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Anti-shock activity of lipid free radical oxidation inhibitors
J Mol Cell Cardiol 21 (Supplement 19
II) (1989)
IONIC SUBCELLULAR ALTERATIONS DURING HYPOXIA AND REOXYGENATION IN ISOLATED NEONATAL RAT VENTRICULAR MYOCYTES. Fl- THANDROYEN, HK HAGLER, D BELLOTTO, B ZIMAN, JT WILLERSON, LM BUJA UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, DALLAS TEXAS 75235 Altered ionic homeostasis is implicated in the progression of cardiac myocyte injury. Cytoplasmic (CY) and mitochondrial (M) elemental content (mmolIKg dry weight) were measured, using electron probe microanalysis, during hypoxia (H) (O-5 hr) and upon reoxygenation (R) (1 hr after 3-5 hr H) in isolated neonatal rat ventricular myocytes. At 2 hr H, cell ATP loss was associated with Mg (30?3 vs 49k3, p-zO.05; n=29 to 38 in CY) and K (775k30 vs 901+28, ~~0.05; n=29 to 38 in CY) loss from CY and M; myocyte injury was not present. At 3-5 hr H, myocyte injury (morphology and membrane phosphotipid release) was associated with progressive Na (327k40 to 629k46 vs 91fl0, ~~0.05; n=38 to 45 in CY) and Ca (IQ3 to 31k3 vs 4k1, peO.05: n =38 to 45 in CY) loading and further K and Mg depletion in CY and M. Reoxygenation after 3 hr H resulted in the development of complete recovery from K (906k40 vs 9Olk28) and Mg (43k3 vs 49k3) depletion, and Na (4lk9 vs 91+10) and Ca (1 Ok3 vs 4+1) loading in 1 population of myocytes; and in further Ca (55+11 vs 15k3, ~~0.05; n=6 to 38) loading and severe Mg (0 vs 4913, pcO.O5), K and Na inhomeostasis in another population of myocytes. In isolated heart cells: early hypoxia results in Mg and K loss independent of Na change; longer duration hypoxia results in Mg depletion, progressive K loss, Na loading and Ca loading; hypoxia followed by reoxygenation results in heterogenous response with both recovery and deterioration of elemental content in individual myocytes.
20 A FUNCTIONAL TISSUE RENIN-ANGIOTENSIN SYSTEM (RAS) IN THE RAT ISOLATED, PERFUSED WESENTERIC VASCULATURE. B. Klinkefus,
T.
Major,
R.
Panek,
S. Rapundalo,
R.
E.
Parke-Davis Pharm. Res. Div., Warner-Lambert Co., Ann Arbor, MI 48105. The present study was designed to investigate the role of the tissue RAS in modulating the vasoconstrictor responses to electrically evoked nerve stimulation in studies, perfused the rat isolated perfused mesenteric vasculature. For these mesenteric vasculature from spontaneously hypertensive rats (SHR'S) and normotensive rats (SD's) were stimulated to constrict by periarterial nerve Sprague-Dawley These pressor responses were potentiated by both stimulation (8 Hz, 30 set duration). tetradecapeptide renin substrate (RS; 0.1-1000 nM) and isoproterenol (ISO; 1.0-1000 in mesenteric nN). The degree of potentiation for ISO,, but not for RS, was greater vasculature from SHR's than SD's. The response to RS was completely blocked by the algiotensin II (AiI) antagonist saralasin (lOnM), suggesting that RS was converted to Such conversion is suggested by the finding that i) AI1 by the mesenteric vasculature. infusion of RS resulted in a concentration-dependent increase in AI1 in the effluent, and ii) infusion of AI1 mimicked the response to RS. The response to IS0 was not blocked by saralasin, and IS0 did not increase AI1 in the effluent, suggesting that the actions of the tissue RAS. These potentiating effect of IS0 was not due to altered resuits provide evidence for a functional tissue RAS which could play an important role in mediating nerve-stimulated pressor responses. Weishaar.
21 ANTI-SHOCK
ACTIVITY OF LIPID FREE RADICAL OXIDATION INHIBITORS. A.Kubatiev, S.Grachev, L.Smirnov, Y.Bobkov, T.Nefedova, Z.Yadigarova, A.Turgiev, M.Yakovlev, K.Dumayev. Central Institute of Postgraduate Medical Training, Moscow, USSR. We compared the anti-shock activity of lipid free radical oxidation inhibitors derived from 3-oxypyridine, tetramethylpiperidine and indolylthioacetate. The model of endotoxic shock was prepared in rabbits by intravenous injection of Salmonella typhimurium lipopolysaccharide in a dose of IO mg/kg. The pharmacological agents were used in a dose of 30 mg/kg. Maximal anti-shock activity was demonstrated by derivatives of 3-oxypyridine and indolylthioacetate which suppressed to a similar extent as early as I hr after their administration the deleterious effects of endotoxin on the functional parameters of the cardiovascular system and reduced the TxB2 level in peripheral blood and left ventricular myocardium, while inducing a rise in the PGI3 level in pulmonary and coronary vessels. Tetramethylpiperidines, as well as acetylsalicylic acid used in the control group of rabbits, were ineffective. s.7
II) (1989)
IONIC SUBCELLULAR ALTERATIONS DURING HYPOXIA AND REOXYGENATION IN ISOLATED NEONATAL RAT VENTRICULAR MYOCYTES. Fl- THANDROYEN, HK HAGLER, D BELLOTTO, B ZIMAN, JT WILLERSON, LM BUJA UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, DALLAS TEXAS 75235 Altered ionic homeostasis is implicated in the progression of cardiac myocyte injury. Cytoplasmic (CY) and mitochondrial (M) elemental content (mmolIKg dry weight) were measured, using electron probe microanalysis, during hypoxia (H) (O-5 hr) and upon reoxygenation (R) (1 hr after 3-5 hr H) in isolated neonatal rat ventricular myocytes. At 2 hr H, cell ATP loss was associated with Mg (30?3 vs 49k3, p-zO.05; n=29 to 38 in CY) and K (775k30 vs 901+28, ~~0.05; n=29 to 38 in CY) loss from CY and M; myocyte injury was not present. At 3-5 hr H, myocyte injury (morphology and membrane phosphotipid release) was associated with progressive Na (327k40 to 629k46 vs 91fl0, ~~0.05; n=38 to 45 in CY) and Ca (IQ3 to 31k3 vs 4k1, peO.05: n =38 to 45 in CY) loading and further K and Mg depletion in CY and M. Reoxygenation after 3 hr H resulted in the development of complete recovery from K (906k40 vs 9Olk28) and Mg (43k3 vs 49k3) depletion, and Na (4lk9 vs 91+10) and Ca (1 Ok3 vs 4+1) loading in 1 population of myocytes; and in further Ca (55+11 vs 15k3, ~~0.05; n=6 to 38) loading and severe Mg (0 vs 4913, pcO.O5), K and Na inhomeostasis in another population of myocytes. In isolated heart cells: early hypoxia results in Mg and K loss independent of Na change; longer duration hypoxia results in Mg depletion, progressive K loss, Na loading and Ca loading; hypoxia followed by reoxygenation results in heterogenous response with both recovery and deterioration of elemental content in individual myocytes.
20 A FUNCTIONAL TISSUE RENIN-ANGIOTENSIN SYSTEM (RAS) IN THE RAT ISOLATED, PERFUSED WESENTERIC VASCULATURE. B. Klinkefus,
T.
Major,
R.
Panek,
S. Rapundalo,
R.
E.
Parke-Davis Pharm. Res. Div., Warner-Lambert Co., Ann Arbor, MI 48105. The present study was designed to investigate the role of the tissue RAS in modulating the vasoconstrictor responses to electrically evoked nerve stimulation in studies, perfused the rat isolated perfused mesenteric vasculature. For these mesenteric vasculature from spontaneously hypertensive rats (SHR'S) and normotensive rats (SD's) were stimulated to constrict by periarterial nerve Sprague-Dawley These pressor responses were potentiated by both stimulation (8 Hz, 30 set duration). tetradecapeptide renin substrate (RS; 0.1-1000 nM) and isoproterenol (ISO; 1.0-1000 in mesenteric nN). The degree of potentiation for ISO,, but not for RS, was greater vasculature from SHR's than SD's. The response to RS was completely blocked by the algiotensin II (AiI) antagonist saralasin (lOnM), suggesting that RS was converted to Such conversion is suggested by the finding that i) AI1 by the mesenteric vasculature. infusion of RS resulted in a concentration-dependent increase in AI1 in the effluent, and ii) infusion of AI1 mimicked the response to RS. The response to IS0 was not blocked by saralasin, and IS0 did not increase AI1 in the effluent, suggesting that the actions of the tissue RAS. These potentiating effect of IS0 was not due to altered resuits provide evidence for a functional tissue RAS which could play an important role in mediating nerve-stimulated pressor responses. Weishaar.
21 ANTI-SHOCK
ACTIVITY OF LIPID FREE RADICAL OXIDATION INHIBITORS. A.Kubatiev, S.Grachev, L.Smirnov, Y.Bobkov, T.Nefedova, Z.Yadigarova, A.Turgiev, M.Yakovlev, K.Dumayev. Central Institute of Postgraduate Medical Training, Moscow, USSR. We compared the anti-shock activity of lipid free radical oxidation inhibitors derived from 3-oxypyridine, tetramethylpiperidine and indolylthioacetate. The model of endotoxic shock was prepared in rabbits by intravenous injection of Salmonella typhimurium lipopolysaccharide in a dose of IO mg/kg. The pharmacological agents were used in a dose of 30 mg/kg. Maximal anti-shock activity was demonstrated by derivatives of 3-oxypyridine and indolylthioacetate which suppressed to a similar extent as early as I hr after their administration the deleterious effects of endotoxin on the functional parameters of the cardiovascular system and reduced the TxB2 level in peripheral blood and left ventricular myocardium, while inducing a rise in the PGI3 level in pulmonary and coronary vessels. Tetramethylpiperidines, as well as acetylsalicylic acid used in the control group of rabbits, were ineffective. s.7