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)

Left ventricular hypertrophy is considered to be an independent risk factor giving rise to ischemia, arrhythmias, and left ventricular dysfunction. Slow movement of intracellular calcium contributes to the impaired contraction and relaxation function of hypertrophied myocardium. Myofibril content may also be shifted to fetal-type isoforms with decreased contraction and relaxation properties in left ventricular hypertrophy. Myocyte hypertrophy and interstitial fibrosis are regulated independently by mechanical and neurohumoral mechanisms. In severely hypertrophied myocardium, capillary density is reduced, the diffusion distance for oxygen, nutrients, and metabolites is increased, and the ratio of energy-production sites to energy-consumption sites is decreased. The metabolic state of severely hypertrophied myocardium is anaerobic, as indicated by the shift of lactate dehydrogenase marker enzymes. Therefore, the hypertrophied myocardium is more vulnerable to ischemic events. As a compensatory response to severe cardiac hypertrophy and congestive heart failure, the ADP/ATP carrier is activated and atrial natriuretic peptide is released to increase high-energy phosphate production and reduce cardiac energy consumption by vasodilation and sodium and fluid elimination. However, in severely hypertrophied and failing myocardium, vasoconstrictor and sodium- and fluid-retaining factors, such as the renin-angiotensin system, aldosterone, and sympathetic nerve activity, play an overwhelming role. Angiotensin-converting enzyme inhibitors (ACEIs) are able to prevent cardiac hypertrophy and improve cardiac function and metabolism. Under experimental conditions, these beneficial effects can be ascribed mainly to bradykinin potentiation, although a contribution of the ACEI-induced angiotensin II reduction cannot be excluded.
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PMID:Substrate metabolism, hormone interaction, and angiotensin-converting enzyme inhibitors in left ventricular hypertrophy. 852 2

When the heart is subjected to a transient non-lethal period of ischemia, it quickly adapts itself to become resistant to infarction from a subsequent ischemic insult. This adaptation, termed preconditioning, occurs in all species studied, including man. The protection has been shown to be mediated by stimulation of adenosine and probably bradykinin receptors. Recent studies reveal that these receptors may protect by activating protein kinase C in cardiomyocytes. In this review the evidence supporting the protein kinase C hypothesis and therapeutic possibilities for employing the preconditioning phenomenon in clinical situations are discussed.
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PMID:Signal transduction in ischemic preconditioning. 858 77

Long lasting myocardial ischemia causes death of myocytes despite the restoration of coronary blood flow. Short period of ischemia and reperfusion transiently injures myocytes and is followed by the prolonged but reversible contractile dysfunction called myocardial stunning. Additionally, after a short time ischemia the postischemic myocardium shows enhanced tolerance towards subsequent, long time ischemia, so called ischemic preconditioning. The mechanisms responsible for both phenomena are not completely understood. Myocardial stunning is probably caused by injury to the heart at the molecular level (for example the transient inactivation or damage of proteins of the sarcoplasmic reticulum or the contractile machinery). Since contractility of stunned myocardium recovers, this injury is reversible. The presence of anti-oxidant enzymes system in the heart as well as endogenous protective substances like adenosine or bradykinin and synthesis of stress proteins like hsp 70, hsp 27 or ubiquitin might represent the molecular defense mechanisms against ischemia/reperfusion injury.
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PMID:[Molecular mechanisms for protecting the heart]. 858 24

We have investigated the effect of bradykinin on microvascular perfusion failure and enzyme release after ischemia/reperfusion of the pancreas in rats. Using intravital fluorescence microscopy in 21 anesthetized Sprague-Dawley rats, quantitative analysis of the microcirculation, including functional capillary density (FCD) and leukocyte-endothelium interaction, was performed in an ischemia/reperfusion model of the pancreas. Bradykinin was dissolved in phosphate buffer and given as a bolus injection (injection group, 10 microgram/kg body wt i.a.; n = 7) or continuously infused (infusion group, 125 microgram/kg body wt/hr i.a.; n = 7) 15 min before the end of 2 hr of ischemia. Two further groups underwent sham operation (control group, n = 7) or an ischemia of 2 hr (ischemia group, n = 7) without bradykinin administration. Continuous infusion of bradykinin resulted in a significant enhancement of capillary perfusion failure after ischemia during reperfusion. In the bradykinin infusion group less than 25% of the capillaries were perfused (FCD 98 +/- 9 cm -1) after 2 hr of reperfusion, whereas in the ischemia group without bradykinin, 50% of capillaries were perfused (FCD 192 +/- 11 cm -1). Both of these values are significantly different from the baseline value of the control group (408 +/- 9 cm -1). The rise in pancreas amylase concentration was significantly more pronounced in the infusion group (basal: 1812 +/- 114 U/1; 2 hr of reperfusion 3375 +/- 268 U/1) when compared to the ischemia group (basal: 2386 +/- 283 U/1; 2 hr of reperfusion 3486 +/- 268 U/1). These findings suggest that bradykinin has an additive role in aggravation of pancreatic microcirculatory failure after ischemia/reperfusion of the pancreas.
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PMID:Exogenous bradykinin enhances ischemia/reperfusion injury of pancreas in rats. 860 2

Limited recovery of contractile function and loss of coronary reactivity have been observed following prolonged hypothermic storage and transplantation of the heart. Since lipid peroxidation has a significant role in these deficits, we investigated the cardioprotective effects of a 21-aminosteroid. U74389G, 3 mg/kg i.v., was given daily for 2 consecutive days to donor Lewis rats before the hearts were harvested and to recipient Lewis rats for 3 consecutive days after heart transplantation. Donor hearts were preserved for 4 hr in cold saline (4 degree C) before transplantation. Left ventricular developed pressure (LVP), basal coronary perfusion, and coronary reactivity to endothelium-dependent dilation (bradykinin, 0.1 microM) or endothelium-dependent dilation (sodium nitroprusside, 0.5 microM) were studied in isolated, buffer-perfused heart, using a modified Langendorff model. Cold preservation alone significantly reduced LVP and coronary perfusion. Coronary reactivity to bradykinin and sodium nitroprusside was also significantly impaired. In U74389G-treated donor hearts, 4 hr of cold ischemia did not alter contractile function, coronary perfusion or endothelial reactivity, although the response to sodium nitroprusside did not fully recover. In untreated recipients, in vivo reperfusion (transplantation) resulted in reduced LVP and perfusion deficits. Treating donors and recipients with U74389G improved left ventricular contractibility and coronary perfusion, although endothelium-dependent and -independent coronary reactivity remained affected. These results indicate that the lazaroid U74389G exerts significant cardioprotection during both preservation and transplantation of the heart. Donor and recipient pretreatment is mandatory for maximal efficacy with U74389G.
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PMID:Cardioprotective effects of the lazaroid U74389G following cold preservation and transplantation of rat hearts. 862 80

Ischaemia-reperfusion of the pancreas was performed in 35 anaesthetized Sprague-Dawley rats. The effects of two bradykinin antagonists, HOE-140 (13 micrograms kg-1 intravenous bolus injection, n = 7) and CP-0597 (18 micrograms kg-1 h-1 intravenous infusion, n = 7) on pancreatic microvascular perfusion and leucocyte-endothelium interaction were quantitatively analysed by intravital fluorescence microscopy. Three further groups underwent sham operation (n = 7), ischaemia of 2 h without treatment (n = 7), and ischaemia of 2 h with infusion of phosphate buffer (n = 7). Functional capillary density was significantly greater in animals treated with HOE-140 or CP-0597 than in sham-treated animals, and was decreased to only 60 per cent. Adherence of leucocytes to the endothelium of postcapillary venules was significantly reduced when compared with ischaemia without antagonist. These results demonstrate a positive effect of the two bradykinin antagonists HOE-140 and CP-0597 on microvascular perfusion failure after ischaemia-reperfusion of the pancreas.
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PMID:Bradykinin antagonists HOE-140 and CP-0597 diminish microcirculatory injury after ischaemia-reperfusion of the pancreas in rats. 868 61

The assessment of endothelial function in hypertensive patients receiving acetylcholine has revealed conflicting results. Whether an impaired flow response to acetylcholine is explained solely by a diminished endothelial synthesis of nitric oxide (NO) remains unclear as yet. In the present study, we tested the hypothesis that mechanisms other than reduced NO synthesis contribute to the hypertension-associated impairment of endothelium-dependent vasodilation. Therefore, the dilatory response to endogenous and exogenous NO was measured in resistance arteries and cutaneous microvessels in the forearm circulation of 12 normotensive individuals and 17 hypertensive patients. In addition, the overall dilatory capacity was assessed by peak flow during reactive hyperemia after 3 minutes of ischemia. Forearm blood flow was quantified by venous occlusion plethysmography at rest, during application of the NO donor sodium nitroprusside, and during stimulation of endogenous NO synthesis by acetylcholine and bradykinin. Blood flow velocity in the cutaneous microvasculature was measured with laser-Doppler flowmetry in parallel. Resting forearm flow was comparable in both groups (3.1 +/- 0.2 and 3.4 +/- 0.2 mL.min-1.100mL-1 tissue), whereas blood pressure and thus peripheral vascular resistance was significantly elevated in hypertensive compared with normotensive subjects. Hyperemic peak flow was significantly blunted in hypertensive patients. Sodium nitroprusside, acetylcholine, and bradykinin increased flow in a dose-dependent manner to a comparable extent in the control group (13.3 +/- 0.8, 13.6 +/- 1.3, and 14.6 +/- 0.7 mL.min-1.100mL-1 tissue, respectively). In contrast, in hypertensive patients maximum increase in resting flow was significantly reduced (sodium nitroprusside, -36%; acetylcholine, -44%; and bradykinin, -56%). The flow response after stimulation of endogenous NO synthesis by bradykinin was significantly more blunted compared with that of exogenous NO after application of sodium nitroprusside. In the cutaneous microvasculature, bradykinin-induced increases in blood flow velocity were selectively impaired in hypertensive patients, whereas flow response to acetylcholine was preserved. Thus, we conclude that in arterial hypertension endothelium-dependent, NO-mediated dilation of resistance arteries and cutaneous microvessels of the forearm vasculature is heterogeneously impaired, depending on the type of endothelial receptor stimulated. Furthermore, the present data suggest that in hypertensive patients the impairment of NO-dependent dilation of resistance arteries is caused by at least three different mechanisms: (1) a reduced endothelial synthesis of NO due to either a disturbed signal-transduction pathway and/or a reduced activity of NO synthase, (2) an accelerated NO degradation within the vessel wall, and (3) alterations in the vessel architecture resulting in an overall reduced dilatory capacity of resistance arteries.
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PMID:Evidence for a multifactorial process involved in the impaired flow response to nitric oxide in hypertensive patients with endothelial dysfunction. 869 36

In the phenomenon termed "ischemic preconditioning," a brief period of ischemia prior to a more prolonged one improves myocardial function (after reperfusion) and diminishes infarction. This phenomenon has been described extensively in experimental animals and now in humans. It is triggered by several agents released by ischemic cells and can be reproduced by infusion of agonists coupled to protein kinase C (PKC), e.g. adenosine, angiotensin, phenylephrine, bradykinin, and endothelin. The intracellular signaling pathway involves a phospholipase, either C or D, which metabolizes membrane phospholipids to produce diacylglycerol, a necessary endogenous cofactor for PKC activation. Which protein(s) is phosphorylated by PKC is not yet known, nor is the identity of the end-effector that actually mediates protection of the ischemic cell. Identification of the end-effector may make it possible in the routine treatment of patients with ischemic heart disease to precondition and thereby salvage ischemic myocardium and improve survival.
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PMID:Myocardial preconditioning promises to be a novel approach to the treatment of ischemic heart disease. 871 75

The effects of a clinically used purified micronized flavonoid fraction (S5682) containing 90% diosmin and 10% hesperidin on increased microvascular permeability induced by histamine, bradykinin and leukotriene B4 (LTB4) were investigated by intravital microscopy in the cheek pouch preparation of diabetic hamsters. We also investigated the effects of S 5682 on macro- molecular permeability increase and leukocyte adhesion during ischemia-reperfusion using the same preparation. Diabetes was induced by an intraperitoneal injection of streptozotocin (50 mg/kg). S 5682, suspended in 10% lactose solution, or vehicle (10% lactose) was administered orally for 25 days at 20 mg/kg/day (10 mg/kg twice a day), starting 5 days after the streptozotocin injection. Fluorescein isothiocyanate-labelled dextran (molecular weight 150,000) was given intravenously, 30 min after completion of the cheek pouch preparation. The leukocytes were stained by continuous intravenous infusion of acridine orange (0.5 mg/ kg/min). Histamine (2 microMs), bradykinin (1 microM), and LTB4 (0.01 microM), applied topically for 5 min, increased the number of fluorescent vascular leakage sites in postcapillary venules. A temporary ischemia (duration: 30 min) with total circulatory arrest of the cheek pouch was obtained by clamping the neck of the everted pouch. The maximum number of leaky sites (per cm2 in the prepared area) which occurs either at 5 min after the beginning of each topical application or 10 min after the onset of reperfusion was quantified in UV light microscopy. The results from 60 animals divided into ten groups of 6 animals each are presented as means +/- SEM. In comparison with vehicle, S 5682 significantly inhibited the macromolecular permeability increasing the effect of histamine (343.8 +/- 18.5 vs. 91.0 +/- 8.2 leaks/ cm2; p > 0.001), bradykinin (347.0 +/- 14.6 vs. 110.3 +/- 8.5 leaks/cm2; p < 0.001) and LTB4 (323.0 +/- 15.5 vs. 161.3 +/- 13.8 leaks/cm2; p < 0.001). At reperfusion, after 30 min ischemia, S 5682 significantly decreased the observed macromolecular permeability (168.5 +/- 19.7 vs. 52.7 +/- 6.3 leaks/cm2; p < 0.01). Flavonoid-treated animals also tended to have a lower number of leukocytes adhering to the venular endothelium (104.8 +/- 11.0 vs. 75.8 +/- 9.7/6 mm2; p > 0.05). These results demonstrate that oral administration of S 5682 for 25 days at 20mg/kg body weight/day has a protective effect on leakage of macromolecules after application of permeability-increasing substances and during ischemia-reperfusion in the cheek pouch microvasculature of diabetic hamsters. In conclusion, the present data illustrating the inhibitory effect of a clinically relevant doses of S 5682 on the inflammatory processes induced in this in vivo model of microcirculation may serve as a rational basis to explain its clinical efficacy.
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PMID:Effects of oral administration of purified micronized flavonoid fraction on increased microvascular permeability induced by various agents and on ischemia/reperfusion in diabetic hamsters. 872 38

Abdominal ischemia activates ischemically sensitive sympathetic visceral afferents and evokes reflex excitation of the cardiovascular system. These afferents respond to ischemic metabolites, including lactic acid, bradykinin, prostaglandins, and reactive oxygen species. Severe hypoxemia also has been shown to activate these afferents. It is not known, however, if the regional tissue hypoxia induced by abdominal ischemia directly or indirectly activates ischemically sensitive visceral afferents. To determine the role of tissue hypoxia in activation of ischemically sensitive abdominal afferents, continuous single-unit activity of ischemically sensitive abdominal sympathetic C-fiber afferents (conduction velocity = 0.51-1.48 m/s) and regional tissue PO2, measured by a polarographic oxygen electrode in the porta hepatis, duodenum, or pancreas, were recorded simultaneously in anesthetized cats before and during 10-15 min of ischemia. Abdominal ischemia rapidly decreased regional tissue PO2 from 161 +/- 10 to 8 +/- 2 mmHg (P < 0.01) within an interval of 136 +/- 12 s. By contrast, after longer latency (399 +/- 24 s, P < 0.01 vs. PO2 interval), the activity of these afferents increased from 0.06 +/- 0.01 to 0.33 +/- 0.07 imp/s (P < 0.01). Furthermore, the activity of ischemically sensitive afferents gradually increased throughout ischemia with peak activity (0.68 +/- 0.14 imp/s) occurring at 600 +/- 39 s, although tissue PO2 remained constant. There was no correlation between the changes of tissue PO2 and discharge activity of these afferents (r = -0.428, P = 0.144). These data suggest that tissue hypoxia induced by abdominal ischemia is not directly responsible for activation of ischemically sensitive sympathetic visceral afferents but likely acts in an indirect fashion by promoting formation of other metabolic products capable of activating these nerve endings.
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PMID:Hypoxia does not directly stimulate ischemically sensitive abdominal visceral afferents during ischemia. 876 Jan 83


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