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)

We have investigated the contribution of the renin-angiotensin system to the damage caused by 40-min global ischemia in the isolated rat heart. A converting enzyme inhibitor, enalaprilat (70 nM), an angiotensin II receptor antagonist, compound 89 (2 microM), and an inhibitor of rat renin, CGP 44099A (20 nM), given before ischemia reduced the median duration of ventricular fibrillation on reperfusion to a similar extent (5.53, 5.72, and 5.14 min, respectively, compared to 13.98 min in the control group) but had no effect on creatine phosphokinase release (22.2 +/- 2.6, 22.1 +/- 6.8, and 24.1 +/- 3.6, IU/30 min, respectively, compared to 19.9 +/- 1.9 IU/30 min) or recovery or left ventricular developed pressure (67 +/- 6, 73 +/- 7 and 71 +/- 6%, respectively, compared to 66 +/- 3% after 30 min reperfusion). The increase in coronary resistance and left ventricular diastolic pressure on reperfusion was not affected by any of the agents. All three agents also tended to reduce the duration of ventricular fibrillation when given only on reperfusion. We conclude that angiotensinogen is present in the rat heart and it is converted to angiotensin I by a renin or a renin-like aspartic proteinase. The angiotensin I is converted to angiotensin II by converting enzyme. The angiotensin II formed is an important mediator of postreperfusion ventricular fibrillation in the isolated rat heart but does not contribute to the reduction in mechanical function produced by global ischemia in this preparation.
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PMID:Involvement of the renin-angiotensin system in ischemic damage and reperfusion arrhythmias in the isolated perfused rat heart. 171 94

The effects of the converting enzyme inhibitors ramiprilat and enalaprilat on ischemia-induced release of noradrenaline (NA) were examined in the isolated perfused rat heart, submitted to 30 min of total flow restriction followed by 5 min of reperfusion. Ramiprilat (2.6 nM-2.6 microM) caused a concentration-dependent decrease in the efflux of NA at reperfusion. The maximal effect (about 70% reduction) was observed at a concentration of 26 nM. In contrast, enalaprilat (10 nM-10 microM) caused no reduction in NA efflux until at a high concentration (10 microM, NA efflux reduced by about 20%). Moreover, the prodrugs ramipril and enalapril (added to the perfusion medium) were without any significant effects on ischemia-induced NA release. Both the angiotensin II receptor antagonist saralasin (0.1 microM) and bradykinin (0.1 and 1 nM) caused marked reductions in ischemic NA efflux. However, when indomethacin (10 microM) was added to the perfusion medium, the effects of bradykinin (1 nM) and ramiprilat (26 nM) on NA efflux were abolished. Likewise, in the presence of angiotensin II (0.1 microM) the effect of ramiprilat was no longer evident. The magnitude of cellular injury, expressed as efflux of creatine kinase during reperfusion, was reduced by bradykinin (0.1 and 1 nM) and by ramiprilat (by about 55% at 2.6 microM). It is concluded that ramiprilat, at therapeutically relevant concentrations, attenuates the ischemia-induced mobilization of NA via a reduction in local angiotensin II production and/or bradykinin degradation. The lack of effect of enalaprilat in this model may reflect differences between converting enzyme inhibitors regarding tissue accumulation or the potency of local enzyme inhibition.
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PMID:Ramiprilat attenuates the local release of noradrenaline in the ischemic myocardium. 279 89

The aim of the present study was to assess the participation of angiotensin II receptors in the triggering mechanism of ischemic preconditioning. Isolated buffer-perfused rabbit hearts were subjected to 40 min of regional ischemia (37 degrees C) followed by 60 min of reperfusion. Ischemic preconditioning was induced with three cycles of 5-min ischemia and 10-min reperfusion given prior to the 40-min ischemic period. Infarct size and ventricular function were assessed. Ischemic preconditioning reduced infarct size to 5.2 +/- 1.2% of the area at risk (mean +/- S.E.M., P<0.001) when compared to controls (26.4 +/- 3.0%), but did not protect against ventricular dysfunction. Activation of angiotensin II receptors with angiotensin II (100 nM) also limited infarct size (9.6 +/- 2.2%, P<O.01 v control group). Inhibition of angiotensin II receptors with [Sar1, Val5, Ala8]-angiotensin II (saralasin, 1 microM) blocked the protection of ischemic preconditioning against necrosis (29.7 +/- 3.2%) while it did not increase infarct size in saralasin-treated control hearts (31.5 +/- 3.9%). Furthermore, inhibition of the AT1 subtype of the angiotensin II receptor with losartan (20 microM), but not inhibition of the AT2 subtype with PD-123,319 ditrifluoroacetate (10 microM), abolished the infarct size-limiting effect of ischemic preconditioning. We conclude that the AT1 angiotensin II receptor participates in ischemic preconditioning. Thus, in the isolated rabbit heart, activation of AT1 receptors must occur before prolonged ischemia for ischemic preconditioning to limit infarction.
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PMID:Selective blockade of AT1 angiotensin II receptors abolishes ischemic preconditioning in isolated rabbit hearts. 904 28

To assess the efficacy of losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4-yl)methyl]imidazole, potassium salt), an angiotensin II receptor antagonist, on acute myocardial ischemia, 36 four-month-old spontaneously hypertensive rats were used. The animals underwent 45 min of left coronary artery occlusion and 1 h of reperfusion and were randomly assigned to control and losartan-treated groups (2, 5, and 10 mg/kg, intravenously). Losartan was administered 15 min before ischemia. Electrocardiograms (lead II) were monitored continuously throughout the experiment. To assess the anti-infarct effect of losartan, the area at risk was determined by methylene blue dye and the infarct size was determined by nitroblue tetrazolium chloride staining. The areas of risk and infarct were measured by computerized planimetry. Results demonstrated that the low and intermediate doses (2 and 5 mg/kg) of losartan significantly decreased the incidence of ventricular fibrillation and mortality during the ischemic period induced by left coronary artery occlusion. However, a significant reduction in infarct size, calculated as a percentage of the area at risk, was noted in all three losartan-treated groups (control: 41.5% +/- 5.2%, losartan, 2 mg/kg: 11.2% +/- 5.8%, 5 mg/kg: 8.5% +/- 2.7% and 10 mg/kg: 13.7% +/- 1.6%). The results suggest that losartan may be useful in the treatment of ventricular arrhythmias induced by acute myocardial infarction and attenuation of reperfusion injury in hypertension.
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PMID:Losartan attenuates myocardial ischemia-induced ventricular arrythmias and reperfusion injury in spontaneously hypertensive rats. 927 79

There is no agreement on the effect of angiotensin II receptor blockade in the setting of ischemic reperfusion. Our aim was to assess the acute effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II AT1-subtype receptor blockade in pig heart. Five groups of open-chest pigs received 1 hour of left anterior descending (LAD) coronary artery occlusion and 2 hours of reperfusion. Left ventricular pressure was monitored by an intraventricular catheter, and regional segment shortening (%SS) in the LAD-supplied territory was measured by ultrasonic crystals implanted in the subendocardium. Group 1 (n = 6) served as the control; groups 2 (n = 6) and 3 (n = 6) received the angiotensin II receptor blocker, EXP 3174 (C22H21Cl1N6O2), and the ACE inhibitor, enalaprilat, respectively, prior to LAD occlusion; group 4 (n = 6) was preconditioned with two cycles of 10 minutes of coronary occlusion and 30 minutes of reperfusion; and group 5 (n = 6) underwent preconditioning with additional administration of EXP 3174 prior to the 60-minute occlusion period. Infarct sizes were measured by p-nitrobluetetrazolium staining and were expressed in percent of the ischemic area of risk. The angiotensin II receptor blocker EXP 3174 and enalaprilat reduced infarct sizes significantly (35.3 +/- 17.1% and 40.1 +/- 15.1%, respectively) compared with controls (71.2 +/- 12.8%, P < 0.05), and EXP 3174 augmented the infarct size-limiting effects of preconditioning by ischemia (10.5 +/- 6% vs. 28.6 +/- 5.3%, P < 0.05). Regional contractile dysfunction during reperfusion demonstrated no changes after angiotensin II receptor blockade. Angiotensin II receptor blockade reduced infarct size comparable with that obtained with angiotensin converting-enzyme inhibition. The infarct size-limiting effects of ischemic preconditioning were augmented by administration of the angiotensin II receptor antagonist EXP 3174. These data support the concept that blockade or inhibition of angiotensin II before coronary occlusion is protective in a swine model of acute ischemia and reperfusion.
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PMID:Angiotensin II receptor antagonist EXP 3174 reduces infarct size comparable with enalaprilat and augments preconditioning in the pig heart. 949 8

The renin-angiotensin system is activated during myocardial ischemia, and local angiotensin II formation occurs in ischemic hearts. At least two angiotensin II receptor subtypes, the AT1 and AT2 receptor, have been identified. The cardiovascular effects of angiotensin II have been largely attributed to activation of AT1 receptors. In ventricular preparations from normal rat and pig hearts, the density of AT1 receptors is higher than that of AT2 receptors, whereas data on the AT receptor subtype density and its distribution in human hearts remain controversial. AT1 receptor blockade increases coronary blood flow during ischemia in dogs and during reperfusion in rats. It also reduces the incidence of ischemia-related arrhythmias in rats and guinea pigs, limits infarct size in pigs, improves functional and metabolic recovery following myocardial ischemia, and attenuates ventricular remodelling post-myocardial infarction in rats. The potential mechanisms responsible for the cardioprotection by AT1 receptor blockade remain to be elucidated in detail, but appear to involve AT2 receptor activation and the subsequent action of bradykinin, prostaglandins, and/or nitric oxide. Patients under treatment with AT1 receptor antagonists for indications such as hypertension and ventricular dilatation after myocardial infarction are likely to have improved prognosis when suffering an acute myocardial infarction.
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PMID:AT1 receptor blockade in experimental myocardial ischemia/reperfusion. 983 69

The hippocampal formation of Mongolian gerbils expresses high amounts of atypical angiotensin II type-1 receptors. We studied the expression of these receptors by in situ hybridization using specific [35S]-labeled riboprobes and by receptor autoradiography using [125I]Sarcosine1-angiotensin II. Angiotensin II receptor mRNA was found in the pyramidal cell layer of the CA1, CA2 and CA3 subfields, with the highest expression in the CA2 subfield, and in the granular cell layer of the dentate gyrus. Angiotensin II binding was detected in the stratum oriens and stratum radiatum of the CA1 and CA2 subfields, in the stratum oriens of the CA3 subfield, and in the molecular layer of the dentate gyrus. We then studied the effect of ischemia on hippocampal angiotensin II receptor expression, 1, 4 and 15 days after bilateral occlusion of the common carotid arteries for 5 min. No changes in angiotensin II receptor mRNA or binding were detected 1 day after ischemia. Delayed, progressive loss of angiotensin II mRNA and binding occurred 4 and 15 days after ischemia, in the CA1, CA2 and CA3 subfields. The decline was faster in the CA1 subfield, and paralleled the loss of neurons after ischemia. In the dentate gyrus, angiotensin II receptor mRNA and angiotensin II binding were not changed when compared to sham operated controls. The decrease of angiotensin II receptor expression may reflect the loss of angiotensin II receptor-producing neurons rather than a down-regulation of receptor expression.
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PMID:Ischemia-induced neuronal cell loss is associated with loss of atypical angiotensin type-1 receptor expression in the gerbil hippocampal formation. 988 9

The renin-angiotensin system is activated during myocardial ischemia, and local angiotensin II formation occurs in ischemic hearts. At least two angiotensin II receptor subtypes, the AT1 and the AT2 receptor, have been identified. The cardiovascular effects of angiotensin II have been attributed largely to activation of AT1 receptors. In ventricular preparations from normal rat and pig hearts, the density of AT1 receptors is higher than that of AT2 receptors, whereas data on the AT receptor subtype density and its distribution in human hearts remain controversial. AT1 receptor blockade increases coronary blood flow during ischemia in dogs and during reperfusion in rats, reduces the incidence of ischemia-related arrhythmias in rats and guinea pigs, limits infarct size in pigs, improves functional and metabolic recovery after myocardial ischemia, and attenuates ventricular remodeling post-myocardial infarction in rats. The potential mechanisms responsible for the cardioprotection by AT1 receptor blockade remain to be elucidated in detail, but appear to involve AT2 receptor activation and the subsequent action of bradykinin, prostaglandins, and/or nitric oxide. Patients under treatment with AT1 receptor blockers for indications such as hypertension and ventricular dilation after myocardial infarction are likely to have improved prognosis when suffering an acute myocardial infarction.
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PMID:AT1 receptor blockade in experimental myocardial ischemia/reperfusion. 989 53

We examined the effects of enalapril and 4'-[(1, 4'-dimethyl-2'-propyl-[2,6'-bi-1H-enzimidazole]-1'-yl)methyl]-[1, 1'-biphenyl]-2-carboxylic acid (BIBR-277), an angiotensin II receptor antagonist, on contractile dysfunction in the stunned myocardium. Dogs were subjected to 20-min ligation of the coronary artery, followed by 60-min reperfusion. Saline, enalapril (1 mg/kg or 3 mg/kg), or BIBR-277 (3 mg/kg) was injected i.v. 10 min before ligation. D-Arginyl-L-arginlyl-L-prolyl-trans-4-hydroxy-L-prolylglycyl -3-(2-thi enyl)-L-alanyl-L-seryl-D-1,2,3, 4-tetrahydro-3-isoquinolinecarbonyl-L-(2alpha, 3beta, 7abeta)-octahydro-1H-indole-2-carbonyl-L-arginine (Hoe-140), a bradykinin B(2) receptor antagonist, at 300 microg/kg was injected i. v. 10 min before drug injection. Contractile function was assessed on the basis of percentage segment shortening (%SS). ATP levels were measured in 60-min reperfused hearts. %SS significantly decreased during ischemia, and recovered during reperfusion, although the %SS was significantly less than the pre-ischemic level. Both enalapril at either dose and BIBR-277 significantly enhanced %SS recovery during reperfusion, an effect which was associated with a tendency toward energy preservation. Hoe-140 completely abolished the effect of enalapril at either dose, while it did not modify that of BIBR-277. Inhibition of angiotensin II formation and bradykinin breakdown may be separately related to the improvement of myocardial stunning.
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PMID:Participation of angiotensin II and bradykinin in contractile function in dog stunned myocardium. 1055 69

There is recent evidence that angiotensin-converting enzyme (ACE) inhibition reduces postischemic injury and angiotensin II receptor inhibition may have similar effects. We therefore further characterized the role of ACE- vs. AT1-receptor inhibition on cell injury and temporal association of leukocyte endothelial interaction in response to ischemia-reperfusion. A combined in vivo and in vitro study comparing the ACE inhibitor enalapril and the AT1-receptor antagonist losartan was performed. The extent and temporal correlation of cellular damage (propidium-iodide staining), microvascular perfusion failure and leukocyte-endothelial interaction (leukocyte adherence) were investigated by means of intravital microscopy, after the application of hemodynamically ineffective doses of enalapril and losartan (5 mg/kg). A hamster dorsal skinfold model with a 4-h tourniquet ischemia was used. In vitro, the effect of enalapril and losartan on polymorphonuclear cell (PMN) adherence, as well as adhesion molecule expression (ICAM-1, VCAM-1), on hypoxia- or IL-1beta-stimulated endothelial cells (HUVEC) was assessed using a PMN-adhesion assay and flow cytometry, respectively. Ischemia-reperfusion responses revealed a biphasic pattern, comprised of an early phase (30 min) of acute cellular damage and microvascular perfusion failure, followed by a late increase (240 min) in leukocyte adherence in vivo. Enalapril significantly reduced early cellular damage, microvascular perfusion failure, and leukocyte adherence in response to ischemia-reperfusion. Conversely, AT1 receptor inhibition with losartan proved to be ineffective at attenuating postischemic microcirculatory disorders (leukocyte-endothelial interactions, microvascular perfusion failure) and aggravated cellular injury. In vitro, enalapril reduced PMN adherence and ICAM-1 and VCAM-1 expression, while losartan was ineffective in the same respect. Following ischemia-reperfusion injury, ACE- versus AT1-receptor inhibition induce differential effects concerning the extent and temporal association of cell injury and leukocyte-endothelial interaction. The use of enalapril combines the beneficial effects of preventing cell and vascular injury immediately after reperfusion, with a delayed inhibition of the inflammatory response. Since the AT1-receptor inhibitor losartan did not mimic effects obtained with ACE inhibition, it is conceivable that the responses in ischemia-reperfusion are mediated by a non-angiotensin II-AT1 receptor-dependent mechanism.
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PMID:Differential effects of short-term ace- and AT1-receptor inhibition on postischemic injury and leukocyte adherence in vivo and in vitro. 1071 75


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