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Role of oxy-radicals in postischemic myocardial dysfunction (”myocardial stunning”)
J Mol Cell Cardiol20
(Supplement
V) (1988)
R-1 3 PHYSIOLOGICAL AND PHARMACOLOGICAL CONTROL OF FREE RADICALS: CLINICAL APPLICABILITY OF ANTlOXlDANT THERAPY E Riva, Cardiovascular Research, The Rayne Institute, St Thomas Hospital, London SEl, UK Free oxygen radicals, formed in living organisms, have been imphcated in more than sixty disorders, including coronary heart disease, cancer, Alzheimer’s disease, Parkinson’s disease, rheumatoid arthritis, or in hearts undergoing bypass surgery and hearts and kidneys used in transplants. In many impressive experimental studies, various substances (eg vitamin E, beta-carotene, and vitamin C), or antioxidant enzyme (eg superoxide dismutase, catalase afid glutathione pcroxidase) have been shown to exert dramatic protection either by inhibiting oxygen radical formation or by scavanging radicals once formed. Physiological protection mechanisms are thought to be overwhelmed under some conditions (eg ischemia and reperfusion) and a variety of compounds have been developed or isolated to supplement these endogenous mechanism. These are now being tested in both animals and patients in a variety of pathological conditions where organ damage is believed to be mediated by free radicals. One major therapy, which could come into clinical use soon, involves the treatment of myocardial infarction with both thrombolytic therapy and an oxvIten radical scavanger (h-R SOD). SOD mav also Drove useful in limiting renerfusion iniurv after ischemic %diac arrest durini ca&ac suriery as wefi as thi reperfusion injury o&&ring in the *co&se of cardiac and renal transplantation. Clinical trials are also in progress to investigate the therapeutic role of free radicals scavangers iri inflammatory chronic disease, n&rological diseases and oxygen-induced lung toxicity. probably in only a few cases will free radicals prove to be the whole answer but nonetheless they are likely to represent important contributors to many disorders and as such the need for their manipulation stimulate the development of new pharmacological approaches,
R- .14
ROLE 0~ OXY-RADICALS IN POSTISCHEMIC MYOCARDIAL OYSFUNCTION (I~MY~CAROIAL STUNNINGLY). Roberto Bolli. Bavlor Colleoe of Medicine. Houston. TX 77030. Myocardium rep&fused af
15 FREE RADICAL-MEDIATED REPERFUSIW INJURY & NEUTROPHILS - A CAUTIONARYNOTE. Kevin Mullane, Research Department, Pharmaceuticals Division, CIBA-GEIGY Corp. Surmnit, New Jersey, USA The elegant EPR studies of Zweier and others (Proc. Nat. Acad Sci. USA 84: 1404, 1987) demonstrate free radical (FR) production by the isolated heart v&en reoxygenated after a period of ischemia. Consequently, tissue sources of FRs are implicated in reperfusion injury., This concept makes 2 assumptions. First, that any FR formation produces injury, and second, that the tissue production is sufficient to account for reperfusion injury when extrapolated to the whole animal/patient. The isolated liver sujected to ischemia/reperfusion also generates FRs, however Jaeschke and co-workers (JCI 81:1240, 1988) found the tissue had the capacity to detoxify 1000 x more FRs than were produced, and there was no evidence for oxidative stress. Thus, tissue FR production per se need not be injurious because of sufficient intracellular defense mechanisms. Neutrophils are professional generators of FRs which can overwhelm endogenous detoxification systems, and have been implicated in cardiac reperfusion injury. Recognition of the role played by neutrophils may offer alternative therapeutic strategies to FR scavengers for the limitation of post-ischemic injury. Drugs directed against 5-lipoxygenase, adhesive glycoproteins, complement factors, etc., may remove an important source of FRs to pre-empt myocellular damage. However, if such interventions release neutrophils from the marginated pool at an inappropriate time, increasing circulating cells, this could have dire consequences for the post-ischemic heart. s.15
(Supplement
V) (1988)
R-1 3 PHYSIOLOGICAL AND PHARMACOLOGICAL CONTROL OF FREE RADICALS: CLINICAL APPLICABILITY OF ANTlOXlDANT THERAPY E Riva, Cardiovascular Research, The Rayne Institute, St Thomas Hospital, London SEl, UK Free oxygen radicals, formed in living organisms, have been imphcated in more than sixty disorders, including coronary heart disease, cancer, Alzheimer’s disease, Parkinson’s disease, rheumatoid arthritis, or in hearts undergoing bypass surgery and hearts and kidneys used in transplants. In many impressive experimental studies, various substances (eg vitamin E, beta-carotene, and vitamin C), or antioxidant enzyme (eg superoxide dismutase, catalase afid glutathione pcroxidase) have been shown to exert dramatic protection either by inhibiting oxygen radical formation or by scavanging radicals once formed. Physiological protection mechanisms are thought to be overwhelmed under some conditions (eg ischemia and reperfusion) and a variety of compounds have been developed or isolated to supplement these endogenous mechanism. These are now being tested in both animals and patients in a variety of pathological conditions where organ damage is believed to be mediated by free radicals. One major therapy, which could come into clinical use soon, involves the treatment of myocardial infarction with both thrombolytic therapy and an oxvIten radical scavanger (h-R SOD). SOD mav also Drove useful in limiting renerfusion iniurv after ischemic %diac arrest durini ca&ac suriery as wefi as thi reperfusion injury o&&ring in the *co&se of cardiac and renal transplantation. Clinical trials are also in progress to investigate the therapeutic role of free radicals scavangers iri inflammatory chronic disease, n&rological diseases and oxygen-induced lung toxicity. probably in only a few cases will free radicals prove to be the whole answer but nonetheless they are likely to represent important contributors to many disorders and as such the need for their manipulation stimulate the development of new pharmacological approaches,
R- .14
ROLE 0~ OXY-RADICALS IN POSTISCHEMIC MYOCARDIAL OYSFUNCTION (I~MY~CAROIAL STUNNINGLY). Roberto Bolli. Bavlor Colleoe of Medicine. Houston. TX 77030. Myocardium rep&fused af
15 FREE RADICAL-MEDIATED REPERFUSIW INJURY & NEUTROPHILS - A CAUTIONARYNOTE. Kevin Mullane, Research Department, Pharmaceuticals Division, CIBA-GEIGY Corp. Surmnit, New Jersey, USA The elegant EPR studies of Zweier and others (Proc. Nat. Acad Sci. USA 84: 1404, 1987) demonstrate free radical (FR) production by the isolated heart v&en reoxygenated after a period of ischemia. Consequently, tissue sources of FRs are implicated in reperfusion injury., This concept makes 2 assumptions. First, that any FR formation produces injury, and second, that the tissue production is sufficient to account for reperfusion injury when extrapolated to the whole animal/patient. The isolated liver sujected to ischemia/reperfusion also generates FRs, however Jaeschke and co-workers (JCI 81:1240, 1988) found the tissue had the capacity to detoxify 1000 x more FRs than were produced, and there was no evidence for oxidative stress. Thus, tissue FR production per se need not be injurious because of sufficient intracellular defense mechanisms. Neutrophils are professional generators of FRs which can overwhelm endogenous detoxification systems, and have been implicated in cardiac reperfusion injury. Recognition of the role played by neutrophils may offer alternative therapeutic strategies to FR scavengers for the limitation of post-ischemic injury. Drugs directed against 5-lipoxygenase, adhesive glycoproteins, complement factors, etc., may remove an important source of FRs to pre-empt myocellular damage. However, if such interventions release neutrophils from the marginated pool at an inappropriate time, increasing circulating cells, this could have dire consequences for the post-ischemic heart. s.15