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)

To investigate the role of catecholamine and prostacyclin in ischemia reperfusion-induced ventricular fibrillation, experiments were performed in rat hearts using methods of radioimmunoassay and fluorohistochemistry. Regional myocardial ischemia was induced by ligation of the left coronary artery followed by reperfusion. In the ischemia reperfusion group, ventricular fibrillation during reperfusion took place in 78% of the hearts. In the group pretreated with captopril, the incidence of ventricular fibrillation decreased significantly (65.5%). In comparison with the ischemia reperfusion group, myocardial catecholamine content and 6-keto-PGF1 alpha of the captopril group were significantly increased (P < 0.01) while thromboxane B2 (TxB2) and TxB2/6-keto-PGF1 alpha were decreased (P < 0.01). In Ang II group, infusion of angiotensin II reversed the protective effect of captopril and restored the incidence of ventricular fibrillation (85%), while myocardial catecholamine content was not different from the ischemia reperfusion group (P > 0.05). Above results suggest that reduction of the incidence of ischemia reperfusion-induced ventricular fibrillation by captopril may be due to its inhibition on angiotensin II production with consequent reduction of the release of myocardial catecholamine, suppression of TxB2 and promotion of PGI2 synthesis.
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PMID:[Reduction of incidence of ischemia-reperfusion induced ventricular fibrillation by captopril]. 876 46

The Na+/H+ antiport and Na(+)-HCO3- coinflux carrier contribute to recovery from intracellular acidosis in cardiac tissue. The effects of angiotensin II (10(-12)-10(-6) M) on H+ fluxes after intracellular acid loading and during reperfusion after myocardial ischemia have been investigated in the isovolumic, Langendorff-perfused ferret heart. Intracellular pH (pHi) was estimated using 31P nuclear magnetic resonance (NMR) spectroscopy from the chemical shift of intracellular deoxyglucose-6-phosphate or inorganic phosphate. Angiotensin II produced concentration-dependent stimulation (maximum at 10(-6) M: 67%) of 5-(N-ethyl-N-isopropyl)amiloride (EIPA)-sensitive Na(+)-dependent of H+ efflux consistent with stimulation of the Na+/H+ antiport. Half-maximal stimulation of H+ efflux occurred at approximately 10(-9) M, which is close to the dissociation constant of the cardiac angiotensin AT1 receptor. Stimulation via this receptor was confirmed with the nonpeptide AT1 receptor blocker, GR-117289. Angiotensin II had less pronounced effects on HCO3(-)-dependent pHi recovery after acid loading with no effect on pHi recovery after intracellular alkalosis. During reperfusion, angiotensin II significantly increased H+ extrusion but impaired contractile recovery. The results support the hypothesis that angiotensin II facilitates H+ extrusion in the heart. This may help maintain physiological homeostasis, but the hypothesized obligated Na+ influx could exacerbate cellular dysfunction during reperfusion.
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PMID:Angiotensin II stimulates sodium-dependent proton extrusion in perfused ferret heart. 876 51

Angiotensin converting enzyme inhibitors (ACE-I) have been reported to prevent the recurrence of cardiovascular events. The mechanism of this decrease, however, can not be completely explained by anti-hypertensive and anti-hypertrophic effects of ACE-I. To investigate the mechanism of this decrease, we studied the regulation of plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (TPA), tissue factor (TF), and tissue factor pathway inhibitor (TFPI) by angiotensin II (Ang II) in cultured rat aortic endothelial cells. Ang II increased PAI-1 and TF mRNA expression without affecting that of TPA or TFPI. These inductions were accompanied by increases in PAI-1 and TF activities and were inhibited by a type I Ang II receptor antagonist. The results suggest that Ang II decreases the antithrombotic properties of endothelial cells which increases the chance of thrombosis. Thus, inhibition of the renin-angiotensin system may be beneficial to prevent thrombus formation in treatment of ischemic heart disease.
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PMID:Angiotensin II increases plasminogen activator inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. 924 56

Cardiac expression of angiotensin II (Ang II) AT1 and AT2 receptor subtypes is species dependent, and changes in their relative proportion may influence myocardial hypertrophy and fibrosis. Regional differences in the distribution of Ang II receptors in the normal and failing human heart were assessed using 125I-(Sar1,Ile8)Ang II binding and quantitative autoradiography. Receptor subtypes were distinguished by their affinity for selective nonpeptide antagonists (losartan and PD123319) and sensitivity to dithiothreitol. Ventricular and atrial tissues displayed a heterogeneous distribution of ligand binding sites. AT2 receptors predominated, representing 70% to 77% of the sites in normal and noninfarcted myocardium. Endocardial, interstitial, perivascular and infarcted regions in the ventricles of patients with end-stage ischemic heart disease or dilated cardiomyopathy exhibited a significantly greater density (P < .001) of high affinity AT2 binding sites (Kd = 0.57 nmol/liter) compared with adjacent noninfarcted myocardium. Regions displaying the relative increase in AT2 binding sites corresponded to areas of fibroblast proliferation and collagen deposition, shown by picrosirius red staining. AT1 binding sites were localized to nerves, occurred at relatively low density in coronary vessels and represented only 23% to 29% of myocardial 125I-(Sar1,Ile8)Ang II binding sites. The border zone between infarcted and noninfarcted myocardium characteristically contained numerous microvessels, exhibiting perivascular AT2 receptors and endothelial angiotensin converting enzyme activity, as demonstrated by binding of 125I-351A. Specific myocardial AT2 receptor mRNA transcripts (approximately 3 kb) were identified and exhibited alternative splicing of untranslated 5' exons. The differential distribution of cardiac Ang II receptor subtypes and selective increase in binding to AT2 sites in the diseased heart suggest that cells bearing the AT2 receptor represent a significant target for Ang II, possibly contributing to its growth-related actions.
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PMID:Differential distribution of angiotensin AT2 receptors in the normal and failing human heart. 943 95

Angiotensin-converting enzyme (ACE) inhibitors reduce myocardial ischemia/reperfusion injury. It is unclear whether reduced formation of angiotensin II or attenuated degradation of bradykinin is responsible for the beneficial effects. We investigated the role of endogenous angiotensin II in ischemia/reperfusion injury by studying the effects of the angiotensin II type 1 receptor antagonist candesartan on myocardial function, infarct size, and perfusion after ischemia/reperfusion. Anesthetized pigs were subjected to 45 min of regional ischemia and 240 min of reperfusion. Starting 5 min before reperfusion, four groups of pigs (n = 6 in each) received coronary venous retroinfusion of candesartan (0.2, 2, or 20 microg/kg) or vehicle for 30 min. Myocardial regional blood flow was measured with radioactive microspheres in two separate groups (n = 6 in each) given 20 microg/kg candesartan or vehicle. Retroinfusion of 20 microg/kg of candesartan improved recovery of left ventricular systolic segment shortening measured by sonomicrometry in the ischemic area compared with 0.2 microg/kg of candesartan and vehicle. Infarct size, as a percentage of the area at risk, was smaller in the 2 and 20 microg/kg groups than in the vehicle group (39.1 +/- 11.6% and 34.8 +/- 10.2% vs. 78.3 +/- 8.9%, p < 0.01). There was no difference between candesartan and vehicle in their effects on regional myocardial blood flow. Angiotensin II type 1 receptor blockade supports myocardial functional recovery and reduces infarct size. This effect is not related to improved regional myocardial blood flow during reperfusion.
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PMID:Angiotensin II type 1 receptor blockade with candesartan protects the porcine myocardium from reperfusion-induced injury. 970 Sep 85

The renin-angiotensin system plays an important role in myocardial ischemia-reperfusion injury. Angiotensin II (Ang II) contributes to the evolution of ischemic coronary events through its hemodynamic, hemostatic and mitogenic effects. Angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor antagonists have been shown to be cardioprotective in experimental animal models, with ischemia-reperfusion injury and in patients with congestive heart failure. Ang II receptors include at least two different subtypes, AT1 and AT2. Both AT1 and AT2 are expressed in the rat heart. Myocardial AT1 receptor density increases in association with ACE expression, and AT1 receptor activation is related to collagen formation following myocardial infarction in rats. Studies from the authors' laboratory have shown significant myocardial dysfunction in association with a concurrent increase in AT1 receptor expression in the rat myocardium immediately following a brief period of ischemia and reperfusion. Application of antisense oligodeoxynucleotides (AS-ODN) directed at AT1 receptor messenger RNA and AT1 receptor antagonist, losartan, significantly attenuates myocardial dysfunction induced by ischemia-reperfusion in the isolated rat heart. These observations suggest that myocardial AT1 receptor expression is involved in myocardial dysfunction following ischemia-reperfusion. Unlike losartan, which upregulates the plasma Ang II level, administration of AS-ODN does not affect plasma Ang II level. Although the reason for this is not clear, the difference in plasma Ang II levels implies that AS-ODN may be, at least theoretically, more beneficial than losartan in limiting ischemia-reperfusion-induced cardiac dysfunction. Apoptosis, or programmed cell death, also contributes to the outcome of myocardial ischemia-reperfusion injury. Recent studies from the authors' laboratory have demonstrated that Ang II induces apoptosis in cultured human coronary artery endothelial cells via activation of AT1 receptors and this can be blocked by losartan. These observations collectively underscore the importance of myocardial AT1 receptor expression in ischemia-reperfusion injury.
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PMID:Myocardial angiotensin II receptor expression and ischemia-reperfusion injury. 979 75

Currently at least 11 protein kinase C (PKC) isoforms have been identified and may play different roles in cell signaling pathways leading to changes in cardiac contractility, the hypertrophic response, and tolerance to myocardial ischemia. The purpose of the present study was to test the hypothesis that responses of individual PKC isoforms to distinct pathological stimuli were differentially regulated in the adult guinea pig heart. Isolated hearts were perfused by the Langendorff method and were exposed to ischemia, hypoxia, H(2)O(2), or angiotensin II. Hypoxia and ischemia induced translocation of PKC isoforms alpha, beta(2), gamma, and zeta, and H(2)O(2) translocated PKC isoforms alpha, beta(2), and zeta. Angiotensin II produced translocation of alpha, beta(2), epsilon, gamma, and zeta isoforms. Inhibition of phospholipase C with tricyclodecan-9-yl-xanthogenate (D609) blocked hypoxia-induced (alpha, beta(2), and zeta) and angiotensin II-induced (alpha, beta(2), gamma, and zeta) translocation of PKC isoforms. Inhibition of tyrosine kinase with genistein blocked translocation of PKC isoforms by hypoxia (beta(2) and zeta) and by angiotensin II (beta(2)). By contrast, neither D609 nor genistein blocked H(2)O(2)-induced translocation of any PKC isoform. We conclude that hypoxia-induced activation of PKC isoforms is mediated through pathways involving phospholipase C and tyrosine kinase, but oxidative stress may activate PKC isoforms independently of Galphaq-phospholipase C coupling and tyrosine kinase signaling. Because oxidative stress may directly activate PKC, and PKC activation appears to be involved in human heart failure, selective inhibition of the PKC isoforms may provide a novel therapeutic strategy for the prevention and treatment of this pathological process.
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PMID:Responses of cardiac protein kinase C isoforms to distinct pathological stimuli are differentially regulated. 1043 69

Angiotensin II (Ang II) promotes norepinephrine (NE) release from cardiac sympathetic nerve endings. We assessed in a human model in vitro whether locally formed Ang II contributes to NE release in myocardial ischemia. Surgical specimens of human right atrium were incubated in anoxic conditions. After 70 min of anoxia, NE release (carrier-mediated; caused by NE transporter reversal) was 8-fold greater than normoxic release. Angiotensin-converting enzyme inhibition with enalaprilat failed to reduce anoxic NE release. In contrast, prevention of chymase-dependent Ang II formation with chymostatin, Bowman-Birk inhibitor, or alpha(1)-antitrypsin significantly inhibited anoxic, but not exocytotic, NE release. Two mast-cell stabilizers, cromolyn and lodoxamide, markedly reduced NE release, implicating cardiac mast cells as a major source of chymase. Angiotensin type 1 receptor (AT(1)R) blockade with EXP3174 inhibited NE release, whereas angiotensin type 2 receptor (AT(2)R) blockade with PD123319 did not. Interestingly, PD123319 reversed the inhibitory effect of EXP3174. Furthermore, synergisms were uncovered between EXP3174 and an AT(2)R agonist, and between EXP3174 and a Na(+)/H(+) exchanger inhibitor. Thus, angiotensin-converting enzyme-independent Ang II formation via chymase is important for carrier-mediated ischemic NE release in the human heart. Locally generated Ang II promotes NE release by acting predominantly at AT(1)Rs, which are likely coupled to the Na(+)/H(+) exchanger. Effects of Ang II at AT(2)Rs, seemingly opposite to those resulting from AT(1)R activation, are uncovered when AT(1)Rs are blocked. Because NE release is associated with coronary vasoconstriction and arrhythmias, and mast-cell density and chymase content increase in the ischemic heart, the notion that chymase-generated Ang II plays a major role in carrier-mediated NE release may have important clinical implications.
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PMID:Angiotensin-converting enzyme-independent angiotensin formation in a human model of myocardial ischemia: modulation of norepinephrine release by angiotensin type 1 and angiotensin type 2 receptors. 1087 19

To evaluate the effects of left ventricular (LV) dysfunction upon the sympathetic nervous and renin-aldosterone-angiotensin systems, neurohormonal factors were measured in patients with ischemic heart disease. Eleven patients were divided into two groups by their LV ejection fraction based on previous catheterization; preserved (EF > or = 60%) and impaired (EF < 60%) LV systolic function groups. They performed supine ergometer exercise and blood samples were drawn at rest and at peak exercise. After dynamic exercise, plasma norepinephrine was significantly (p < 0.05) increased in patients with preserved LV function, whereas it was not altered in patients with impaired LV function (norepinephrine 20.8 +/- 20.5 vs 45.8 +/- 41.9, respectively). We observed no differences in basal or peak levels of neurohormonal factors, including plasma renin activity, aldosterone, and brain natriuretic peptide (BNP), between the groups. Although the plasma levels of angiotensin I and II were not different in the two groups at rest or at peak exercise, their increasing ratios from rest to peak exercise were significantly higher in patients with impaired LV function compared to those with preserved LV function (angiotensin I; -18.6 +/- 31.0% vs 64.8 +/- 66.5%, p < 0.05, angiotensin II; -5.9 +/- 41.2% vs 60.7 +/- 40.4% , p < 0.05). These results suggest that the increasing ratios of angiotensin I and II are superior to BNP as predictors of LV dysfunction, and that the sympathetic nervous system has already been activated even at rest and did not respond to dynamic exercise in patients with LV dysfunction in ischemic heart disease.
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PMID:Augmented responses of angiotensin I and II in patients with ischemic heart disease: relation to left ventricular function. 1098 47

The cardiac ATP-sensitive potassium (K(ATP)) channel is potentially composed of an inward rectifier potassium channel (Kir6.1 and/or Kir6.2) subunit and the cardiac type of sulfonylurea receptor (SUR2A). We reported that cardiac Kir6.1 mRNA and protein are specifically upregulated in the non-ischemic as well as the ischemic regions in rats with myocardial ischemia, suggesting that humoral and/or hemodynamic factors are responsible for this regulation. In the present study, pretreatment with TCV-116, an angiotensin (Ang) II type 1 receptor antagonist, completely inhibited the upregulation of Kir6.1 mRNA and protein expression in both regions of rat hearts subjected to 60 min of coronary artery occlusion followed by 24 h of reperfusion; whereas pretreatment with lisinopril, an Ang converting enzyme (ACE) inhibitor, partly inhibited this upregulation. Except for rats pretreated with TCV-116, Kir6.1 mRNA levels were positively correlated with those for brain natriuretic peptide (BNP), a molecular indicator of regional wall stress, in both the non-ischemic and the ischemic regions. Plasma Ang II levels were not elevated in rats with control myocardial ischemia compared with sham rats. Thus, the stress-related induction of cardiac Kir6.1 mRNA and protein expression under myocardial ischemia is inhibited by pretreatment with an AT1 antagonist, but also in part by an ACE inhibitor, suggesting that activation of local renin-angiotensin system may play a role.
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PMID:Angiotensin II type 1 receptor blockade abolishes specific K(ATP)channel gene expression in rats with myocardial ischemia. 1111 99


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