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)

Endopeptidase 24.11 (EC 3.4.24.11) enzymatic activity was spectrofluorimetrically measured in human urine, using a synthetic peptidic substrate. Urinary endopeptidase 24.11 output (Uendo) was determined in 24-hour urine samples of 10 kidney transplant recipients during the first 2 weeks after surgery. In 9 patients, a large increase in Uendo levels was noted during the 1st and/or the 2nd postoperative days (mean +/- SEM of peak Uendo 624 +/- 122 micrograms/24 h, p = 0.0003 as compared to 239 +/- 20 micrograms/24 h in a healthy control population). This occurred whether patients received OKT3 (n = 6) or cyclosporine A (n = 3) as primary immunosuppression. Uendo returned to normal between the 3rd and the 5th postoperative day. We conclude that renal transplantation is associated with an early and marked release of endopeptidase 24.11 in urine. This could be due to the potentially toxic effects of ischemia and/or immunosuppressive drugs on the proximal tubular epithelium. The clinical usefulness of urinary endopeptidase 24.11 as a marker of tubular injury remains to be assessed.
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PMID:Pathological release of urinary endopeptidase 24.11 early after renal transplantation. 130 55

Hypertension after renal transplantation continues to affect 50% or more of patients, despite use of modern immunosuppressive regimens. Relationships between poor control of blood pressure and reduced chronic allograft survival have been clearly demonstrated, and are analogous to the well-known acceleration of progressive renal disease by coexisting hypertension. It is likely, although to date it has not been formally proven by prospective study, that effective blood pressure control has a beneficial effect on chronic allograft outcome, as in progressive dysfunction of native kidneys. A further key question is whether differing classes of antihypertensive therapy may have differing effects on long-term graft outcome. It has been proposed that glomerular hypertension, hyperfiltration and hypertrophy, secondary both to inadequate nephron mass and to loss of functioning nephrons, may contribute to chronic allograft failure. If this is true, then use of converting enzyme inhibitors may particularly benefit long-term graft outcome. However, post-transplant hypertension in cyclosporine-treated patients is associated with sodium retention and renin system suppression, and a relative lack of renoprotective action of ACE inhibitors might be predicted in this context. An alternative hemodynamic factor underlying chronic allograft failure is glomerular ischemia, secondary to the vascular changes associated with chronic rejection and to cyclosporine-related afferent arteriolar vasoconstriction. In this setting, calcium channel blockers which lower systemic blood pressure in combination with afferent arteriolar vasodilatation may improve long-term allograft outcome. New strategies with a similar rationale include endothelin receptor antagonists and neutral endopeptidase inhibitors such as candoxatril, which in acute experimental and clinical studies reverse cyclosporine-induced reductions in renal blood flow and glomerular filtration rate. Long-term prospective controlled comparative studies are needed to assess the effect of all these differing therapeutic approaches on chronic allograft outcome.
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PMID:Does antihypertensive therapy modify chronic allograft failure? 858 70

Angiotensin-converting enzyme inhibitors (ACEi) protect the heart against ischemia/reperfusion injury. Part of this cardioprotective effect may be mediated through kinins. Because kinins are also metabolized by neutral endopeptidase (NEP) 24.11 in vivo, we hypothesized that (a) inhibition of NEP-24.11 would afford cardioprotection similar to that of ACEi and potentiate the effect of ACEi; and (b) these effects are mediated by kinins or atrial natriuretic peptide (ANP) or both. In Lewis inbred rats, the left anterior descending coronary artery (LAD) was occluded for 30 min, followed by 120-min reperfusion. Immediately before reperfusion rats received vehicle, the ACEi ramiprilat, the NEP-24.11 inhibitor (NEPi) CGS24592, or both. To test whether the effect of NEPi could be suppressed by blocking kinins or ANP, the kinin-receptor antagonist icatibant or ANP antagonist HS-142-1 was administered before LAD occlusion. In controls, infarct size/risk area was 69 +/- 4%; NEPi reduced this to 24 +/- 4% (p < 0.001) and ramiprilat to 20 +/- 3% (P < 0.001). NEPi did not potentiate the effect of ramiprilat (infarct size/risk area, 18 +/- 4%). The protective effect of NEPi was blocked by icatibant; infarct size/risk area, 61 +/-4%, significantly larger than NEPi along (p < 0.001) but no different from controls. The effect of NEPi was slightly diminished by the ANP antagonist HS-142-1 (infarct size/risk area, 35 +/- 3%; NS vs. NEPi alone). Thus NEP-24.11 participates in catabolism of kinins in the heart; inhibition of NEP-24.11 may increases cardiac kinins, which are responsible for the cardioprotective effect of NEPi.
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PMID:Effect of neutral endopeptidase 24.11 inhibition on myocardial ischemia/reperfusion injury: the role of kinins. 905 75

The present study determined the effect of either occlusion of the left renal artery for 60 min (ischemia) or sham operation on angiotensin (ANG) receptors and tissue and urinary levels of ANG peptides between 24 and 72 h recovery in male Sprague-Dawley rats. At 24 h postischemia, urinary concentrations of ANG I and ANG-(1-7) rose by an average of 83 and 64%, respectively (P < 0.05) but had declined to control levels by 72 h. Tissue ANG II rose at 24 h in postischemic kidneys by an average of 63% compared with the contralateral nonischemic kidney (P < 0.05). Whereas the enzymatic activity of angiotensin-converting enzyme and neprilysin was reduced after ischemia, renal renin activity in ischemic kidneys rose by 74% compared with sham-operated kidneys. Receptor autoradiography using (125)I-labeled [Sar(1),Thr(8)]ANG II ((125)I-Sarthran) (0.8 nM) revealed a decreased apparent density of ANG receptors (>80% AT(1)) in ischemic kidneys with a trend for a decrease in the contralateral nonischemic kidneys compared with the kidneys from sham-operated rats. Twenty-four hours after ischemia, ANG II receptors decreased by 68% in glomeruli (P < 0.05), 49% in the outer cortical tubulointerstitial area (P < 0.05), and 48% in the inner cortical-outer medullary area of the vasa recta (P < 0.05). Medullary binding decreased approximately 50% in both the ischemic kidney and the contralateral nonischemic kidney compared with sham. In all regions of the ischemic kidney, receptors recovered by 72 h to levels not different from sham control rats. The marked change in urinary ANG I and ANG-(1-7) at 24 h following occlusion indicates these peptides may be potential urinary markers for acute renal ischemia. The reduction of receptors in vascular and tubular regions of the ischemic kidney provides a mechanism for the loss of vasoconstrictor responses to ANG II following ischemia previously reported by others.
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PMID:Differential actions of renal ischemic injury on the intrarenal angiotensin system. 1099 13

In experimental animals, kinins protect the myocardium from ischemia-reperfusion injuries and reduce left ventricular hypertrophy and progression of heart failure. This suggests that in humans, also, the presence of an intact kinin system is critical for the prevention of heart failure. In addition to the kinin-generating system, the concentration of kinins, and consequently the extent of their actions, is regulated by their degradation. In the vascular bed of the human heart, bradykinin (BK) is degraded by angiotensin-converting enzyme (ACE). In contrast, in the interstitium of the human heart, BK is degraded by neutral endopeptidase (NEP). For potentiating the beneficial effects of BK, one strategy is elevation of the BK concentration by inhibition of BK-degrading enzymes. An even more effective form of pharmacological control of BK elevation than inhibition of ACE alone might be the combined inhibition of ACE and NEP.
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PMID:Kinin-degrading pathways in the human heart. 1115 Jul 28

Diabetes mellitus impairs the cardiac kallikrein-kinin system by reducing cardiac kallikrein (KLK) and kininogen levels, a mechanism that may contribute to the deleterious outcome of cardiac ischemia in this disease. We studied left ventricular (LV) function and bradykinin (BK) coronary outflow in buffer-perfused, isolated working hearts (n = 7) of controls and streptozotocin (STZ)-induced diabetic rats before and after global ischemia. With the use of selective kininase inhibitors, the activities of angiotensin I-converting enzyme, aminopeptidase P, and neutral endopeptidase were determined by analyzing the degradation kinetics of exogenously administered BK during sequential coronary passages. Basal LV function and coronary flow were impaired in STZ-induced diabetic rats. Neither basal nor postischemic coronary BK outflow differed between control and diabetic hearts. Reperfusion after 15 min of ischemia induced a peak in coronary BK outflow that was of the same extent and duration in both groups. In diabetic hearts, total cardiac kininase activity was reduced by 41.4% with an unchanged relative kininase contribution compared with controls. In conclusion, despite reduced cardiac KLK synthesis, STZ-induced diabetic hearts are able to maintain kinin liberation under basal and ischemic conditions because of a primary impairment or a secondary downregulation of kinin-degrading enzymes.
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PMID:Cardiac kinin level in experimental diabetes mellitus: role of kininases. 1263 59

Bradykinin is an important endogenous trigger of myocardial ischemic preconditioning (IPC). Through simultaneous inhibition of neutral endopeptidase and angiotensin converting enzyme, omapatrilat prevents enzymatic degradation of bradykinin. The aim of this study was to investigate if omapatrilat, through its ability to augment bradykinin levels, can augment a subthreshold IPC stimulus (Sub-IPC) and to compare the action of omapatrilat with the angiotensin-converting enzyme inhibitor, captopril. Langendorff perfused rat hearts were subjected to 35 min left coronary artery occlusion and 120 min reperfusion. Full IPC was induced with 5 min global ischemia/10 min reperfusion and substantially limited infarct size (21.5 +/- 3.5% of risk zone vs 53.4 +/- 2.0% in controls, P < 0.01). Sub-IPC (2 min global ischemia/10 min reperfusion) did not limit infarct size (48.4 +/- 3.8%). Omapatrilat (10 micromol/L) or captopril (200 micromol/L) were administered alone or in conjunction with Sub-IPC. Reduced infarct size comparable to that observed with the full IPC protocol was seen when sub-IPC was combined with either omapatrilat (19.7 +/- 2.5%) or captopril (20.3 +/- 4.9%). Omapatrilat alone caused modest reduction of infarct size (34.6 +/- 1.5%, P < 0.01 v control), an effect not observed with captopril. Hoe140, a selective kinin B(2) receptor antagonist, eliminated the cardioprotective effect of omaptrilat alone or in combination with sub-IPC. We conclude that omapatrilat elicits cardioprotection via inhibition of bradykinin degradation and that dual inhibition of angiotensin-converting enzyme and neutral endopeptidase may have beneficial effects beyond standard angiotensin-converting enzyme inhibitor therapy in patients with acute coronary syndromes who are at risk of myocardial infarction.
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PMID:Omapatrilat limits infarct size and lowers the threshold for induction of myocardial preconditioning through a bradykinin receptor-mediated mechanism. 1516 74

The origin of the endothelial damage leading to the ischemia-reperfusion injury after lung transplantation has not been elucidated. We postulated that neurotransmitters released during the preservation of the donor lung might explain this vascular derangement. Thus, in isolated rabbit lungs preserved over 24 hours, we evaluated the release of acetylcholine (ACh) and substance P (SP), the activity of their major degrading enzymes, acetylcholinesterase (AChE) and neutral endopeptidase (NEP), and changes in the capillary permeability. Both neurotransmitters showed the highest release rate in the first 15 minutes, followed by a sharp exponential decrement at 1, 6, 12 and 24 hours. AChE and NEP activities showed no variation at these time intervals. Basal capillary permeability significantly increased (P<0.01) after 24 hours preservation with saline. This increased permeability was avoided (P<0.01) by the SP fragment 4-11 (an SP receptors antagonist), but not by atropine. These results suggest for the first time a pathogenic role of SP in the ischemia-reperfusion injury, and thus the potential usefulness of SP antagonists as additives in the lung preservation solutions should be explored.
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PMID:Possible role of substance P in the ischemia-reperfusion injury in the isolated rabbit lung. 1528 Jun 94

The levels of amyloid beta-peptides (Abeta) in the brain represent a dynamic equilibrium state as a result of their biosynthesis from the amyloid precursor protein (APP) by beta- and gamma-secretases, their degradation by a team of amyloid-degrading enzymes, their subsequent oligomerization, and deposition into senile plaques. While most therapeutic attention has focused on developing inhibitors of secretases to prevent Abeta formation, enhancing the rate of Abeta degradation represents an alternative and viable strategy. Current evidence both in vivo and in vitro suggests that there are three major players in amyloid turnover: neprilysin, endothelin converting enzyme(s), and insulin-degrading enzyme, all of which are zinc metallopeptidases. Other proteases have also been implicated in amyloid metabolism, including angiotensin-converting enzyme, and plasmin but for these the evidence is less compelling. Neprilysin and endothelin converting enzyme(s) are homologous membrane proteins of the M13 peptidase family, which normally play roles in the biosynthesis and/or metabolism of regulatory peptides. Insulin-degrading enzyme is structurally and mechanistically distinct. The regional, cellular, and subcellular localizations of these enzymes differ, providing an efficient and diverse mechanism for protecting the brain against the normal accumulation of toxic Abeta peptides. Reduction in expression levels of some of these proteases following insults (e.g., hypoxia and ischemia) or aging might predispose to the development of Alzheimer's disease. Conversely, enhancement of their levels by gene delivery or pharmacological means could be neuroprotective. Even a relatively small enhancement of Abeta metabolism could slow the inexorable progression of the disease. The relative merits of targeting these enzymes for the treatment of Alzheimer's disease will be reviewed and possible side-effects of enhancing their activity evaluated.
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PMID:Targeting amyloid-degrading enzymes as therapeutic strategies in neurodegeneration. 1568 97

Alzheimer's disease (AD) is linked to certain common brain pathologies (e.g., ischemia, stroke, and trauma) believed to facilitate its development and progression. One of the logical approaches to this problem is to study the effects of ischemia and hypoxia on the metabolism of amyloid precursor protein, which plays one of the key roles in the pathogenesis of AD. This involves an analysis of (1) proteases, which participate in proteolysis of amyloid precursor protein either by the nonamyloidogenic route (alpha-secretase) or the amyloidogenic pathway and lead to formation of toxic beta-amyloid peptides (beta- and gamma-secretases) and (2) several metallopeptidases that might play a role in degradation of beta-amyloid peptide (Abeta). The study of the effects of prenatal hypoxia and acute hypoxia in adult animals allowed us to conclude that oxygen deprivation results not only in an increase of amyloid precursor protein expression in the brain but also in a decrease in the activity of alpha-secretase. In some brain structures involved in AD pathology (the cortex and striatum), we also observed a decrease in the expression of two of the Abeta degrading enzymes, neprilysin and endothelin-converting enzyme, after hypoxia. A decrease in expression of these metalloproteases was also observed in the model of four-vessel occlusion ischemia in rats with their restoration to the control levels after reperfusion. Preconditioning to mild hypoxia both in the prenatal period and in adults appeared to have a neuroprotective effect restoring, in particular, the levels of amyloid precursor protein, activity of alpha-secretase, and expression of neprilysin and endothelin-converting enzyme to their control values.
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PMID:Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid-degrading enzymes. 1568 98


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