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)

Adenosine is cardioprotective in models of myocardial stunning and infarction, but the precise compartment within the heart in which adenosine elicits its cardioprotective effects has not been determined. The goals of the present study were to (i) investigate the effects of a novel adenosine regulating agent, GP531 (5-amino-1-beta-n-(5-benzylamino-5-deoxyribofuranosyl) imidazole-4-carboxamide), on post-ischemic myocardial function, and (ii) examine the contribution of endogenous adenosine in the intravascular and interstitial compartments in mediating the beneficial effects. Pigs were instrumented for measurement of myocardial segment shortening, and for sampling of coronary venous blood and myocardial interstitial fluid for determination of adenosine concentration. Myocardial dysfunction was induced by 4 x 8 min coronary occlusions, and recovery of regional function was monitored for 2 h. In control pigs, function recovered to 24 +/- 2% of baseline after 2 h. Treatment with GP531 improved functional recovery to 55 +/- 3%. GP531-mediated cardioprotection was prevented by adenosine receptor blockade with 8-sulfophenyltheophylline (23 +/- 2%). GP531 did not affect basal adenosine levels, but caused a 2-fold greater increase in vascular adenosine concentration with ischemia (54.6 +/- 10.6 vs. 28.1 +/- 8.0 microM in controls. P < 0.05). In contrast, the interstitial adenosine concentration was not significantly different in treated vs. untreated control pigs (9.4 +/- 3.9 vs. 15.0 +/- 1.8 microM in controls). These data indicate that (1) GP531 improves recovery of myocardial function following ischemia reperfusion injury via an adenosine receptor-dependent mechanism, and (2) the cardioprotection is associated with increased intravascular, but not interstitial, adenosine concentration during ischemia. Therefore, we conclude that cardioprotection elicited by GP531-enhanced endogenous adenosine is dependent on an intravascular site of action.
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PMID:Cardioprotection with a novel adenosine regulating agent mediated by intravascular adenosine. 909 89

It has been postulated that the adenosine A1 receptor subtype, but also A2a receptors, are involved in mediating the beneficial properties of adenosine during ischemia and reperfusion. We investigated the effects of the selective A1 adenosine receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), the selective A2A adenosine receptor agonists, 2-[p-(2-carboxyethyl)phenetylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680), 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA), and the non selective agonist, 5'-N-ethylcarboxamidoadenosine (NECA), on ischemia-reperfusion injury in Langendorff-perfused rat hearts. Global ischemia was induced for 15 min in paced hearts followed by 60 min reperfusion. Control hearts developed left ventricular dysfunction, as indicated by the increase in end diastolic pressure to 40.8 +/- 5.1 vs 5.9 +/- 1.0 mm Hg baseline, and in coronary perfusion pressure to 57.6 +/- 8.4 vs 28.8 +/- 2.2 mm Hg before ischemia. After 15 min of reperfusion, ventricular function (LVDP) recovered by 83%, but creatine kinase levels were still significantly increased (294 +/- 55 IUl(-1) vs basal), indicating the occurrence of myocardial injury. All adenosine agonists added to the perfusion medium 15 min prior to ischemia exerted protective effects against myocardial dysfunction and reperfusion injury. Thus, 2HE-NECA (100 nM), CGS 21680 (10 nM), CCPA (3 nM) and NECA (100 nM) significantly (P < 0.05) decreased end diastolic pressure by 50-75% as compared with the control group. Similarly, all compounds significantly (P < 0.05) reduced coronary perfusion pressure by 30-45% vs control. For all drugs, recovery of LVDP occurred immediately after restoration of coronary flow. At 15-min reperfusion the adenosine agonists decreased myocardial creatine kinase release by 80-95% (P < 0.05 vs control). These findings indicate that both A1 and A2A adenosine receptors are involved in protecting the myocardium against ischemia and reperfusion in isolated rat heart, even if through different mechanisms.
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PMID:Cardioprotective effects of adenosine A1 and A2A receptor agonists in the isolated rat heart. 914 17

Interruption of ischemia by brief reperfusions (I/R) is better tolerated by the heart than continuous ischemia. The present study aims to determine the metabolic profiles of isolated rat hearts during intermittent ischemia, the possible cardioprotective role of adenosine and the influence of I/R on intracellular volumes, using multinuclear NMR spectroscopy. After five I/R (5/5 min) episodes, hearts paced at 5 Hz developed pressures comparable to those of hearts continuously perfused for 50 min at 37 degrees C (CP). Following the first 5 min episode of no-flow ischemia, [ADP] dropped from 72 +/- 9 to 43 +/- 5 microM (P < 0.001) and remained stable at the end of the following reperfusions, despite a 2.5-4-fold increase during each episode of 5 min ischemia. Intracellular volumes were stable during CP at a value of 2.50 +/- 0.06 ml/g dry weight, and decreased by 4, 8, and 12% after 1, 3, and 5 I/R episodes. The phosphorylation potentials decreased from 54 +/- 8 to 4 mM-1 during each period of 5 min ischemia and were 40 +/- 6 and 28 +/- 6 mM-1 after CP and I/R5, respectively. Cardiac glycogen had decreased during 50 min of CP from 103 +/- 13 to 81 +/- 9 mumol/g dry weight and lactate production was 116 +/- 15 mumol/heart. Five I/R episodes decreased glycogen to 46 +/- 7 mumol/g dry weight (P < 0.005 v CP) and increased lactate efflux to 262 +/- 31 mumol/ heart (P < 0.005 v CP). These findings suggest that a brief ischemia/reperfusion episode increases anaerobic metabolism of exogenous glucose, reduces [ADP] and induces cellular shrinkage. Administration of the adenosine receptor blocker 8-phenyl theophylline (8PT) during intermittent perfusion depressed the developed pressure to 78 +/- 7%, accentuated the decrease in phosphorylation potential (14 +/- 4 mM-1), abolished cellular shrinkage, reduced lactate efflux and blunted the decrease in ADP following the first I/R episode. In variance, no detectable changes were observed during intermittent ischemia when the ATP-sensitive potassium channel blocker glibenclamide was administered. These data demonstrate: (a) a brief episode of ischemia/reperfusion stimulates anaerobic metabolism of exogenous glucose and lowers intracellular ADP concentration: (b) adenosine receptors are partially responsible for the glycolytic stimulation during intermittent ischemia; (c) cellular shrinkage is related to the rate of glycolysis during intermittent ischemia/reperfusion.
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PMID:Intermittent ischemia: energy metabolism, cellular volume regulation, adenosine and insights into preconditioning. 922 Mar 57

Cardiomyocytes and vascular cells readily form, transport, and metabolize the endogenous adenine nucleoside adenosine and act to regulate both interstitial and plasma adenosine concentrations. Cardiovascular cells also have membrane adenosine receptors. Cell and tissue distributions, signal transduction pathways, and pharmacology of each of the four subtypes of adenosine receptors are subjects of intense investigation. The A1-adenosine receptors mediate the negative dromotropic, chronotropic, inotropic, and the anti-beta-adrenergic actions of adenosine. Activation of A(2A)- and perhaps A(2B)-adenosine receptors causes vasodilation. Evidence of novel actions mediated by A(2B)- and A3-adenosine receptors is accumulating. Adenosine is cardioprotective during episodes of cardiac hypoxia/ischemia; several potential mechanisms may be involved. Pharmacologic tools are currently available for laboratory investigation of the actions of adenosine, and the development of adenosine receptor subtype-selective agonists and antagonists for therapeutic purposes is beginning.
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PMID:Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology. 922 56

Cardiomyocytes isolated from rabbit hearts were preconditioned in vitro by 10 min of ischemia or treatment with 100 microM adenosine. Protection was assessed as average integrated mortality following osmotic swelling and determination of viability by trypan blue exclusion over 60-180 min ischemia. Repetitive sub-maximal stimulations with 1 microM adenosine amplified the protective response. Treatment with adenosine only at the onset of prolonged ischemia afforded a dose-dependent protection. The PKC inhibitor calphostin C (500 nm) blocked preconditioning and, when added during ischemic incubation of non-preconditioned cells, significantly increased injury. The memory of adenosine-induced preconditioning decayed over a 60 min post-incubation period. Light activation of calphostin C initially added to preconditioned ischemic cells in the dark indicated that a 10 min period of PKC activity at the onset of ischemia affords full protection. The reversible PKC inhibitors chelerythrine (5 microM) or staurosporine (100 nM) added only to bracket induction of ischemia, reduced but did not abolish protection. Protection was abolished when either drug was present during induction and a subsequent 30 min post-incubation period. Staurosporine included during initiation and post-incubation but washed out in the final 5 min of post-incubation allowed significant protection to occur. It is concluded that a single adenosine receptor-stimulation induces protection as it preconditions, and PKC activity appears to be required for both induction and protection. Memory may reside in post-receptor amplification of an initial protective response.
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PMID:Preconditioning of isolated rabbit cardiomyocytes: no evident separation of induction, memory and protection. 928 59

The effects of nonselective (theophylline), A1-(DPCPX) or A2A-selective (SCH 58261) adenosine receptor antagonists administered before or after neonatal hypoxia-ischemia (HI) were studied on the extent of brain injury in 7-day-old rats evaluated after 14 days. A possible effect of theophylline (20 mg/kg) on expression of immediate early genes was studied with in situ hybridization. Theophylline (20, 30 or 60 mg/kg) given prior to HI reduced brain damage by 48% (P < 0.001), 36% (P < 0.01) and 34% (P < 0.05), respectively, compared to control rats. This effect was not explained by changes in temperature, cerebral blood flow, blood gas/acid base status or blood glucose during the insult. Theophylline enhanced the upregulation of c-fos and NFGI-A during reperfusion but did not prevent the decrease in adenosine A1 receptor mRNA. Posttreatment with SCH 58261 (0.2 or 2 mg/kg) reduced brain damage by 19% (P < 0.05) and 14% (NS), respectively, compared to control rats which was unrelated to the core temperature. DPCPX (2 or 10 mg/kg) had no effect on the development of brain injury. In conclusion, nonselective and A2A adenosine receptor antagonists reduced brain injury in a model of HI in immature animals.
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PMID:Neonatal cerebral hypoxia-ischemia: the effect of adenosine receptor antagonists. 936 88

We preformed this study to determine the effect on ocular blood flow and the electroretinogram of either nitric oxide synthase (NOS) inhibition, adenosine receptor blockade or the combination of both after 1 hr of ocular ischemia. Thirty-seven cats under general anesthesia were subjected to 1 hr of complete ischemia in one eye by raising the intraocular pressure above systolic blood pressure. The other eye in each animal served as a non-ischemic control. Arterial blood gas tension, systemic arterial pressure, body temperature, hematocrit, and anesthetic level were controlled in each experiment. Cats were divided into four groups. Group 1 received normal saline injections [intravenous (i.v.) and intravitreal], Group 2 adenosine receptor blockade (0.1 ml of 0.01 M 8-sulfophenyltheophylline intravitreal) and saline i.v., Group 3 NOS inhibition (30 mg/kg l-NG-nitroarginine-methyl-ester i.v.) and saline intravitreal, and Group 4 intravitreal adenosine receptor blockade and NOS inhibition i.v. A subset of Group 3 received l-arginine to investigate the reversibility of NOS inhibition, after the blood flow measurements were completed. Five minutes after the end of ischemia, blood flows in retina and choroid were measured using injections of radioactively labeled microspheres. Electroretinographic (ERG) studies were carried out before treatment, before ischemia, during ischemia, and 1, 2, 3, and 4 hr after ischemia ended. NOS inhibition significantly reduced basal blood flow in the choroid, and in the retina when combined with adenosine receptor blockade. Adenosine receptor blockade completely attenuated post-ischemic hyperemia in the retina, but retinal hyperemia reappeared when adenosine receptor blockade and NOS inhibition were combined. Adenosine receptor blockade had no effect on ERG recovery after ischemia. NOS inhibition led to a reduction of ERG a- and b-wave amplitudes in control eyes, that could be reversed by l-arginine. Nitric oxide (NO) appears to be a significant factor in the regulation of basal blood flow in the choroid. Adenosine appears to be a major mediator of retinal hyperemia after 60 min of ischemia. Since NOS inhibition appeared to have direct effects on ERG wave amplitudes, short-term ERG studies may be of limited use in assessing the role of NO in postischemic recovery of the retina. Our observations correlate well with the emerging role of NO as a neurotransmitter in the retina.
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PMID:Adenosine receptor blockade and nitric oxide synthase inhibition in the retina: impact upon post-ischemic hyperemia and the electroretinogram. 942 22

It has been theorized that adenosine is a leading candidate for the metabolite responsible for ischemic muscle pain. The purpose of this study was to determine the effect of the non-selective adenosine receptor antagonist, caffeine, on ischemic skeletal muscle contraction pain. Seven healthy adult volunteers with no history of pain disorders, systemic disease, or habitual caffeine use, were chosen for the two-session, cross-over, double-blind study. Every subject received either 200 mg of caffeine (NoDoz, Bristol-Myers) or identical placebo 1 hour before each of the two trials. Ischemia of the forearm was achieved by inflation of a blood pressure cuff to 250 mm Hg. Forearm muscle activity was generated by performance of wrist curis using a 5-gram bar at a rate of 40 cycles per minute. Pain was rated at 15-second intervals for 1 minute using a visual analog scale (0 to 10) with verbal descriptors. Significance was determined by univariate and multivariate analyses of variance and covariance including repeated measures. Pain ratings at 15 seconds in the caffeine trial were significantly lower (P < 0.02) than those in the placebo trial. This effect continued at 30 seconds (P < 0.05). However, by 45 seconds, pain in the caffeine trial was not significantly lower (P = 0.4) than that in the placebo trial. These results show that high-dose caffeine exhibits considerable analgesic efficacy in experimental muscle pain, adding support for a role of adenosine in producing ischemic muscle contraction pain.
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PMID:Hypoalgesic effect of caffeine in experimental ischemic muscle contraction pain. 943 87

Attenuation of S-T segment elevation between the first and subsequent balloon inflations of a coronary angioplasty procedure has been assumed to indicate a transition to a preconditioned state, but there has been no validation of this assumption. Open-chest rabbits were instrumented with a coronary snare and epicardial electrode. The coronary artery was occluded twice for 5 min with each occlusion followed by 10 min of reflow before a final 30 min occlusion. The evolving S-T elevation was quantitated as the voltage-time integral. For the first coronary occlusion total S-T segment elevation averaged 40.8+/-5.4 mV x min, significantly greater than 26.2+/-4.6 mV x min for the second occlusion (p < 0.001). There was no further change during the initial 5 min of the third occlusion (24.5+/-4.5 mV x min). When the protection of ischemic preconditioning was blocked by intravenous infusion of 8-(p-sulfophenyl)theophylline, an adenosine receptor antagonist, attenuation of S-T segment elevation was no longer apparent. When preconditioning was pharmacologically triggered by tyramine rather than ischemia, there also was no alteration in S-T segment elevation among the 3 occlusions. Therefore, S-T elevation was diminished during the second episode of ischemia only when a transition occurred from non-preconditioned to preconditioned state between occlusions. An attenuated S-T segment is a valid marker for the presence of the preconditioned state.
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PMID:Attenuation of S-T segment elevation during repetitive coronary occlusions truly reflects the protection of ischemic preconditioning and is not an epiphenomenon. 946 67

Isolated pigeon hearts were perfused with Krebs-Henseleit bicarbonate buffer with 1.25 mM Ca++ at a pressure of 60 cm H2O and paced at 210 beats per min. After an equilibration perfusion of 30 min, hearts were subjected to 10 min global ischemia and then reperfused for 30 min. Left ventricular +dP/dtmax, systolic, and end diastolic pressures differed significantly from baseline values during reperfusion as did the release of lactate dehydrogenase (LDH). When the hearts were preconditioned by interruption of flow for two 2.5-min intervals, followed by 10 min of ischemia and then reperfusion, the short periods of ischemia, followed by reperfusion, protected the hearts against the longer bout of ischemia as evidenced by significant differences between the left ventricular (LV) pressure, +dP/dtmax, LV end diastolic pressure and LDH values obtained from the hearts of control vs. preconditioned hearts. Substitution of 1 microM adenosine for the preconditioning ischemia also resulted in the preconditioning response. Ischemic preconditioning (IP) was not blocked by addition of 100 microM 8-(-p-sulfophenyl) theophylline, an adenosine receptor antagonist. Therefore, isolated, perfused bird hearts can be preconditioned, and the mechanism may involve adenosine receptors, although their activation is not necessary for i.p. to occur. Factors in addition to adenosine are likely involved.
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PMID:Ischemia and ischemic preconditioning in the buffer-perfused pigeon heart. 956 74


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