Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of the calcium antagonist diltiazem to protect against reperfusion-induced arrhythmias in hypertrophied myocardium was studied. Hearts from normotensive and DOCA-salt hypertensive rats were Langendorff perfused and subjected to 10 minutes of stabilization, 10 minutes of left coronary artery occlusion, and 5 minutes of reperfusion. The incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during reperfusion were determined and the effects of diltiazem or vehicle (given as a single bolus 3 minutes before coronary artery occlusion) were assessed in hypertrophied and normal hearts. In vehicle-treated (control) hypertrophied hearts, VF incidence was 91% compared with 67% in normal hearts, and the median duration of VF was 272 seconds (mean 207.4 +/- 32.3) compared with 27 seconds (mean 110.6 +/- 36.6; p < 0.05), respectively, suggesting that reperfusion VF is more severe in hypertrophied hearts. In normal hearts, diltiazem 18 micrograms reduced VT incidence from 92% to 55%, reduced VF from 67% to 27%, and sustained VF from 42% to 9%. In hypertrophied hearts, 18 micrograms diltiazem reduced the VT incidence from 100% to 58%, reduced VF from 91% to 25% (p < 0.01), and sustained VF from 82% to 8% (p < 0.01). Median VF duration in this group was reduced to 0 seconds (p < 0.05; mean 24.7 +/- 22.6). Diltiazem did not significantly affect heart rate or coronary flow rate decreases during ischemia. However, developed tension, at the onset of ischemia, was lower in diltiazem-treated groups than in the control groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Attenuation of reperfusion-induced ventricular fibrillation in the rat isolated hypertrophied heart by preischemic diltiazem treatment. 835 76

The kidney responds to periods of ischemia with vasoconstriction and a decrease in glomerular filtration rate (GFR) on reperfusion. The mediators of this response have not been fully identified. In this study, we examined the contribution of angiotensin II (AII), thromboxane A2 (TXA2) and the interaction between them to this response. Anesthetized dogs were subjected to 30 min of clamping of both renal arteries. Renal hemodynamics and function were followed from 60 min before and for 105 min after clamping. Dogs were divided into salt-depleted (AII-stimulated) and captopril-treated (AII-inhibited) groups. Each group included dogs that received either the TXA2 synthase inhibitor CGS 13080 or its vehicle (controls) starting 30 min before renal artery clamping and lasting to the end of the experiment. In captopril-treated control dogs, 30 min of ischemia induced a 25% fall in renal blood flow (RBF). GFR initially fell by 75%, but recovered to 64% of base-line value 60 to 90 min after release of the clamp. In captopril-treated dogs, CGS 13080 prevented the fall in RBF, but the GFR response was similar to vehicle-treated dogs. In control dogs, both GFR and RBF responses were enhanced in salt-depleted compared with captopril-treated dogs; the decrease in RBF (44%) was greater, and the recovery in GFR, which fell by 89%, less. In salt-depleted, CGS 13080-treated dogs, the 30% fall in RBF was less than its control, but greater than dogs treated with captopril and CGS 13080. The change in GFR was similar to the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction between thromboxane A2 and angiotensin II in postischemic renal vasoconstriction in dogs. 845 Apr 63

A series of experiments was performed to characterize the effects of tissue trauma, extracellular calcium concentration, and prior ischemia on oxidative stress, measured by the accumulation of malondialdehyde-like materials (MDA-LM) in slices of rat liver. Liver tissue was rendered ischemic for 1 hour at 37 degrees C, either minced (to create traumatized fragments) or cleanly cut and washed (to create nontraumatized fragments), and then reoxygenated for 30 minutes in flasks of buffered salt solution. Nonischemic tissue was incubated similarly but without the 60-minute prior ischemia. The production of MDA-LM in the tissues was used as an indicator of lipid peroxidation. Production of MDA-LM in the tissues was used as an indicator of lipid peroxidation. Production of MDA-LM was always enhanced by prior ischemia and reoxygenation. However, trauma also increased the production of MDA-LM both in nonischemic liver slices in vitro and in those subjected to ischemia and reoxygenation. Furthermore, the elimination of calcium from incubation buffer significantly reduced MDA-LM production both in nontraumatized, ischemic, and reoxygenated tissues and in traumatized, nonischemic tissues; while the addition of the calcium ionophore A23187 (10 mumol/L) increased MDA-LM production in nontraumatized tissues independently of ischemia and reoxygenation. In nonischemic, traumatized tissues, the iron chelators deferoxamine and CGP-46,700A (1,2-diethyl-3-hydroxypyrid-4-one) quenched MDA-LM production. These data indicate that either ischemia or mechanical trauma may predispose liver tissue to calcium-dependent and iron-dependent oxidative stress.
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PMID:Traumatic versus postischemic induction of oxidative stress in rat liver. 845 55

This study tested the hypothesis that, due to intraluminal pressure changes, the order of constrictor-dilator administration alters stenotic hemodynamic responses. Canine carotid arteries were perfused with a physiologic salt solution under constant pressure (100 mm Hg). An intraluminal stenosis partially obstructed the arteries. Pressures proximal and distal to the artery and the flow were continually recorded as norepinephrine (10(-9)-10(-6) M) was added to the perfusate. Adding diltiazem (10(-7) M) before norepinephrine shifted the effective half maximum dose (ED50) of the norepinephrine flow curve from 7.35 +/- 0.66 X 10(-8) M to 6.39 +/- 0.72 X 10(-7) M (p < 0.05). More important, adding 10(-7) M diltiazem after norepinephrine-induced constriction did not reestablish stenotic pressure or flow: A 30-fold increase in diltiazem concentration (3.16 X 10(-6)M) was required to reestablish stenotic pressure (62.6 +/- 4.4 mm Hg) and flow (25.4 +/- 3.2 ml/min). Similarly, adding nitroglycerin (10(-7) M) before norepinephrine shifted the ED50 from 7.21 +/- 0.58 X 10(-8) to 5.94 +/- 0.78 X 10(-6) (p < 0.05). Adding 10(-7) M nitroglycerin after norepinephrine did not reestablish stenotic pressure or flow: 3.16 X 10(-6) M nitroglycerin was required to reestablish stenotic pressure (59.2 +/- 4.8 mm Hg) and flow (23.2 +/- 2.7 mL/min). This constrictor-dilation history did not occur in isolated arterial rings (norepinephrine + nitroglycerin = 38.1 +/- 13.9 g/cm2; nitroglycerin + norepinephrine = 42.2 +/- 9.4 g/cm2; p = not significant [NS]) or in normal arteries (norepinephrine + nitroglycerin = 4.89 +/- 0.14 mm [external diameter]; nitroglycerin + norepinephrine = 4.92 +/- 0.23 mm; p = NS). In stenotic arteries, intraluminal pressure influenced the order of constrictor-dilator administration on hemodynamic response, which was not observed in isolated arterial rings or in normal arteries. This pressure-dependent sensitivity affects vasomotor tone and may be important in the pathophysiology of ischemia.
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PMID:The order of dilator-constrictor administration affects stenotic hemodynamic responses. 850 96

We investigated the mechanism of the decreased myofilament Ca2+ responsiveness in stunned myocardium. The steady state force-[Ca2+] relationship was measured before and after skinning in thin ventricular trabeculae from control or stunned (20 minutes of ischemia, 20 minutes of reperfusion) rat hearts.[Ca2+]i was determined using microinjected fura 2 salt in intact muscles, whereas the myofilaments of chemically skinned trabeculae were activated directly with solutions of varied [Ca2+]. Maximal Ca2+- activated force (F max) before and after skinning was identical within either the control or stunned groups but was markedly depressed in both groups of stunned trabeculae (P < .001)). After ischemia and reperfusion, the [Ca2+] required for 50% of maximal activation (Ca50) was increased in both intact (control, 0.60 +/- 0.09 micromol/L; stunned, 0.85 +/- 0.09 micromol/L;P < .001) and skinned (control, 1.13 +/- 0.24 micromol/L; stunned 1.39 +/- 0.21 micromol/L; P = .0025) trabeculae. These data indicate that the decreased Ca2+ responsiveness of stunned myocardium is due to intrinsic alterations of the myofilaments. Therefore, we tested the hypothesis that activation of proteases by reperfusion-induced Ca2+ overload decreases the Ca2+ responsiveness of the cardiac myofilaments. Force-[Ca2+] relations were compared before and 5 to 30 minutes after direct exposure of skinned trabeculae to calpain I (18 microgram/mL, 20 minutes at [Ca2+]=10.8 micromol/L), a Ca2+-activated protease that is present in myocardium. Calpain I reduced F max from 94.3 +/- 8.3 to 56 +/- 8.5 mN/mm2 while increasing Ca50 from 0.94 +/- 0.11 to 1.36 +/- 0.21 micromol/L (P < .01). Calpastatin, a specific calpain inhibitor prevented the effects of calpain I on skinned trabeculae. The results show that the reduced Ca2+ responsiveness of stunned myocardium reflects alteration of the myofilaments themselves, not of soluble cytosolic factors, which can be faithfully reproduced by exposure to Ca2+-dependent protease.
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PMID:Intrinsic myofilament alterations underlying the decreased contractility of stunned myocardium. A consequence of Ca2+-dependent proteolysis? 859 4

This study was undertaken to determine the effect of dichloroacetate (DCA) on myocardial functional and metabolic recovery following global ischemia. Isolated rabbit hearts were subjected to 120 min of mildly hypothermic (34 degrees C), cardioplegic arrest with multidose, modified St. Thomas' cardioplegia. Hearts were reperfused with either physiologic salt solution (PSS) as controls, (CON, n = 10) or PSS containing DCA (DCA, n = 6) at a concentration of 1 mM. Functional and metabolic indices were determined at baseline and at 15, 30, and 45 min of reperfusion. In four DCA and four CON hearts, myocardial biopsies were taken at baseline, end-ischemia, 15 and 45 min for nucleotide levels. Functional recovery was significantly better in hearts reperfused with DCA as demonstrated by recovery of baseline developed pressure (DCA = 69 +/- 5%, CON = 45 +/- 9%) and dP/dt (DCA = 64% +/- 10% versus CON = 48% +/- 10%). Coronary blood flow was not different between groups either at baseline or during reperfusion, but myocardial oxygen consumption (MVO2) was increased in the DCA versus CON hearts (79% +/- 20% of baseline vs 50% +/- 18%). Recovery of myocardial adenylate energy status was improved in the DCA versus CON hearts (ATP recovered to 45% +/- 20% versus 8% +/- 6% of baseline). Coronary sinus lactate concentration was decreased in DCA perfused hearts at 45 min of reperfusion. Percent of baseline NADH values was similar at 15 min of reperfusion, but at 45 min, DCA hearts showed a decrease in NADH levels, while CON hearts showed an increase (DCA = 48%; CON = 121%). The enhanced myocardial function and improved metabolic status noted with DCA may result from increased oxidative phosphorylation due to altered pyruvate dehydrogenase (PDH) activity.
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PMID:Dichloroacetate enhanced myocardial functional recovery post-ischemia : ATP and NADH recovery. 866 Dec 1

In skeletal muscle, 4 h of ischemia followed by 30 min of reperfusion depolarizes the fibers, markedly increases the Cl- and glibenclamide-sensitive K+ conductances and reduces the excitability of the fibers. The ischemia-reperfusion also significantly decreases the ATP content of the muscles. In the present work, the electrical parameters of reperfused extensor digitorum longus muscle of rats were measured in vitro at 30 degrees C, by a computerized two-intracellular microelectrode technique, before and after in vivo pretreatment with equimolar doses of phosphocreatine disodium salt tetrahydrate, phosphocreatine di-L-arginine salt and L-arginine hydrochloride. In the same experimental situations the ATP content of the muscles was also measured. Both phosphocreatine salts prevented the increase of membrane ion conductance due to muscle reperfusion by preloading the muscle fibers with extra ATP. Phosphocreatine disodium salt also prevented the depolarization and restored the normal excitability of the reperfused fibers. In contrast, phosphocreatine di-L-arginine salt did not restore the resting potential nor the excitability of the fibers, but it decreased the amplitude of the action potential by reducing the overshoot. The pretreatment with L-arginine also failed to protect the electrical parameters of the fibers from the ischemic-reperfusion insult. Furthermore, the L-amino acid produced a more pronounced reduction of the excitability of the fibers by increasing the threshold current needed to elicit an action potential and reducing it overshoot. The in vitro application of L-arginine to the muscle also reduced the overshoot of the action potential, suggesting a direct interaction of the L-amino acid with Na+ channels.
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PMID:Effects of high energy phosphates and L-arginine on the electrical parameters of ischemic-reperfused rat skeletal muscle fibers. 866 21

The normal functional state of the vasculature and the events leading to the development of significant arterial disease involve the interaction of important vasoactive substances, which play important modulating or initiating roles in the development of hypertension and arteriosclerosis. Three endothelins have now been identified, of which ET-1 is the best characterized. ET-1 is produced by epithelial, mesangial, neuronal and glial, and liver cells, and is the most potent vasoconstrictor yet found. Each endothelin is derived from a different gene on separate chromosomes, and each binds to at least 2 types of receptor. The plasma half-life of ET-1 is about 7 min, and this provides a rapid mechanism for adjusting vascular resistance or blood pressure. The actions of endothelin are mediated through several pathways of postreceptor signaling, including activation of the mitogen-activated protein kinase cascade, which give rise to its growth-stimulating properties. Secretion of ET-1 from cultured endothelial cells is stimulated by a wide range of substances, and is inhibited by some prostaglandins. Endothelin in turn stimulates secretion of nitric oxide, arginine vasopressin and atrial natriuretic peptide, and participates in the hormonal control of salt and water balance. Hypoxia and ischemia augment ET-1 secretion, as does insulin, and this could play a role in the accelerated vascular disease of diabetes. ET-1 also causes bronchoconstriction and has been implicated in the development of acute asthma, primary pulmonary hypertension and pulmonary fibrosis. Its role in hypertension is still debatable, though most of the manifestations of congestive heart failure can theoretically be explained by the actions of ET-1. Endothelin also has extensive renovascular and parenchymal effects in the kidney. It is hoped that a fuller understanding of the role of endothelins in normal or pathologic vasculature will lead to effective therapy based on antagonism or augmentation of specific functions.
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PMID:Endothelins as cardiovascular peptides. 873 84

The present investigation seeks to elucidate the molecular mechanism responsible of the transformation of redox-cycling ubiquinone (UQ) from a save electron carrier to an O2.- generator as observed in toluene-treated mitochondria as well as in mitochondria exposed to conditions of organ ischemia/reperfusion. Starting from the earlier finding that for thermodynamic grounds autoxidation of ubisemiquinone (SQ.-) requires the accessibility of protons, two possibilities were considered: a) protons from the aqueous phase may penetrate into the phospholipid bilayer and react with SQ.- due to a decreased hydrophobicity of the membrane, b) the physical state of the membrane remains unchanged while the binding of redox-cycling UQ is changed such that SQ.- will come into contact with the aqueous phase in the polar head group section. Spin probes were used to follow changes of the physical order of phospholipids of the inner mitochondrial membrane. Binding changes of mitochondrial SQ.- were assessed from power saturation experiments and spin-spin interactions with a Cr3+ salt of the aqueous phase were studied to recognize orientation changes via the polar head group section of the membrane. Our results show that autoxidation of SQ.- occurs in two different ways. In the case of membrane insertion of toluene, the physical property of the membrane was affected such that protons could penetrate and allow SQ.- to undergo autoxidation. In contrast, mitochondrial respiration of cytosolic NADH accumulating during ischemia involves a low saturating SQ.- species that readily autoxidizes due to its spatial orientation close to the aqueous face of the membrane. We conclude from these observations that in line with thermodynamics autoxidation of SQ.- in mitochondria requires protons that normally have no access.
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PMID:Conditions allowing redox-cycling ubisemiquinone in mitochondria to establish a direct redox couple with molecular oxygen. 874 41

Defibrotide is a polydeoxyribonucleotide sodium salt extracted from mammalian organs. Its mean molecular weight is 15,000-30,000 daltons. Defibrotide contains aptamers, i.e., single-stranded polynucleotides with a well-defined base sequence and composition (5'-GGTTGG-ATT-GGTTGG-3' and 5'-GGTTGG-ATC-GGTTGG-3') that bind thrombin. For the time being, these aptamers are the only ones that have been identified in defibrotide, but there may also be other aptamers that bind proteins other than thrombin. Defibrotide has no anticoagulant activity, but in some other aspects it probably parallels heparin. Heparin is a sulfated polysaccharide sodium salt with a mean molecular weight ranging from 5,000 to 40,000 daltons extracted from mammalian organs. It contains disaccharide sequences of well-defined structure and frequency. Heparin binds an array of proteins, enzymes, and growth factors and shows inhibitory or stimulatory or protective activity. Defibrotide has a spectrum of interesting pharmacological properties that make this drug very useful for the treatment of arterial and venous thrombotic diseases. In fact, defibrotide has profibrinolytic, antithrombotic-thrombolytic, anti-ischemic, and antiatherosclerotic activity and protective activity in shock. What have all the above activities to do with a single drug? The explanation is that atherosclerosis, myocardial, renal, and liver ischemia, hemorrhagic and septic shock, and shock induced by occlusion of splanchnic artery and thrombosis are different facets of the same entity: the polyhedric inflammatory process.
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PMID:An integrated view of the activities of defibrotide. 880 33


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