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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myocardial ischemia, even if it persists for a prolonged period of time, does not inevitably induce irreversible damage. Recent studies have identified 2 phenomena that are characterized by endogenous cardioprotective features, i.e., myocardial hibernation and ischemic preconditioning. Myocardial hibernation is characterized by chronic contractile dysfunction during persistent ischemia. The myocardium remains viable, and function is restored upon reperfusion. Ischemic preconditioning is characterized by delayed development of infarct size when prolonged and severe myocardial ischemia is preceded > or = 1 short-lasting episodes of ischemia and reperfusion. While ischemic preconditioning involves the activation of the adenosine A1 receptor, the bradykinin receptor, and activation of adenosine triphosphate (ATP)-dependent potassium channels, the mechanisms underlying myocardial hibernation are still unclear.
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PMID:Endogenous protective mechanisms in myocardial ischemia: hibernation and ischemic preconditioning. 929 53

Left ventricular hypertrophy (LVH) is considered to be an independent risk factor giving rise to ischemia, arrhythmia, and left ventricular dysfunction. In this article, we summarize recent studies performed in our laboratory to investigate (1) the contribution of the renin-angiotensin system to the cardiac remodeling process, which is triggered by myocardial infarction (MI) or hypertension-induced cardiac hypertrophy; (2) the effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin AT1 receptor antagonism on cardiac parameters, such as myocardial infarct size, cardiac hypertrophy, heart function, and myocardial metabolism; (3) the mechanism of an ACE inhibitor-induced increase in cardiac capillary density in spontaneously hypertensive rats (SHR) and stroke prone SHR (SHR-SP). We observed that AT1 receptor gene expression in rat vascular smooth muscle cells (but not in rat coronary endothelial cells) was markedly enhanced after an ischemic insult in vitro. In a rat model in which MI was induced by coronary artery ligation, the AT1 receptor mRNA levels were transiently increased after MI and reached a peak level 24 hours post-MI. The AT2 receptor gene expression increased in a pattern similar to that of the AT1 receptor. ACE expression at the protein level in the repairing scar, which was demonstrated by monoclonal antibody staining, started to increase 2 weeks after MI and reached a peak level 3 weeks post-MI. Furthermore, long-term treatment with an ACE inhibitor limited infarct size, prevented cardiac hypertrophy, and improved heart function in the rat MI model. In SHR-SP, long-term treatment with either an ACE inhibitor or an AT1 receptor antagonist improved cardiac function and metabolism. Cardiac metabolism was even improved after low-dose ACE inhibitor treatment, which did not prevent hypertension and cardiac hypertrophy. In both SHR and SHR-SP, we found that the ACE inhibitor ramipril significantly increased capillary length density independently of its antihypertensive and antihypertrophic actions. Most of the cardiac effects of the ACE inhibitor could be abolished by a bradykinin B2 receptor antagonist. Thus, these cardiac effects of ACE inhibitors can be ascribed, at least under our experimental conditions, to ACE inhibitor-induced bradykinin potentiation.
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PMID:Effects of angiotensin-converting enzyme inhibition and angiotensin II AT1 receptor antagonism on cardiac parameters in left ventricular hypertrophy. 929 63

Myocardial ischemia results in the release of a variety of vasoactive substances from coronary vascular endothelial cells and/or from cardiac myocytes. Some of these substances appear to be protective and include nitric oxide and bradykinin. One hypothesis for the pronounced antiarrhythmic effects of preconditioning involves the early generation of bradykinin and, subsequently, nitric oxide. Evidence for early bradykinin release has come from clinical studies involving patients undergoing coronary angioplasty where, in 4 of 5 patients, there was evidence for elevated kinin levels in coronary sinus blood either during balloon inflation (i.e., ischemia) or deflation (reperfusion). The levels reached are sometimes considerable (increases 10-20 fold). The second piece of evidence comes from dogs subjected to a preconditioning stimulus (2 x 5 min periods of ischemia), followed 20 min later by occlusion of the same artery for a 25-min period. This preconditioning procedure markedly reduces ischemia-induced ventricular arrhythmias and, although under resting conditions there was little difference between arterial and coronary sinus bradykinin levels (125 +/- 22 and 157 +/- 41 pg/mL, respectively), there was a marked increase in coronary sinus levels in preconditioned dogs before the prolonged occlusion (637 +/- 293 pg/mL compared with 114 +/- 18 pg/mL in nonpreconditioned dogs); levels at the end of the prolonged occlusion in the preconditioned dogs were also higher (577 +/- 305 pg/mL compared with 162 +/- 34 pg/mL in control dogs). Other evidence for the involvement of bradykinin and nitric oxide comes from studies in which the generation, or effects, of these mediators have been suppressed (e.g., with the bradykinin B2 receptor blocking agent icatibant, with inhibitors of the L-arginine-nitric oxide pathway, and by methylene blue). The conclusion is that early bradykinin release is protective under conditions of ischemia, is presumably enhanced during therapy with angiotensin-converting enzyme (ACE) inhibitors and is suppressed under conditions of endothelial dysfunction.
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PMID:Bradykinin and endothelial-cardiac myocyte interactions in ischemic preconditioning. 929 65

Kinins have been shown to play an important role in the cardioprotective effect of ACE inhibitors (ACEi) during heart failure and ischemia-reperfusion. However, it is controversial as to whether kinins oppose the hypertensinogenic effect of deoxycorticosterone acetate plus salt (DOCA-salt) or aortic coarctation and whether they mediate both chronic antihypertensive and cardiac antihypertrophic effects of ACEi in hypertension. Using normal 129/SvEvTac mice and mice lacking the bradykinin B2 receptor gene (B2-KO), we investigated whether (1) the hypertensinogenic effect of DOCA-salt or aortic coarctation is enhanced in B2-KO mice and (2) the chronic antihypertensive and antihypertrophic effects of an ACEi (ramipril, 4 mg. kg-1. d-1) are mediated by B2 receptors in aortic coarctation (6 weeks)- and DOCA-salt (4 weeks)-induced hypertension. Before surgery, there was no difference between 129/SvEvTac and B2-KO mice in terms of blood pressure and heart weight, suggesting that kinins are not essential to maintaining normal blood pressure. DOCA-salt (volume expansion) or aortic coarctation (renin-dependent) induced similar hypertension and left ventricular hypertrophy (LVH) in 129/SvEvTac and B2-KO mice, suggesting that kinins do not play an essential role in the development of DOCA-salt- or aortic coarctation-induced hypertension. We found that B2 receptors mediate only the early (1 week) but not the late phase (4 weeks) of the chronic hypotensive effect of ACEi in DOCA-salt hypertension. On the other hand, chronic ACE inhibition prevented the development of hypertension and LVH in both 129/SvEvTac and B2-KO mice given DOCA-salt or subjected to aortic coarctation, suggesting that kinins do not participate in the chronic antihypertensive and antihypertrophic effects of ACEi in these 2 models of hypertension. Thus, in mice, kinins acting via B2 receptors do not participate in (1) maintenance of normal basal blood pressure, (2) establishment and maintenance of hypertension induced by DOCA-salt or aortic coarctation, and (3) chronic antihypertensive and cardiac antihypertrophic effects of ACEi in DOCA-salt and aortic coarctation hypertension.
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PMID:Effect of ACE inhibitor on DOCA-salt- and aortic coarctation-induced hypertension in mice: do kinin B2 receptors play a role? 1060 Nov 37

It is unclear whether losartan, an angiotensin II type 1 (AT1) receptor antagonist, protects the heart against acute ischemia-reperfusion injury. Therefore we evaluated cardiac protection conferred by pre- and postischemic treatment as well as by exclusive postischemic treatment with losartan. Furthermore, we sought to determine both the extent of this protection and its dependence on bradykinin in comparison with quinaprilat, a cardioprotective angiotensin-converting enzyme inhibitor. Cardiac protection was assessed as recovery of coronary flow, left ventricular developed pressure, phosphocreatine, and adenosine triphosphate (ATP) in isolated perfused rat hearts after 15 min of global ischemia and 30 min of postischemic reperfusion. We found that, in hearts pre- and postischemically treated with losartan (1 microM) or quinaprilat (0.1 microM), these variables all recovered significantly better than those in untreated control hearts. In hearts that were only postischemically treated with losartan, these variables also recovered significantly better than those in control hearts. In contrast, in hearts treated with the combination of the bradykinin B2 receptor antagonist Hoe 140 with quinaprilat or losartan, the recovery of the variables no longer differed from that in control hearts. In conclusion, losartan protects the heart against acute ischemia-reperfusion injury. This protection can be achieved by pre- and postischemic treatment as well as by exclusive postischemic treatment with losartan. Furthermore, the extent of this protection is equivalent to that conferred by quinaprilat and, unexpectedly, dependent on bradykinin.
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PMID:Bradykinin-dependent cardioprotective effects of losartan against ischemia and reperfusion in rat hearts. 1022 67

The blood-brain barrier (BBB) which is located in the continuous endothelial lining of cerebral blood vessels rigidly controls exchange of water soluble compounds under physiological conditions. Under pathological conditions such as trauma or ischemia, BBB permeability may increase thus allowing plasma constituents to escape into brain tissue. This "opening" of the BBB may, at least in part, be mediated by massive release of autacoids resulting in vasogenic brain edema. Five criteria have to be fulfilled by an individual autacoid to be considered a mediator candidate of cerebral edema: i) a permeability-enhancing action under physiological conditions, ii) a vasodilatory action, iii) the ability to induce vasogenic brain edema, iv) an increase of concentration in the tissue or interstitial fluid under pathological conditions, and v) a decrease of brain edema by specific interference with the release or action of a given autacoid. Among the mediator candidates considered, bradykinin is the only one to meet all criteria. Histamine, arachidonic acid and free radicals including nitric oxide may also be considered mediators of brain edema, but for each of these compounds evidence is less clear than for bradykinin. Although the concept of mediators inducing brain edema is well established by experimental studies, only a bradykinin receptor antagonist has so far gained entrance into clinical evaluation.
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PMID:Mediators of cerebral edema. 1063 98

Earlier studies have shown that activation of bradykinin B2 receptor triggers protein kinase C (PKC)-mediated cardioprotective mechanism in ischemic preconditioning (PC). In the present study, we examined whether the effector in this B2-receptor triggered pathway of PC is the ATP sensitive potassium (K(ATP)) channel in the mitochondria (mito-K(ATP) channel) or K(ATP) channel in the sarcolemma (sarc-K(ATP) channel). Isolated rabbit hearts were perfused with modified Krebs-Henseleit buffer in a Langendorff mode, and regional myocardial ischemia was induced by occluding a left coronary artery for 30 min and then reperfusing for 2 hours. Infarct size was determined by triphenyltetrazolium chloride staining and expressed as a percentage of area at risk (% IS/AR). Infusion of bradykinin (500 nmol/L) for 15 min prior to ischemia significantly reduced % IS/AR from 37.4 +/- 2.9 (SE) of the untreated controls to 12.0 +/- 3.3%. This protective effect of bradykinin was completely abolished by coinfusion of 5-hydroxydecanoate (5-HD, 50 micromol/L), a selective mito-K(ATP) channel blocker (% IS/AR = 44.2 +/- 6.4). In contrast, a high dose of HMR1098 (20 micromol/L), which is a newly developed sarc-K(ATP) channel selective blocker with IC50 of 0.6 micromol/L, failed to modify the infarct size limitation by preischemic infusion of bradykinin (% IS/AR = 11.7 +/- 3.4). Neither 5-HD nor HMR1098 alone modified infarct size (% IS/AR = 37.8 +/- 3.8 and 35.1 +/- 6.2, respectively). These results suggest that opening of the mito-K(ATP) channel but not the sarc-K(ATP) channel is involved in infarct size limitation by a mechanism triggered by bradykinin B2 receptor activation.
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PMID:Infarct size limitation by bradykinin receptor activation is mediated by the mitochondrial but not by the sarcolemmal K(ATP) channel. 1110 Nov 97

The role of cardiac adenosine triphosphate-sensitive K+ (K(ATP)) channels induced by angiotensin II type 1 (AT1) receptor antagonist, CV-11974, on myocardial metabolism and contraction during ischemia, and reperfusion by the phosphorus 31-nuclear magnetic resonance in Langendorff-perfused rabbit hearts was investigated. After 20 min of continuous normothermic global ischemia, 30 min of postischemic reperfusion was carried out. CV-11974 with or without the K(ATP) channel blocker, glibenclamide, or the bradykinin B2 receptor antagonist, D-Arg-[Hyp3,D-Phe7]bradykinin, was administered 40 min prior to the global ischemia. Adenosine triphosphate (ATP), creatine phosphate (PCr), inorganic phosphate (Pi), intracellular pH (pHi), left ventricular systolic developed pressure, left ventricular end-diastolic pressure (LVEDP), and coronary flow were measured. Twenty-eight hearts were divided into 4 experimental groups consisting of 7 hearts each. Group I consisted of controls, Group II perfused with CV-11974 (10(-6) mol/L), Group III perfused with CV-11974 (10(-6) mol/L) in combination with glibenclamide (10(-6) mol/L), and Group IV perfused with CV-11974 (10(-6) mol/L) in combination with D-Arg-[Hyp3,D-Phe7]bradykinin (10(-6) mol/L). Group II showed a significant inhibition of the decrease in ATP during ischemia and reperfusion compared with Group I (p<0.01), being 42+/-3% and 19+/-4% at ischemia, 69+/-3% and 47+/-4% at reperfusion in Group II and Group I, respectively. Group II also showed a significant inhibition of the increase in LVEDP during ischemia and reperfusion compared with Group I (p<0.01), being 13+/-4 mmHg and 52+/-8 mmHg at ischemia, 8+/-2 mmHg and 26+/-5 mmHg at reperfusion in Group II and Group I, respectively. However, Group II did not inhibit the decrease in ATP and the increase in LVEDP during ischemia and reperfusion. Group IV also showed no inhibition of the aforementioned parameters during the same period. These results suggest that CV-11974 has a significant beneficial effect for improving myocardial energy metabolism and relaxation during both myocardial ischemia and reperfusion, which is provided by K(ATP) channels and bradykinin B2 receptor. The cardioprotective quality of the AT1 receptor antagonist is caused by the K(ATP) channels that are mediated by the bradykinin B2 receptor.
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PMID:Role of cardiac ATP-sensitive K+ channels induced by angiotensin II type 1 receptor antagonist on metabolism, contraction and relaxation in ischemia-reperfused rabbit heart. 1134 52

Activation of bradykinin B2 receptor has been shown to confer short-term cardioprotection against a prolonged ischemic insult. The present study was designed to delineate the role of B2 receptor in the late phase of ischemic preconditioning. Anesthetized, open chest, male rabbits were assigned to 1 of 6 groups (n=8/group). Ischemic preconditioning was elicited by four 5-min occlusion periods interspersed with 10 min of reperfusion. To test the role of B2 receptors, rabbits were pretreated with specific receptor antagonist, HOE-140 (1 microgm/kg IV bolus), 15 min prior to ischemic preconditioning. Additionally, two separate groups of animals were treated by intra-atrial infusion with either bradykinin (0.05 microg/kg/min for 15 min) or saline. Twenty-four hours later, the animals were subjected to 30 min of ischemia and 3 h of reperfusion. Infarct size was determined by tetrazolium staining. Ischemic preconditioning reduced infarct size from 43.09+/-4.66 to 20.65+/-1.87 (% risk area, P<0.05), which was blocked by HOE-140 as indicated by increase in infarct size (36.72+/-4.04%, P<0.05). HOE-140 treatment had no significant effect on infarct size in the sham group. Similarly, intra-atrial infusion of bradykinin caused decrease in the infarct size from 52.36+/-2.17% in the saline control group to 22.83+/-1.71% (P<0.05). The degree of infarct limitation with bradykinin was comparable to ischemic preconditioning (20.65+/-1.87%v 22.83+/-1.71%, P>0.05). For the first time, these results provide evidence for the involvement of B2 receptor in the genesis of late phase of ischemic preconditioning.
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PMID:Bradykinin B2 receptor is involved in the late phase of preconditioning in rabbit heart. 1143 41

Certain calcium antagonists, in addition to their classic actions, can increase blood flow during ischemia via bradykinin- and nitric oxide (NO)-dependent mechanisms and protect the ischemic myocardium against reperfusion injury by enhancing NO bioavailability. The current study aimed to investigate the possible involvement of bradykinin and NO in the cardioprotective action of the short-acting calcium antagonist clevidipine during late ischemia and reperfusion. Anesthetized pigs were subjected to 45-min ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Four groups were given vehicle, clevidipine, clevidipine in combination with the bradykinin B2 receptor antagonist HOE 140 or clevidipine in combination with HOE 140 and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) into the LAD during the last 10 min of ischemia and the first 5 min of reperfusion. There were no significant differences in hemodynamics among the groups before ischemia or during ischemia-reperfusion. The infarct size (IS) was 87% +/- 2% of the area at risk in the vehicle group. Clevidipine reduced the IS to 60% +/- 3% (p < 0.001 vs vehicle). When clevidipine was administered together with HOE 140, the protective effect of clevidipine was abolished (IS, 80% +/- 3%; p < 0.001 vs clevidipine), whereas addition of SNAP restored cardioprotection (IS, 62% +/- 5%; p < 0.001 vs vehicle). The increase in LAD blood flow by endothelium-dependent dilator substance P was significantly larger in the clevidipine group than in the other groups. The results suggest that the cardioprotective effect of clevidipine during late ischemia and early reperfusion is mediated via bradykinin- and NO-related mechanisms.
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PMID:Calcium antagonist clevidipine reduces myocardial reperfusion injury by a mechanism related to bradykinin and nitric oxide. 1235 18


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