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 dose-response characteristics for the effect of ATP upon cardiac function and vascular tone have been investigated in the isolated perfused rat heart. Vasodilation was observed with low ATP concentrations (0.01-0.1 mM) whereas severe vasoconstriction occurred with high concentrations (1.0-10.0 mM). At all doses studied, heart rate and pressure-rate product were reduced in a dose-dependent manner, with 10 mM ATP almost complete cardiac arrest was observed. Analysis of epicardial electrograms revealed that ATP induced arrhythmias, prolonged the P-R interval and induced partial blockade of S-A nodal activity and A-V conduction. Investigating possible mechanisms for the vascular and contractile effects of ATP, it was possible to exclude the calcium chelating properties of ATP and the effects of coincident ischemia arising as a consequence of ATP-induced vasoconstriction. Pharmacological studies revealed the ATP-induced vasoconstriction to be unresponsive to a range of coronary vasodilators and also allowed exclusion of prostaglandins, catecholamines and adrenergic receptors in the mediation of ATP effects. Investigations with acetylcholine revealed remarkably similar effects upon both contractile and vascular activity but studies with atropine suggested that the muscarinic receptor was not involved. Studies with theophylline allowed a dissociation of the vascular and contractile effects of ATP and indicated a possible involvement of the adenosine receptor in the cellular response to both high and low concentrations of ATP.
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PMID:Vascular and contractile responses to extracellular ATP: studies in the isolated rat heart. 299 28

We have shown previously that theophylline increases both renal plasma flow (RPF) and glomerular filtration rate (GFR) during the initiation phase of post-ischemic acute renal failure (ARF) in rats. The purpose of the present experiments was to determine the effects of theophylline during the maintenance phase of ARF, five days after initiation. Clearance techniques were used to measure renal function in a control group of pentobarbital anesthetized rats (group C) and in three experimental groups, five days after subjecting the left kidney to a thirty-minute period of complete ischemia. Group SS received saline during both the ischemic episode and the clearance measurements; group ST received saline during ischemia and theophylline, acutely, during the clearance measurements; group TS received theophylline during ischemia and saline during the clearance measurements. In comparison with the values for the control group (group C), RPF and GFR of the post-ischemic left kidneys of group SS were approximately half normal. In groups ST and TS, RPF and GFR of the left kidneys were higher than in group SS. Collectively, these results demonstrate that pretreatment with theophylline during the initiation phase of ischemia-induced ARF leads to increased RPF and GFR during the maintenance phase, and that acute theophylline treatment during the maintenance phase acutely increases RPF and GFR. Since increases in GFR were associated with increases in RPF, and since theophylline is an adenosine receptor antagonist, these results are consistent with the hypothesis that adenosine-mediated hemodynamic changes play a pathogenic role in ischemia-induced ARF in rats.
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PMID:Theophylline in rats during maintenance phase of post-ischemic acute renal failure. 335 58

Sixty-five male gerbils were exposed to 30 minutes of cerebral ischemia induced by a bilateral carotid artery occlusion. One group of 15 gerbils received a single injection of 25 microliter of 5 microM cyclohexyladenosine into the cerebral ventricle 15 minutes after release of the occlusion. Another group of 45 gerbils received a similar injection of the vehicle. Five days after ischemia, the hippocampal histology was examined under light microscopy. In the gerbils treated with the adenosine receptor agonist N-6-cyclohexyladenosine, the CA1 region of the hippocampus showed significant quantitative pyramidal cell preservation (p less than 0.01, Mann-Whitney U test). Qualitatively, substantial destruction of CA1 neurons was present in all hippocampi of the vehicle-injected gerbils. The CA1 neurons in the cyclohexyladenosine-treated gerbils did not differ from those seen in the five nonischemic controls. The precise mechanism of the protective action of cyclohexyladenosine is unknown, although it has been demonstrated that adenosine agonists reduce presynaptic glutamate release in vitro. It is possible that postischemic administration of cyclohexyladenosine decreases the release of this neurotransmitter in the intact brain as well. The concomitant reduction of the neurotoxic effect of glutamate may, therefore, result in better histologic preservation of the pyramidal cells in the postischemic CA1.
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PMID:Cyclohexyl adenosine protects against neuronal death following ischemia in the CA1 region of gerbil hippocampus. 341 11

Adenosine as well as hypoxia and ischemia are known to cause atrioventricular conduction block. To test the hypothesis that adenosine is the primary mediator of hypoxia-induced atrioventricular conduction delay in isolated perfused guinea pig hearts, we characterized a) the time courses of hypoxia-induced adenosine release and delay in atrioventricular conduction, b) the relationships between oxygen tension, adenosine concentration in the effluent, and atria-to-His-bundle interval, and c) the adenosine receptor mediating the negative dromotropic effect of hypoxia. Oxygen tension and effluent adenosine levels were linearly related with a correlation coefficient (r) of -0.85 and a slope of -6.3 +/- 0.37 pmol/min/g/torr. Likewise, oxygen tension and atria-to-His-bundle interval prolongation were linearly related with r = -0.85 and a slope of -0.180 +/- 0.013 msec/torr. The EC50 of effluent adenosine in causing atria-to-His-bundle prolongation was 0.26 +/- 0.02 microM. Adenosine deaminase, an enzyme that deaminates adenosine to inosine and is limited to the extracellular space, significantly attenuated (61%) the atria-to-His-bundle interval prolongation caused by hypoxia. This prolongation was further reduced (81%) by a combination of adenosine deaminase and theophylline, an adenosine receptor blocker. Adenosine deaminase also reduced (by 95%) the atria-to-His-bundle interval prolongation in normoxic recipient hearts caused by the effluent of hypoxic donor hearts. Several adenosine antagonists, i.e., theophylline, 8-phenyltheophylline, and 8-(p-sulfophenyl)theophylline antagonized in a dose-dependent manner the negative dromotropic effect of exogenous adenosine and hypoxia. Schild analysis of the antagonism of hypoxia-induced atria-to-His-bundle interval prolongation by 8-(p-sulfophenyl)theophylline yielded the following pA2 values: 5.30 +/- 0.25 and 5.28 +/- 0.31 using oxygen tension and effluent adenosine vs. AH interval prolongation, respectively. 8-(p-Sulfophenyl)theophylline also antagonized to an equal extent atria-to-His-bundle interval prolongations of similar magnitude caused either by adenosine or hypoxia. We conclude that 1) adenosine is the primary mediator of hypoxia-induced atrioventricular conduction delay, and 2) the adenosine receptor that mediates the negative dromotropic effect of hypoxia is similar to that of exogenous adenosine.
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PMID:Effect of adenosine on atrioventricular conduction. II: Modulation of atrioventricular node transmission by adenosine in hypoxic isolated guinea pig hearts. 379 84

Because of ontogenic influences on the pathophysiologic mechanisms of brain injury in the perinatal brain, and in particular, the incomplete development of adenosine receptor systems, we investigated the potential for adenosine to provide cerebro-protection in a well established newborn rat model of hypoxia-ischemia. Fifteen litters of postnatal d 7 animals were subjected to unilateral carotid ligation and exposure to hypoxia (8% oxygen) for 3 h. Immediately after hypoxia-ischemia, animals received either the adenosine deaminase inhibitor deoxycoformycin (DCF; 2.5 mg/kg intraperitoneally) or the adenosine uptake inhibitor propentofylline (PPF; 10 mg/kg intraperitoneally); paired littermates received an equivalent volume of normal saline. On postnatal d 14, injury or protection was assessed by differences in hemispheric weights, morphometric determinations of infarct area, and histopathologic analyses. DCF resulted in a 34% (p = 0.02) and 31% (p = 0.03) reduction in hemispheric weight disparities and infarct area, respectively; for PPF, these reductions were 46% (p = 0.03) and 32% (p = 0.04), respectively. Light microscopic examinations of striatum, thalamus, hippocampus, and cortex revealed that both drugs significantly improved histologic scores as well. Measurements in six separate litters indicated that neither drug significantly reduced core body temperature for at least 6 h postadministration. These findings indicate that potentiation of endogenous adenosine levels in the perinatal brain can significantly ameliorate brain injury. Each of these treatment strategies was effective even when administered after the hypoxic-ischemic insult. Thus, further investigations of adenosinergic therapies are warranted in this and other perinatal models of cerebral ischemia to elucidate in detail their potential for clinical application.
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PMID:Reduction in cerebral ischemic injury in the newborn rat by potentiation of endogenous adenosine. 749 51

We recently observed that dipyridamole pretreatment significantly enhanced the infarct size (IS)-limiting effect of preconditioning (PC), which was attenuated by adenosine receptor antagonist. This potentiation of PC was interpreted to result from inhibition of nucleoside transport by dipyridamole, but contribution of other pharmacologic actions of dipyridamole could not be excluded. To confirm that inhibition of nucleoside transport leads to PC enhancement, we assessed alteration of mild PC by two different nucleoside transport inhibitors, dilazep and R75231, which, unlike dipyridamole, lack action on phosphodiesterase (PDE) and prostacyclin. Myocardial infarction was induced in rabbits by 30-min coronary occlusion and 72-h reperfusion. IS and area at risk (AAR) were determined by histology and fluorescent particles, respectively. Rabbits either were untreated or received dilazep (0.34 mg/kg intravenously, i.v.) or R75231 (0.05 mg/kg i.v.) before coronary occlusion. In other groups of rabbits, PC was conducted with 2-min ischemia and 5-min reperfusion with or without injection of the nucleoside transport inhibitor (0.34 or 0.10 mg/kg dilazep or 0.05 mg/kg of R75231) before PC. IS expressed as percentage of AAR (%IS/AAR) was 43.9 +/- 2.3% (SE) in untreated controls; dilazep (0.34 mg/kg) and R75231 alone did not modify IS (%IS/AAR = 50.6 +/- 4.7 and 42.7 +/- 11.9%, respectively). PC tended to reduce IS (%IS/AAR = 33.3 +/- 3.5%), but the combination of dilazep or R75231 with PC significantly limited %IS/AAR (%IS/AAR = 22.5 +/- 5.0% after low-dose dilazep plus PC, 27.6 +/- 4.9% after high-dose dilazep plus PC, and 19.9 +/- 3.6%, after R75231 plus PC).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nucleoside transport inhibitors enhance the infarct size-limiting effect of ischemic preconditioning. 753 64

The mechanism for the suppression of reperfusion arrhythmia by preconditioning (PC) remains unknown. This study aimed to examine the roles of the adenosine receptor, prostaglandin (PG), and bradykinin (BK) receptor in PC. Under pentobarbital anesthesia, the coronary artery of the rat was occluded for 5 min and then reperfused. In untreated controls, this protocol induced ventricular tachycardia (VT) in 100% of the rats and ventricular fibrillation (VF) in 60%. PC with 2 min ischemia/5 min reperfusion prior to the 5 min coronary occlusion significantly reduced the incidence of reperfusion VT and VF to 30% and 0%, respectively. This antiarrhythmic effect of the PC was not blocked when rats were pretreated with 8-phenyltheophylline (8-PT, 10 mg/kg), aspirin-DL-lysin (18 mg/kg), or a specific BK receptor antagonist, Hoe140 (20 nmol/kg). None of these agents alone significantly modified the incidence of reperfusion VT or VF. These results suggest that neither the adenosine receptor, endogenous PG, nor BK receptor play a major role in the mechanism of suppression of perfusion arrhythmias by PC in the rat heart.
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PMID:Suppression of reperfusion arrhythmia by ischemic preconditioning in the rat: is it mediated by the adenosine receptor, prostaglandin, or bradykinin receptor? 757 77

We have proposed that ischemic preconditioning in the rabbit heart is initiated by adenosine A1 receptor stimulation which results in an upregulation of protein kinase C (PKC). Subsequent sustained ischemia then causes renewed stimulation of adenosine A1 receptors with rapid reactivation of PKC and phosphorylation of a target protein(s) which mediates the protection. If the above theory is correct then angiotensin II (AII) receptor stimulation, which is known to activate PKC, should also protect the heart. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium staining. Pretreating hearts with 100 mM AII for 5 min, followed by 10 min of drug-free perfusion prior to the prolonged ischemia limited infarction (7.2 +/- 2.0% of the risk area v 31.1 +/- 3.4% in control animals, P < 0.01). This protection could be blocked by the AT1 receptor blocker losartan (10 microM), but not by the AT2 receptor blocker PD 123319 (10 microM). Polymyxin B (50 microM), a PKC inhibitor, also blocked the protective effect of AII. These observations demonstrated that activation of PKC by AT1 receptor stimulation prior to ischemia does mimic ischemic preconditioning. Following AII infusion, administration, during the 30 min ischemic period, of either SPT [8-(p-sulfophenyl)theophylline] (an adenosine receptor blocker) or losartan failed to block AII's protective effect. However, co-administration of SPT and losartan did abort AII's protection suggesting that AII may not be completely washed out during the 10 min drug-free perfusion allowing residual agonist to reactivate PKC during the 30 min ischemia even when adenosine receptors are blocked. Thus, if only one of the receptors (AT1 or adenosine) were activated during the ischemic period, protection would occur. We conclude that activation of PKC by AII, prior to ischemia, can limit myocardial infarction. While PKC must be reactivated during ischemia to realize protection, the specific receptor type initiating reactivation is not crucial.
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PMID:Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. 760 6

Significant hyperemia results after 1 h of retinal ischemia in cats. Adenosine receptor blockade significantly attenuates the increase in retinal blood flow that occurs in response to systemic hypoxia. Synthesizing these findings, I hypothesized that adenosine receptor antagonism would attenuate the increase in blood flow that follows retinal ischemia. In these experiments, blood flows were measured with radioactively labeled microspheres in the retina and choroid of adult cats anesthetized with chloralose and acepromazine. Ischemia was induced for 1 h in both eyes by elevation of intraocular pressure above systolic arterial pressure. Blood flows were measured before ischemia and 5 min after the return of normal intraocular pressure. In each animal, after baseline blood flows were determined and approximately 10-15 min before ischemia was induced, one eye received 0.1 ml of intravitreal 0.01M 8-sulfophenyltheophylline, a polar adenosine receptor antagonist, while the opposite eye, the control, received an equal volume of intravitreal saline. Arterial blood gas tensions, systemic arterial pressure, hematocrit, and anesthetic level were kept constant during the experimental protocol. Compared with control eyes, hyperemia was significantly attenuated in the retinal circulation after ischemia in eyes injected with 8-sulfophenyltheophylline. Increase in post-ischemic choroidal blood flow was not affected. Although adenosine is involved in the vasodilatation that occurs when blood flow is restored after retinal ischemia, adenosine receptor blockade did not completely abolish hyperemia, implying that blockade was incomplete or other vasoactive substances also affect post ischemic hyperemia in the retina.
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PMID:Post-ischemic hyperemia in the cat retina: the effects of adenosine receptor blockade. 760 19

2-chloro-adenosine induced apoptosis of astroglial cells in rat brain cultures, as shown by flow cytometry and morphological analysis. The adenosine analogue was far more potent than several previously characterized sugars (including 2-deoxy-D-ribose and D-ribose, the sugar moiety of 2-chloro-adenosine), which trigger apoptosis in a variety of cell-lines [8-10], suggesting that the effects of 2-chloro-adenosine are only partially dictated by its sugar moiety. Nevertheless, 2-chloro-adenosine and 2-deoxy-D-ribose attenuated each other's cell death when used in combination, suggesting the involvement of common intracellular mechanisms. It is suggested that 2-chloro-adenosine may induce apoptosis via a yet-to-be identified adenosine receptor, which may have intriguing implications for both nervous system development and brain response to trauma and ischemia.
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PMID:A novel action for adenosine: apoptosis of astroglial cells in rat brain primary cultures. 765 53


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