Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine (Ado) has been reported to be cardioprotective in several models of myocardial ischemia. The nucleoside transport inhibitor R-75231 (R-75) has been reported to enhance local Ado concentrations and postischemic recovery of function, but little is known regarding its effects on myocardial infarct size. The purpose of the present study was to determine the effects of R-75 on infarct size and to measure myocardial regional Ado concentrations. Studies were conducted in pentobarbital-anesthetized swine undergoing 60 min of coronary artery occlusion and 2 h of reperfusion. Control pigs (n = 8) were compared with those receiving R-75 (0.1 mg/kg i.v.) 15 min before either occlusion (Pre R-75, n = 8) or reperfusion (Rep R-75, n = 8). Interstitial fluid (ISF) Ado, coronary venous Ado, and infarct size (% of the region at risk) were measured. In the Pre R-75 group, ISF Ado concentrations were significantly increased before and during ischemia, reaching a peak value of 71.8 +/- 8.6 microM (vs. 16.8 +/- 0.8 microM in control). ISF inosine and hypoxanthine concentrations were significantly reduced during ischemia in Pre R-75 animals. Infarct size was smaller in Pre R-75 compared with control (21.6 +/- 1.9 vs. 38.4 +/- 2.6%, P < 0.05). The Rep R-75 group had significantly elevated coronary venous Ado concentrations but no increases in ISF Ado or reduction in infarct size (33.5 +/- 3.5%). These data indicate that R-75 increases myocardial Ado and reduces infarct size when administered before coronary occlusion. The R-75-induced reduction in infarct size appears to be related to the augmentation of ISF Ado before ischemia rather than to increased plasma Ado during reperfusion.
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PMID:Infarct size reduction with the nucleoside transport inhibitor R-75231 in swine. 913 72

The increased tolerance to myocardial ischemia observed during the second of two sequential exercise tests, i.e. the warm-up phenomenon, has been proposed as a clinical model of ischemic preconditioning. Adenosine appears to be a mediator of ischemic preconditioning in both experimental and clinical settings. The purpose of this study was to investigate the role of A1 adenosine receptors in the warm-up phenomenon. A double-blind, placebo-controlled, cross-over design was used. Twelve patients with coronary artery disease and positive exercise test were randomized to receive either bamiphylline, a selective A1 adenosine receptor antagonist, or placebo, immediately prior to two consecutive treadmill exercise tests carried out on day 1. Then, on day 2 all patients underwent two consecutive exercise tests immediately after administration of the remaining treatment. During the first exercise test, bamiphylline, compared to placebo, increased the time to and rate-pressure product at 1.5 mm ST-segment depression (from 317 +/- 118 to 423 +/- 127 s, p < 0.05 and from 199 +/- 38 to 230 +/- 36 b/min.mmHg.10(2), p < 0.05, respectively). After both placebo and bamiphylline infusions, time to 1.5 mm ST-segment depression during the second exercise test was greater than that during the first test (445 +/- 121 vs 317 +/- 118 s, p < 0.001 and 483 +/- 128 vs 423 +/- 127 s, p < 0.05, respectively), as was rate-pressure product at 1.5 mm ST-segment depression (228 +/- 40 vs 199 +/- 38 b/min.mmHg.10(2), p < 0.01 and 253 +/- 42 vs 230 +/- 36 b/min.mmHg.10(2), p < 0.05, respectively). In conclusion, bamiphylline, at a dose able to increase ischemic threshold and exercise tolerance compared to placebo, does not prevent the warm-up phenomenon. These findings suggest that, in the setting of the warm-up phenomenon, A1 adenosine receptor blockade is insufficient to prevent ischemic preconditioning.
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PMID:Effects of A1 adenosine receptor blockade on the warm-up phenomenon. 918 7

At the turn of this century, it was proposed that ischemic cardiac pain might be related to distension of the ventricular wall ("mechanical hypothesis"). Three decades later, it was hypothesized that ischemic pain might be elicited by the intramyocardial release of pain-producing substances induced by ischemia ("chemical hypothesis"). Studies carried out in the past 10 years have given strong support to the chemical hypothesis, because they have consistently shown that adenosine is a mediator of ischemic cardiac pain. Adenosine-induced ischemic cardiac pain is mediated primarily by stimulation of A1 receptors located in cardiac nerve endings and is potentiated by substance P. Conversely, the magnitude and rate of left ventricular dilation during ischemia do not predict the severity of angina. It is worth noting, however, that stretching of epicardial coronary arteries appears to potentiate the severity of angina caused by myocardial ischemia. The nervous activity generated by myocardial ischemia is modulated in intrinsic cardiac, mediastinal, and thoracic ganglia. Then it is further modulated in the central nervous system and projects bilaterally to the cortex, as demonstrated in humans by positron emission tomography, where it is decoded as a painful sensation. The causes responsible for the lack of angina during myocardial ischemia are probably different in patients who present both pain-free and painful myocardial ischemia, in patients with predominantly painless ischemia, and in diabetic patients.
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PMID:New look to an old symptom: angina pectoris. 939 81

Although ischemic preconditioning (IP) in several species can be pharmacologically mimicked by selective adenosine A1 or A3 receptor agonists, it is currently unclear which receptor subtype (A1 and/or A3) is physiologically involved in mediating IP. To investigate this question, we determined (a) the affinity of adenosine for rabbit adenosine A1 and A3 receptors, and (b) the effects of selective rabbit A1 receptor blockade on IP and adenosine-mediated cardioprotection in a rabbit Langendorff model of myocardial ischemia-reperfusion injury. Adenosine was 19-fold selective for inhibition of N6-(4-amino-3-[125I]iodobenzyl)adenosine (125I-ABA) binding to recombinant rabbit A1 v rabbit A3 receptors (A1 Ki: 28 nm; A3 Ki 532 nm). Buffer-perfused rabbit hearts were exposed to 30 min regional ischemia and 120 min of reperfusion, and infarct size was measured by tetrazolium staining and normalized for area-at-risk (IA/AAR). Ischemic preconditioning (5 min global ischemia and 10 min reperfusion) or adenosine (20 micro M, 5 min) perfusion reduced infarct size (IA/AAR) to 17+/-3 and 14+/-2%, respectively (controls: 59+/-2%). Ischemic preconditioning and adenosine-mediated cardioprotection were completely blocked (57+/-2 and 61+/-4% IA/AAR, respectively) in the presence of a rabbit A1-selective concentration (50 nm) of the antagonist BWA1433 (rabbit A1 Ki: 3 nm; A3 Ki; 746 n m). Thus, whereas recent studies have demonstrated that selective A1 or A3 receptor agonists can both pharmacologically mimic IP, the results of the present study suggest that the adenosine-mediated component of IP in the isolated rabbit heart is preferentially mediated by adenosine A1 receptors, potentially due to adenosine's selectivity for this receptor subtype.
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PMID:Relative importance of adenosine A1 and A3 receptors in mediating physiological or pharmacological protection from ischemic myocardial injury in the rabbit heart. 951 33

Adenosine consists of one ribose and one purine moiety and binds to specific receptors on cell membranes. The receptors are coupled to G-proteins and additionally to various effector-systems. When a mismatch occurs between energy supply and energy demand, adenosine is produced by the catabolism of adenosine triphosphate. The metabolism of an organ is thereby coupled to the local blood supply (metabolic vasodilation). In addition to vasodilation, adenosine has several electrophysiological, cardioprotective, metabolic, and antiinflammatory properties. Adenosine is rapidly metabolized in blood and interstitial fluid, through cell absorption and degradation by adenosine deaminase. The short half-life of adenosine limits its clinical value. However, there are several ways of increasing the interstitial concentration of adenosine. At present, adenosine or adenosine-potentiating substances are used clinically to terminate supraventricular tachycardias, to induce myocardial ischemia in patients who are unable to exercise, and to reduce myocardial ischemia or reperfusion injury. Caffeine and other methylxanthines are adenosine receptor antagonists, and several of the pharmacodynamic properties of these substances are caused by adenosine receptor antagonism.
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PMID:[Receptor mediated effects of adenosine and caffeine]. 959 4

Adenosine has been shown to modulate myocardial intermediary metabolism. The purpose of this study was to determine whether adenosine-mediated attenuation of in vivo myocardial stunning is associated with improved myocardial phosphorylation potential. Adult, open chest pigs were subjected to 10 minutes of regional myocardial ischemia and 90 minutes reperfusion. Regional ventricular function was assessed by measuring systolic wall thickening. Myocardial phosphorylation potential was estimated from the tissue (CrP/CrxPi) ratio determined in rapid-frozen tissue biopsy samples from normal and stunned myocardium. Control pigs were compared to animals treated prior to ischemia with intracoronary adenosine (50 micrograms/kg/min). Postischemic regional systolic wall thickening in adenosine treated pigs was significantly improved (40 +/- 3% of preischemic values) compared to control untreated pigs (26 +/- 3%). Myocardial stunning was associated with decreased ATP levels, but neither the total creatine pool (CrP + Cr) nor the (CrP/CrxPi) ratio was reduced. Adenosine pretreatment was associated with decreased Pi and Cr contents resulting in improved postischemic (CrP/CrxPi) ratio in the stunned bed compared to controls, but this effect occurred only after postischemic function had attained maximal improvement. These results suggest that adenosine attenuation of in vivo myocardial stunning is independent of elevated myocardial phosphorylation potential.
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PMID:Adenosine attenuates in vivo myocardial stunning with minimal effects on cardiac energetics. 978 73

Chest pain can arise from cardiovascular or noncardiovascular causes. Among the latter are the skin, the chest wall, intrathoracic structures, or subdiaphragmatic organs. The problem to attribute the chest discomfort to either the heart or extracardiac organs arises because the heart, pleura, aorta, and esophagus are all supplied by sensory fibers from the same spinal segments. In contrast to the diseases mentioned above, angina pectoris in sensu strictu is defined as chest pain or discomfort of cardiac origin that arises because of temporary imbalance between myocardial oxygen supply and demand. The metabolic oxygen requirements of the myocardium are essentially dictated by myocardial contraction since only a fraction of the consumed oxygen is needed by the quiescent heart. Therefore, the factors that primarily influence myocardial oxygen consumption include heart rate, the force of cardiac contraction, and myocardial wall tension, as determined by pressure (afterload), volume (preload), and wall thickness. Extracoronary diseases, e.g. hypertensive heart disease, aortic stenosis or cardiomyopathies, can influence these factors and induce angina pectoris (Figure 1). On the other hand, different diseases influencing the oxygen supply, e.g. anemia, can cause angina pectoris, too. In addition, the modulation of the coronary tone by mediators and cytokines can cause angina, coronary spasm being one example. The neurophysiological substrate of angina pectoris are ganglia which are present within the heart, particularly in epicardial fat. The sympathetic nervous system is the main conveyer of afferent pain fibers from the heart and pericardium, but many fibers may travel by the vagus and the phrenic nerves. Therefore, multiple thoracic structures may cause similar pain syndromes in the distressed patient. The blood supply of intrinsic cardiac ganglia arises primarily from branches of the proximal coronary arteries. Adenosine, among a number of substances, can modulate the activity generated by cardiac afferent nerve endings and intrinsic cardiac neurones. During myocardial ischemia adenosine is released in large quantities into the interstitial space. Given as an intravenous bolus to healthy volunteers or to patients with ischemic heart disease and angina pectoris, adenosine provokes angina pectoris-like pain, which is similar to habitual angina pectoris with regard to quality and location. But other mediators (e.g. bradykinin, histamine, prostaglandins, potassium, lactate) can be involved in the development of angina pectoris, too. As most emphasis should be given to the most serious causes first, the cardiologist has to consider ischemic cardiac disease in the differential diagnosis of nearly every case of acute chest pain. The differential diagnosis contains several causes of nonischemic cardiac chest pain. Dissecting aortic aneurysm may cause severe anterior chest pain that can be mistaken for myocardial infarction. Patients frequently will note the sudden onset of the pain rather than the relatively slower onset of ischemic pain. Furthermore, they feel as a tear and describe it as the most severe pain they have ever had. Pericarditis can be characterized as a sharp precordial knife-like pain that is often increased by lying down, breathing, swallowing, or any other thoracic motion. Radiation of pericardial pain is often relieved by sitting up or leaning forward. It may involve the shoulders, upper back, and neck because of the irritation of the diaphragmatic pleura. Acute pulmonary embolism is associated with severe chest pain. It may mimic acute myocardial infarction. Pulmonary embolism should be suspected when dyspnea or tachypnea seems to be disproportionate to the severity of the chest pain. Diffuse esophageal spasm is the extracardiac condition that is confused most often with ischemic cardiac chest pain. This pain presents as a deep thoracic pain that may be present over most of the thorax. It may extend down the anterome
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PMID:[Angina pectoris in extracoronary diseases]. 1037 99

The role of adenosine and prostacyclin in post-ischemic vasodilation was investigated using a model of sequential perfusion of two isolated hearts. Two guinea pig hearts were sequentially perfused (10 ml/min) without (control, n = 4) or with preceding 10-min ischemia (n = 6) of Heart I. Under control conditions no hemodynamic changes were observed in Heart II during sequential perfusion. After 10 min of ischemia of Heart I coronary perfusion pressure decreased by 23% in Heart II at the onset of sequential perfusion. Adenosine A1 and A2 receptor antagonists 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (2 microM) and 3,7-dimethyl-1-propargylxanthine (DMPX) (20 microM) infused simultaneously inhibited this decrease in coronary perfusion pressure by 74%, whereas indomethacin (5 microM) had no effect. DPCPX, DMPX and indomethacin in combination induced a significant increase in coronary perfusion pressure. Adenosine release (HPLC) into the coronary effluent after ischemia was significantly enhanced in the presence of indomethacin. These results suggest that after myocardial ischemia prostacyclin has an inhibitory effect on adenosine release.
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PMID:Interaction of adenosine and prostacyclin in coronary flow regulation after myocardial ischemia. 1044 24

Biological and mechanical stressors such as ischemia, hypoxia, cellular ATP depletion, Ca2+ overload, free radicals, pressure and volume overload, catecholamines, cytokines, and renin-angiotensin may independently cause reversible and/or irreversible cardiac dysfunction. As a defense against these forms of stress, several endogenous self-protective mechanisms are exerted to avoid cellular injury. Adenosine, a degradative substance of ATP, may act as an endogenous cardioprotective substance in pathophysiological conditions of the heart, such as myocardial ischemia and chronic heart failure. For example, when brief periods of myocardial ischemia precede sustained ischemia, infarct size is markedly limited, a phenomenon known as ischemic preconditioning. We found that ischemic preconditioning activates the enzyme responsible for adenosine release, ie, ecto-5'-nucleotidase. Furthermore, the inhibitor of ecto-5'-nucleotidase reduced the infarct size-limiting effect of ischemic preconditioning, which establishes the cause-effect relationship between activation of ecto-5'-nucleotidase and the infarct size-limiting effect. We also found that protein kinase C is responsible for the activation of ecto-5'-nucleotidase. Protein kinase C phosphorylated the serine and threonine residues of ecto-5'-nucleotidase. Therefore, we suggest that adenosine produced via ecto-5'-nucleotidase gives cardioprotection against ischemia and reperfusion injury. Also, we found that plasma adenosine levels are increased in patients with chronic heart failure. Ecto-5'-nucleotidase activity increased in the blood and the myocardium in patients with chronic heart failure, which may explain the increases in adenosine levels in the plasma and the myocardium. In addition, we found that further elevation of plasma adenosine levels due to either dipyridamole or dilazep reduces the severity of chronic heart failure. Thus, we suggest that endogenous adenosine is also beneficial in chronic heart failure. We propose potential mechanisms for cardioprotection attributable to adenosine in pathophysiological states in heart diseases. The establishment of adenosine therapy may be useful for the treatment of either ischemic heart diseases or chronic heart failure.
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PMID:Adenosine and cardioprotection in the diseased heart. 1047 69

The aim of this study was to investigate the flow reserve of a normal left anterior descending coronary artery (LAD) in patients with coronary artery disease (CAD) of other epicardial vessels by Doppler transesophageal echocardiography (TEE). Thirty-one consecutive patients (age 59 +/- 8 years; 23 men) referred for TEE were considered. Eighteen patients had CAD and a 70% or greater LAD stenosis (group 1); 13 patients had right and/or circumflex CAD (>/=70% stenosis) and normal or minimally diseased LAD (group 2). Ten patients (age 54 +/- 11 years) with normal coronary arteries constituted group 3. Baseline and adenosine (0.160 microg/kg per minute intravenously over 60 minutes) flow velocities in the LAD were measured by pulsed Doppler examination during TEE. Peak and mean systolic and diastolic flow velocities were calculated. Adenosine/baseline peak and mean velocity ratios were used for evaluating blood flow reserve in the LAD. Heart rate and arterial pressure values were similar in the 3 groups at baseline and during adenosine infusion. Baseline and adenosine-related flow velocities were comparable in the 3 groups. Peak and mean diastolic velocity ratios were lower in groups 1 and 2 compared with group 3 (peak velocity ratio 1.68 +/- 0.81 and 1.93 +/- 0.35 vs 2.62 +/- 0.32, P <. 05; mean velocity ratio 1.71 +/- 0.86 and 2.01 +/- 0.41 vs 2.84 +/- 0.74, P <.05), whereas no differences were found between groups 1 and 2. No significant differences were found in systolic flow velocity ratios among the 3 groups. Patients with ischemic heart disease have a reduced diastolic flow velocity reserve in the LAD independent from the presence of significant LAD stenosis. Thus the adenosine TEE-Doppler study should be considered a screening test for CAD rather than for LAD disease.
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PMID:Coronary flow reserve of normal left anterior descending artery in patients with ischemic heart disease: A transesophageal Doppler study. 1047 16


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