UMLS:C0151814 - FACTA Search

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Query: UMLS:C0151814 (coronary occlusion)
3,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both free radicals (FRs) and adenosine receptor activation contribute to triggering a mechanism of preconditioning (PC) against infarction. This study examined the possibility that there is some interaction between FRs and adenosine generation during PC. In the first series of experiments, the effects of an FR scavenger, N-2-mercaptopropionyl glycine (MPG), on the interstitial adenosine level during PC and on the infarct size-limiting effect of PC were assessed in the rabbit heart in situ. PC with 5-min ischemia/5-min reperfusion limited infarct size after 30-min coronary occlusion (expressed as a percentage of area at risk, %IS/AR) from 33.2 +/- 4.7% (S.E.) to 10.8 +/- 1.1% (p < 0.05). This cardioprotection was blocked by MPG (1.5 mg/kg/min i.v.) infused before and during PC (%IS/AR = 27.4 +/- 3.6). However, the same dose of MPG did not suppress elevation of the adenosine and inosine levels in the microdialysate from the myocardium during 5-min ischemia/reperfusion. In the second series of experiments, the effect of an FR-generating system (1 mM hypoxanthine and 20 mU/ml xanthine oxidase) on the purine production was compared to that of PC in isolated rabbit hearts. Whereas PC increased the adenosine level in the coronary effluent from 0.17 +/- 0.16 microM under baseline to 1.68 +/- 0.53 microM, infusion of the FR generators over a period of 5 min did not increase the adenosine release. However, infarct size was similarly reduced by PC and by 5-min transient infusion of FR generators, and the cardioprotection by the FR generators was abolished by 300 microM MPG. These results suggest that there is no interaction between free radicals and adenosine during the trigger phase of PC in the rabbit heart.
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PMID:Relationship between free radicals and adenosine in the mechanism of preconditioning: are they interrelated or independent triggers? 1105 47

The goal of this study was to determine whether the protective effects of the A3AR agonist N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (IB-MECA) against myocardial stunning are mediated by the A1AR. Six groups of conscious rabbits underwent a sequence of six 4-minute coronary occlusion (O)/4-minute reperfusion (R) cycles for three consecutive days (days 1, 2, and 3). In vehicle-treated rabbits (group I), the recovery of systolic wall thickening (WTh) in the ischemic/reperfused region was markedly depressed on day 1, indicating the presence of severe myocardial stunning. On days 2 and 3, however, the recovery of systolic WTh was markedly accelerated, indicating the presence of late ischemic preconditioning (PC). When rabbits were pretreated with the A1AR agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 100 microg/kg i.v.) or with IB-MECA (100 microg/kg i.v.) 10 min prior to the first sequence of O/R cycles on day 1 (group III and V, respectively), the recovery of systolic WTh was markedly accelerated compared to vehicle-treated animals (reflected as an approximately 48% decrease in the total deficit of systolic WTh). The magnitude of the protection afforded by adenosine receptor agonists was equivalent to that provided by late ischemic PC. Pre-treating rabbits with the A1AR antagonist N-0861 completely blocked both the hemodynamic and the cardioprotective effects of CCPA (group IV). However, the same dose of N-0861 did not block the cardioprotective actions of IB-MECA (group VI). Importantly, N-0861 did not influence the degree of myocardial stunning in the absence of PC (group II) and it did not block the development of late ischemic PC. Taken together, these results provide conclusive evidence that the cardioprotective effects of IB-MECA are not mediated via the A1AR, supporting the concept that activation of A3ARs prior to an ischemic challenge provides protection against ischemia/reperfusion injury.
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PMID:Protection of IB-MECA against myocardial stunning in conscious rabbits is not mediated by the A1 adenosine receptor. 1160 96

The authors sought to demonstrate the advantages of a selective, potent, short-acting A adenosine receptor agonist, CVT-3146 (2-(N-pyrazolyl)Ado derivative), for potential clinical use as a coronary vasodilator during myocardial perfusion imaging. The use of adenosine in a pharmacological stress test during myocardial imaging is limited by side effects mediated by A1 and A2B adenosine receptors and by its ultrashort duration of action. CVT-3146 (0.1-5 microg/kg) and adenosine (13-267 microg/kg) were given as peripheral intravenous injections in 10 awake dogs instrumented for measurement of coronary blood flow (CBF). CVT-3146 caused a dose-dependent increase of CBF (ED50 = 0.34 +/- 0.08 microg/kg, maximal increase = 221 +/- 18%, n = 6). Adenosine was less potent (ED = 51 +/- 15 microg/kg, p < 0.05) but equieffective (maximal increase in CBF = 227 +/- 11%). The increase in CBF caused by 2.5 microg/kg CVT-3146 reached 84 +/- 5% of the maximal reactive hyperemia following 20 s of coronary occlusion (n = 4). After a 10-s injection of CVT-3146 (2.5 microg/kg), the increase in CBF remained at least twofold above baseline for 97 +/- 14 s, whereas for adenosine (267 microg/kg), the twofold increase in CBF lasted only 24 +/- 2 s (p < 0.01, n = 6). A 30-s injection of 2.5 microg/kg CVT-3146 prolonged the twofold increase in CBF up to 221 +/- 20 s. No atrioventricular block was noted. At 2.5 microg/kg, the peak effect of CVT-3146 on CBF was associated with a short-lasting (20 +/- 6 s) increase in heart rate (78 +/- 9 bpm) and decrease in mean arterial blood pressure (13 +/- 6 mm Hg, p < 0.05, n = 6). CVT-3146 is a potent coronary vasodilator. Its short duration of action, minimal and transient systemic hemodynamic effects, and ease of administration may make this agonist suitable for pharmacological coronary vasodilation during myocardial perfusion imaging for noninvasive detection of subcritical arterial stenosis.
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PMID:Selective A2A adenosine receptor agonist as a coronary vasodilator in conscious dogs: potential for use in myocardial perfusion imaging. 1250 31

The purpose of this study was to determine whether the adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning. Regional stunning was produced by 15 min of coronary artery occlusion and 3 h of reperfusion (RP) in anesthetized open-chest pigs. In acute protection studies, animals were pretreated with saline, low-dose AMP-579 (15 microg/kg iv bolus 10 min before ischemia), or high-dose AMP-579 (50 microg/kg iv at 14 microg/kg bolus + 1.2 microg.kg(-1).min(-1) for 30 min before coronary occlusion). The delayed preconditioning effects of AMP-579 were evaluated 24 h after administration of saline vehicle or high-dose AMP-579 (50 microg/kg iv). Load-insensitive contractility was assessed by measuring regional preload recruitable stroke work (PRSW) and PRSW area. Acute preconditioning with AMP-579 dose dependently improved regional PRSW: 129 +/- 5 and 100 +/- 2% in high- and low-dose AMP-579 groups, respectively, and 78 +/- 5% in the control group at 3 h of RP. Administration of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.7 mg/kg) blocked the acute protective effect of high-dose AMP-579, indicating that these effects are mediated through A1 receptor activation. Delayed preconditioning with AMP-579 significantly increased recovery of PRSW area: 64 +/- 5 vs. 33 +/- 5% in control at 3 h of RP. In isolated perfused rat heart studies, kinetics of the onset and washout of AMP-579 A1 and A2a receptor-mediated effects were distinct compared with those of other adenosine receptor agonists. The unique nature of the adenosine agonist AMP-579 may play a role in its ability to induce delayed preconditioning against in vivo myocardial stunning.
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PMID:Adenosine A1/A2a receptor agonist AMP-579 induces acute and delayed preconditioning against in vivo myocardial stunning. 1527 62

Coronary artery occlusion-induced tachyarrhythmias that culminate in ventricular fibrillation are the leading cause of death in developed countries. The intrinsic adenosine receptor system protects the heart from an ischemic insult. Thus the increased functional demands made on the heart during exercise may produce protective adaptations mediated by endogenous adenosine. Therefore, we tested the hypothesis that a single bout of dynamic exercise increases the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion in conscious hypertensive rats via the intrinsic adenosine receptor system. To test this hypothesis, we recorded the VAT before and on an alternate day after a single bout of dynamic treadmill exercise (12 m/min, 10% grade for 40 min). A single bout of dynamic exercise significantly reduced postexercise arterial pressure (Delta-24 +/- 4 mmHg) and increased VAT (Delta+1.95 +/- 0.31 min). Adenosine receptor blockade with the nonselective adenosine receptor antagonists theophylline or aminophylline (10 mg/kg) attenuated the cardioprotective effects of a single bout of dynamic exercise. Results suggest that strategies that increase myocardial ATP requirements leading to adenosine production provide protection against coronary artery occlusion.
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PMID:Acute exercise increases the ventricular arrhythmia threshold via the intrinsic adenosine receptor system in conscious hypertensive rats. 1587 88

Following myocardial infarction (MI), contractile dysfunction develops not only in the infarct zone but also in noninfarcted regions of the left ventricle remote from the infarct zone. Inflammatory activation secondary to MI stimulates inducible nitric oxide synthase (iNOS) induction with excess production of nitric oxide. We hypothesized that the anti-inflammatory effects of selective A(2A)-adenosine receptor (A(2A)AR) stimulation would suppress inflammation and preserve cardiac function in the remote zone early after MI. A total of 53 mice underwent 60 min of coronary occlusion followed by 24 h of reperfusion. The A(2A)AR agonist (ATL146e, 2.4 microg/kg) was administered intraperitoneally 1, 3, and 6 h postreperfusion. Because of the 1-h delay in treatment after MI, ATL146e had no effect on infarct size, as demonstrated by contrast-enhanced cardiac MRI (n = 18) performed 24 h post-MI. ATL146e did however preserve global cardiac function at that time by limiting contractile dysfunction in remote regions [left ventricle wall thickening: 51 +/- 4% in treated (n = 9) vs. 29 +/- 3% in nontreated groups (n = 9), P < 0.01]. RT-PCR, immunohistochemistry, and Western blot analysis indicated that iNOS mRNA and protein expression were significantly reduced by ATL146e treatment in both infarcted and noninfarcted zones. Similarly, elevations in plasma nitrate-nitrite after MI were substantially blunted by ATL146e (P < 0.01). Finally, treatment with ATL146e reduced NF-kappaB activation in the myocardium by over 50%, not only in the infarct zone but also in noninfarcted regions (P < 0.05). In conclusion, A(2A)AR stimulation after MI suppresses inflammatory activation and preserves cardiac function, suggesting the potential utility of A(2A)AR agonists against acute heart failure in the immediate post-MI period.
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PMID:Stimulation of A2A-adenosine receptors after myocardial infarction suppresses inflammatory activation and attenuates contractile dysfunction in the remote left ventricle. 1628 33

We used pharmacological agents and genetic methods to determine whether the potent A(3) adenosine receptor (AR) agonist 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (Cl-IB-MECA) protects against myocardial ischemia/reperfusion injury in mice via the A(3)AR or via interactions with other AR subtypes. Pretreating wild-type (WT) mice with Cl-IB-MECA reduced myocardial infarct size induced by 30 min of coronary occlusion and 24 h of reperfusion at doses (30 and 100 mug/kg) that concomitantly reduced blood pressure and stimulated systemic histamine release. The A(3)AR-selective antagonist MRS 1523 [3-propyl-6-ethyl-5[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridine-carboxylate], but not the A(2A)AR antagonist ZM 241385 [4-{2-7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol], blocked the reduction in infarct size provided by Cl-IB-MECA, suggesting a mechanism involving the A(3)AR. To further examine the selectivity of Cl-IB-MECA, we assessed its cardioprotective effectiveness in A(3)AR gene "knock-out" (A(3)KO) mice. Cl-IB-MECA did not reduce myocardial infarct size in A(3)KO mice in vivo and did not protect isolated perfused hearts obtained from A(3)KO mice from injury induced by global ischemia and reperfusion. Additional studies using WT mice treated with compound 48/80 [condensation product of p-methoxyphenethyl methylamine with formaldehyde] to deplete mast cell contents excluded the possibility that Cl-IB-MECA was cardioprotective by releasing mediators from mast cells. These data demonstrate that Cl-IB-MECA protects against myocardial ischemia/reperfusion injury in mice principally by activating the A(3)AR.
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PMID:Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor. 1698 66

We tested in the in vivo rat heart the hypothesis that although ischemic preconditioning can employ different signal transduction pathways, these pathways converge ultimately at the level of the mitochondrial respiratory chain. Infarct size produced by a 60-min coronary artery occlusion (69%+/-2% of the area at risk) was limited by a preceding 15-min coronary occlusion (48%+/-4%). Cardioprotection by this stimulus was triggered by adenosine receptor stimulation, which was followed by protein kinase C and tyrosine kinase activation and then mitochondrial K(+)(ATP)-channel opening. In contrast, cardioprotection by 3 cycles of 3-min coronary occlusions (infarct size 27%+/-5% of the area at risk) involved the release of reactive oxygen species, which was followed by protein kinase C and tyrosine kinase activation, but was independent of adenosine receptor stimulation and K(+)(ATP)-channel activation. However, both pathways decreased respiratory control index (RCI; state-3/state-2, using succinate as complex-II substrate) from 3.1+/-0.2 in mitochondria from sham-treated hearts to 2.4+/-0.2 and 2.5+/-0.1 in hearts subjected to a single 15-min and triple 3-min coronary occlusions, respectively (both P<0.05). The decreases in RCI were due to an increase in state-2 respiration, whereas state-3 respiration was unchanged. Abolition of cardioprotection by blockade of either signal transduction pathway was paralleled by a concomitant abolition of mitochondrial uncoupling. These observations are consistent with the concept that mild mitochondrial uncoupling contributes to infarct size limitation by various ischemic preconditioning stimuli, despite using different signal transduction pathways. In conclusion, in the in vivo rat heart, different ischemic preconditioning (IPC) stimuli can activate highly different signal transduction pathways, which seem to converge at the level of the mitochondria where they increase state-2 respiration.
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PMID:Ischemic preconditioning modulates mitochondrial respiration, irrespective of the employed signal transduction pathway. 1806 Nov 24

The goal of this study was to examine whether the A(3) adenosine receptor (A(3)AR) agonist Cl-IB-MECA protects against myocardial ischemia/reperfusion injury when administered at the time of reperfusion in an in vivo mouse model of infarction induced by 30min of coronary occlusion and 24h of reperfusion. Treating B6 wild-type with Cl-IB-MECA during the reperfusion phase (100microg/kg i.v. bolus+0.3microg/kg/min subcutaneously via implantation of Alzet mini-osmotic pumps) reduced myocardial infarct size approximately 37% from 50.1+/-2.5% in vehicle-treated mice to 31.6+/-2.8% in Cl-IB-MECA-treated mice, and significantly reduced the number of leukocytes that infiltrated into the ischemic-reperfused myocardium. Cl-IB-MECA did not reduce infarct size or limit leukocyte accumulation in studies using B6 congenic A(3)AR gene "knock-out" mice or in chimeric mice lacking the expression of A(3)ARs in bone marrow (BM)-derived cells. Subsequent mechanistic studies demonstrated that Cl-IB-MECA inhibited migration of mouse neutrophils isolated from BM towards the chemotactic substance c5a in trans-well migration assays, and inhibited leukocyte migration into the peritoneal cavity in a mouse model of thioglycollate-induced peritonitis. We conclude that treating with the A(3)AR agonist Cl-IB-MECA at the time of reperfusion provides effective protection from ischemia/reperfusion injury in the heart through activation of the A(3)AR expressed in BM-derived cells, potentially by suppressing the robust inflammatory reaction that occurs during reperfusion and neutrophil-mediated tissue injury.
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PMID:A(3) adenosine receptor activation during reperfusion reduces infarct size through actions on bone marrow-derived cells. 2013 22

Brief periods of ventricular pacing during the early reperfusion phase (pacing-induced postconditioning, PPC) have been shown to reduce infarct size as measured after 2 h of reperfusion. In this study, we investigated (1) whether PPC leads to maintained reduction in infarct size, (2) whether abnormal mechanical load due to asynchronous activation is the trigger for PPC and (3) the signaling pathways that are involved in PPC. Rabbit hearts were subjected to 30 min of coronary occlusion in vivo, followed by 6 weeks of reperfusion. PPC consisted of ten 30-s intervals of left ventricular (LV) pacing, starting at reperfusion. PPC reduced infarct size (TTC staining) normalized to area at risk, from 49.0 +/- 3.3% in control to 22.9 +/- 5.7% in PPC rabbits. In isolated ejecting rabbit hearts, replacing LV pacing by biventricular pacing abolished the protective effect of PPC, whereas ten 30-s periods of high preload provided a protective effect similar to PPC. The protective effect of PPC was neither affected by the adenosine receptor blocker 8-SPT nor by the angiotensin II receptor blocker candesartan, but was abrogated by the cytoskeletal microtubule-disrupting agent colchicine. Blockers of the mitochondrial K(ATP) channel (5HD), PKC (chelerythrine) and PI3-kinase (wortmannin) all abrogated the protection provided by PPC. In the in situ pig heart, PPC reduced infarct size from 35 +/- 4 to 16 +/- 12%, a protection which was abolished by the stretch-activated channel blocker gadolinium. No infarct size reduction was achieved if PPC application was delayed by 5 min or if only five pacing cycles were used. The present study indicates that (1) PPC permanently reduces myocardial injury, (2) abnormal mechanical loading is a more likely trigger for PPC than electrical stimulation or G-coupled receptor stimulation and (3) PPC may share downstream pathways with other modes of cardioprotection.
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PMID:Long-term protection and mechanism of pacing-induced postconditioning in the heart. 2033 4

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