibitor, and epicaptopril, ita inactive stereoisomer, possess equivalent antioxidant activities when tested in ‘an aqueous system in which oxygen-centered radicals were generated (3). We have extended this work using ESRspectroscopy with spin trapping agents; the da@ indicate that the beta-blocking and Ca-channel blocking drugs function as chain-breaking antioxidants, similar to alpha tocopherd. Si hydrophobic drugs can concentrate in “non-receptor membrane compertmente” of cardiovascular tissues, they may provide a degree of antioxidant protection wlmm used clinically. (1) We&&i WI& Mah I!T, Simic GM Mechanisms of canii~vaescular druge as antiozi&nb J MaI Cell C&ii01 ZJ 1199-1293 (1990). (2) Ii&k IT, We&&i WB. Comp~mtive anh&xi~t qctiviti~ of p~~pmnolol, ni&iipine, verapwnil and diltiazem against salooled membrane lipid penvidati6n. Cim Rea # 14494452 (19%). (3) i&k n, Fmxlmnn AM, Flickem BF, Weglicki WB. Pmtective @a% of md&ydryl#ntaining ACE inhibitors against bee radical i&y in endothelial cells Biochem PharmacoI #X9), 2169-2175 (19RI). S.23
23 (Supplement
III) (1991)
B-4-4 ~~XL’N4ANUO”ISTS,
NNUTNOPHILS AND REPEWUSION IHJURY Latour, Nontreal Heart Institute and Department of Pathology, University of Hontreal, Hontreai, Canada HlT X8. Preservation of the mitochondrial function and adenosine triphosphate stores of the cardiac work, increases in coronary and collateral blood (ATP), reduction flows, slowing of cellular calcium uptake, and cell membrane stabilization, are the mechanisms commonly held responsible for the observed cardioprotectfve effects of calcium antagonists during ischemia. However, these agents demonstrated little or no benefit in isolated heart preparations at reperfusion. In the recent years, a role for neutrophils has been recognized in reperfusion injury, and calcium antagonists, known to interfere with neutrophil activation, production of free oxygen radicals, release of proteolytic enzymes, phospholipase A2 activation, synthesis of vasoactive and chemotactic agents, and with platelet have been tested in ischemia/reperfusion models. Agents such as aggregation, diltiazem were found to limit infarct size when administered during reperfusion. An interaction with neutrophil mobilization, activation and distribution in the reperfused myocardium. and a prevention of the no-reflow were associated with the observed protection. These results may provide bases for new therapeutic approaches to limit myocardial injury in the clinical set up of coronary thrombolytic therapy.
B-4-5 Tli3 POLE OF SODIUl44ROTON EXCNANGEIN ISC~C/ENPEi!?USXOar
DAMAGE IN TNB NBAET. Grant N. Pierce, Beping Meng. Division of Cardiovascular Sciences, St. Boniface Research Cent-Fe an@ Dept. of Physiology, University of Manitoba, Winnipeg. Canada. During no flow ischemia, myocardial pH drops. Upon reperfusion, the extracellular space is washed out and a transsarcolennaal Ii+ gradient is exchange to remove Ht established which favors the stimulation of Nat-Et from the cell. The resultant influx of Nat will stimulate Nat-CaPt exchange which will elevate [Ca'+]i. If severe enough, this will ultimately result in contractile dysfunction and damage. If this cascade of events is correct, an agent which inhibits Nat -H ’ exchange should block this process and protect the heart. Dimethylamiloride (DMA) is a selective inhibitor of Nat-H+ exchange. We have found that it protects the heart from severe ischemic/reperfusion induced contractile dysfunction and damage. It protects if present only during reperfusion and at a relatively low [DMA] (20 uM). DMA blocks the rise in during reperfusion. Modifying [Na+]i and pH will lNa+li and [Ca’+]i alter reperfusion'damage. We conclude Nat-H+ exchange is an important pathway involved in ischem.ic/reperfusion damage in the heart. Supported by the Heart and Stroke Foundation of Manitoba.
B-4-6 ANTIO$l?ANT
(IWWOVASCULAR DRUG6 AND PItEE IUjDICAL~‘IXD eJNBy William B We&&, Beqjamin F h&ens, Anthony M tied&an, Jay H Kramer, I Tong Mak. Division of Experimental Medicine, The George Washington University Medical Center, Washington, DC 20037. Racently we have analysed several classes of eardiovaseular dti& for a&oxidant properties. Among the beta-blockers, propranold is a very hydrophobic drug wit& sign&ant antioxidant potency in preventing peroxidative illjury of sarc$emmal membranes and ctitiocytes (1). Both D- and Lpropranolol were shown to be equally effective aa antioxidants. Among t& Ca-channel blockers, the dihydropyridines, nifedipine and nicardipine, are highly potent (2) and this may be related to their great solubility in biological membranes. Both captopril, a SIX-ACE inhibitor, and epicaptopril, ita inactive stereoisomer, possess equivalent antioxidant activities when tested in ‘an aqueous system in which oxygen-centered radicals were generated (3). We have extended this work using ESRspectroscopy with spin trapping agents; the da@ indicate that the beta-blocking and Ca-channel blocking drugs function as chain-breaking antioxidants, similar to alpha tocopherd. Si hydrophobic drugs can concentrate in “non-receptor membrane compertmente” of cardiovascular tissues, they may provide a degree of antioxidant protection wlmm used clinically. (1) We&&i WI& Mah I!T, Simic GM Mechanisms of canii~vaescular druge as antiozi&nb J MaI Cell C&ii01 ZJ 1199-1293 (1990). (2) Ii&k IT, We&&i WB. Comp~mtive anh&xi~t qctiviti~ of p~~pmnolol, ni&iipine, verapwnil and diltiazem against salooled membrane lipid penvidati6n. Cim Rea # 14494452 (19%). (3) i&k n, Fmxlmnn AM, Flickem BF, Weglicki WB. Pmtective @a% of md&ydryl#ntaining ACE inhibitors against bee radical i&y in endothelial cells Biochem PharmacoI #X9), 2169-2175 (19RI). S.23