Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple processes lead to neuronal death after ischemia, but the generation of nitric oxide (NO) is a key component in this cascade of events. The mechanisms that regulate the extent of neuronal degeneration during anoxia and NO toxicity are multifactorial. Neuronal death may be modulated by the activity of signal transduction systems that influence the toxicity of NO or its metabolic products such as cGMP. The enzyme responsible for the production of NO, nitric oxide synthase (NOS), is phosphorylated by protein kinase C (PKC), the cAMP-dependent protein kinase (PKA), and the calcium/calmodulin-dependent protein kinase II (CaM-II). We examined in primary cultured hippocampal neurons whether the protein kinases PKC, PKA, CaM-II, and cGMP-dependent protein kinase modified the toxic effects of anoxia and NO. Down-regulation of PKC activity with PMA (1 microM) increased hippocampal neuronal survival during anoxia and NO exposure from approximately 22% to 88%. Inhibitors of PKC activity (H-7, H-8, sphingosine, and staurosporine) also were neuroprotective. Down-regulation of PKC activity increased survival during anoxia even in the presence of the NOS inhibitor, N omega-methyl-L-arginine. Thus, although down-regulation of PKC activity may increase neuronal survival by decreasing NOS activity, it also is likely that PKC contributes to ischemic neuronal death by mechanisms that are independent of NOS. Inhibition of the cGMP-dependent protein kinase activity, but not the activity of the CaM-II also was neuroprotective during NO administration. In contrast to the protective effects of inhibition of PKC and the cGMP-dependent protein kinase, activation rather than inhibition of PKA increased hippocampal neuronal survival during NO exposure. These results indicate that neuronal survival during anoxia and NO exposure is linked to the modulation of PKC, PKA, and cGMP-dependent protein kinase activity but is not dependent on the CaM-II pathway. Understanding the involvement of PKC, PKA, and the cGMP-dependent protein kinase in modulating the effect of neuronal death during ischemia and NO toxicity may help in directing future therapeutic modalities for cerebrovascular disease.
 ...
PMID:Protein kinases modulate the sensitivity of hippocampal neurons to nitric oxide toxicity and anoxia. 823 Mar 23

Endothelin-1 may function pathophysiologically as a counterregulatory vasoconstrictor peptide that is modified in its activity by the opposing action of endothelium-derived relaxing factor(s) (EDRF). The present study determined in part the integrated cardiorenal and endocrine actions of pathophysiologic plasma concentrations of endothelin in the anesthetized dog. In addition, nitroglycerin, which inhibits vascular smooth muscle contraction by increasing cGMP in a mechanism similar to EDRF, acts like an endogenous nitrovasodilator. Therefore, we tested the hypothesis that nitroglycerin would effectively antagonize the cardiac and renal actions of exogenous endothelin. The results confirm that endothelin-1-mediated vasoconstriction in vivo is heterogenous with a greater renal than coronary action. Further, nitroglycerin effectively blocked endothelin-1-mediated coronary flow reductions, but only partially antagonized reductions in renal blood flow. Endothelin-1-induced reduction in cardiac output also was not antagonized by nitroglycerin despite its effects to preserve coronary blood flow. Nitroglycerin did, however, antagonize endothelin-induced elevations in plasma epinephrine, norepinephrine, and aldosterone. These results would suggest that in pathophysiologic states where endothelin-1 is elevated, such as hypertension or congestive heart failure, there is a major compromising of renal function, and also the production of cardiac ischemia. Since exogenous nitroglycerin is relatively ineffective in antagonizing the renal vasoconstrictive effects of endothelin, it may be that the endogenous vasodilating systems, such as ERDF and prostacyclin, are inadequate in such pathologic states to counter the vasoconstrictor effects of endothelin.
 ...
PMID:Endothelin-mediated cardiorenal hemodynamic and neuroendocrine effects are attenuated by nitroglycerin in vivo. 838 58

In conscious rabbits equipped with right ventricular electrode and left ventricular polyethylene catheters, zaprinast and cicletanine, inhibitors of phosphodiesterase (PDE) V and PDEs I and V, respectively, as well as verapamil, a Ca2+ channel blocker, decreased intracavital ST-segment elevation induced by ventricular overdrive pacing (VOP). Zaprinast and cicletanine attenuated VOP-induced QT reduction and increase in left ventricular end-diastolic pressure (LVEDP), whereas verapamil increased LVEDP. These results suggest that inhibition of cGMP-PDEs can protect heart against ischemia.
 ...
PMID:Zaprinast, cicletanine, and verapamil attenuate overdrive pacing-induced myocardial ischemia in conscious rabbits. 839 May 93

Using microdialysis, we evaluated temporal changes in striatal extracellular cGMP level following ischemia and its relationship to nitric oxide (NO) production. In untreated animals, significant elevation of cGMP was observed during ischemia and during 4 h of recirculation. In animals treated with L-NAME ischemia induced a modest increase in the cGMP level, but this level was significantly lower than that observed in the untreated animals. These results demonstrate first, that the microdialysis technique can be used to detect changes in extracellular cGMP levels during ischemia and second, that ischemia and recirculation induce a rise in cGMP which is diminished by nitric oxide synthase inhibition, suggesting a linkage to NO production.
 ...
PMID:Ischemia-induced changes in extracellular levels of striatal cyclic GMP: role of nitric oxide. 854 96

The polyamines are involved in repair processes after intestinal ischemia. Arginine and ornithine, both precursors of polyamines were therefore expected to exert beneficial effects on mucosal barrier dysfunction. Arginine may also generate NO and there is support for the view that NO may be beneficial after an ischemic insult. Male Wistar rats were given, by gavage, isonitrogenous solutions of L-arginine (0.5 g/kg) or L-ornithine (0.7 g/kg) 17 and 2 h before ischemia. Controls received an isonitrogenous solution of casein hydrolysate (1 g/kg). Transient intestinal ischemia was produced in anesthetized rats by occluding the superior mesenteric artery for 90 min. Intestinal morphology, hydrolase activities, polyamine and cGMP contents, and cell proliferation rates were determined 4 h after reperfusion. Administration of arginine or ornithine did not prevent ischemic damage but accelerated morphological repair, enhanced cell proliferation, and polyamine content was observed. Arginine was significantly more effective than ornithine. Formation of cGMP was enhanced after arginine administration. NG-nitroarginine methylester, an inhibitor of NO synthase, prevented the arginine effects on mucosal repair. We conclude that arginine-derived NO is an important mediator in the restitution of intestinal mucosa by minimizing cell injury during reperfusion.
 ...
PMID:Beneficial effects of L-arginine on intestinal epithelial restitution after ischemic damage in rats. 854 84

To elucidate the vascular endothelial function at pulmonary ischemia and reperfusion, cyclic GMP (cGMP) release in lung perfusate at reperfusion after ischemia was examined as a marker of nitric oxide (NO) release from the endothelium in an in situ perfused rabbit lung. The lung was perfused from the pulmonary artery with Krebs-Henselite buffer and cGMP in the lung effluent from the left ventricle was assayed in a time-dependent manner. The inhibition of cGMP release by NG-nitro-L-arginine methyl ester and the reversal of the effect by L-arginine indicated that cGMP released into the perfusate was elicited by NO from the endothelium. There was a significant decrease in cGMP release during reperfusion after warm ischemia (30 min and 60 min) compared with the immediately perfusion without intervening ischemia. These data suggest that NO release is impaired by the endothelial dysfunction at reperfusion after warm ischemia in the perfused rabbit lung and the biochemical studies of the perfusate is useful in assessing the vascular endothelial function.
 ...
PMID:[Influence of warm ischemia and reperfusion on no-derived cyclic GMP release in the perfused rabbit lung]. 855 Oct 71

Hypoxia is a common denominator of ischemic microenvironments. Endothelium subjected to oxygen deprivation maintains cell viability and basic biosynthetic mechanisms, but displays multiple changes in properties relevant to vascular homeostasis, including suppression of the anticoagulant cofactor thrombomodulin, decreased barrier function, and generation of proinflammatory cytokines. Diminished intracellular cAMP during the period of hypoxia and lowered nitric oxide/cGMP in the subsequent reperfusion period are proposed as fundamental mechanisms driving vascular dysfunction impacting on coagulation, permeability, vasomotor tone and leukocyte adhesivity. The period of organ preservation for transplantation, recognized to be associated with hypoxia, primes mechanisms leading to subsequent vascular dysfunction which can be ameliorated by buttressing cAMP and nitric oxide/cGMP intra- and intercellular second messenger systems. A mechanism likely to contribute to hypoxia-mediated generation of cytokines, such as interleukin 6, is activation of the transcription factor NF-IL-6, which occurs in oxygen deprivation. These data indicate that study of cellular mechanisms of endothelial perturbation in hypoxia is likely to provide insights ultimately applicable to ischemia-induced vascular damage.
 ...
PMID:Hypoxia and modification of the endothelium: implications for regulation of vascular homeostatic properties. 856 21

In spite of optimal organ preservation techniques, the heart and the lungs remain extremely vulnerable to the ischemia and reperfusion which accompany the transplantation procedure. Following a period of prolonged preservation, the altered phenotype of the graft vasculature results in vasoconstriction, neutrophil sequestration, edema, and thrombosis in the reperfused graft. These parameters of vascular dysfunction translate into primary graft failure and recipient demise. Using endothelial cells exposed to hypoxia and reoxygenation as a simple paradigm for the vascular milieu during organ preservation/transplantation, we have found that second messenger pathways (cAMP and NO/cGMP) are suppressed, neutrophil-endothelial interactions are enhanced, and prothrombotic mechanisms are activated. Using heterotopic rat heart and orthotopic rat lung transplant models, we have shown that supplemention of second messenger pathways or interference with neutrophil-endothelial interactions can significantly enhance preservation. Understanding mechanisms of vascular dysfunction within the graft should help define clinically relevant therapeutic targets to enhance heart or lung preservation for transplantation.
 ...
PMID:The vascular biology of heart and lung preservation for transplantation. 857 26

To elucidate the mechanisms of ischemic cell damage, biochemical disturbances developing during and following in vitro ischemia of 5, 10 or 15 min duration were compared in hippocampal slices prepared from gerbil and rat brains. During ischemia the release of glutamate from slices into the medium was determined, and after ischaemia and 10 min of recovery slices were analyzed for ATP levels, adenylate energy charge and cGMP content. The release of glutamate into the medium during in vitro ischemia and the recovery of energy metabolism determined after 10 min of recovery was almost identical in slices prepared from gerbil and rat hippocampi. In contrast, cGMP levels measured 10 min following in vitro ischemia were significantly higher in gerbil as compared to rat slices. Since after 10 min of recovery following in vitro ischemia, cGMP levels reflect nitric oxide (NO) synthesis (inhibition by NO synthase blocker), it is concluded that increased NO synthesis may contribute to the higher sensitivity of the gerbil as compared to the rat hippocampus towards transient ischemia.
 ...
PMID:Comparison of biochemical disturbances in hippocampal slices of gerbil and rat during and after in vitro ischemia. 858 22

To examine the intracellular signaling mechanism of NO in ischemic myocardium, isolated working rat hearts were made ischemic for 30 min followed by 30 min of reperfusion. A separate group of hearts were pre-perfused with 3 mM L-arginine in the presence or absence of 650 microM of protoporphyrin, a heme oxygenase inhibitor for 10 min prior to ischemia. The release of NO was monitored using an on-line amperometric sensor placed into the right atrium. The aortic flow and developed pressure were examined to determine the effects of L-arginine on ischemic/reperfusion injury. Induction for the expression of heme oxygenase was studied by Northern hybridization. For signal transduction experiments, sarcolemmal membranes were radiolabeled by perfusing the isolated hearts with [3H] myoinositol and [14C] arachidonic acid. Biopsies were processed to determine the isotopic incorporation into various phosphoinositols as well as phosphatidic acid and diacylglycerol. cGMP was assayed by radioimmunoassay and SOD content was determined by enzymatic analysis. The release of NO was diminished following ischemia and reperfusion and was augmented by L-arginine. L-arginine reduced ischemic/reperfusion injury as evidenced by the enhanced myocardial functional recovery. Protoporphyrin modulated the effects of L-arginine. cGMP, which was remained unaffected by ischemia and reperfusion, was stimulated significantly after L-arginine treatment. The NO-mediated augmentation of cGMP was reduced by protoporphyrin suggesting that part of the effects may be mediated by CO generated through the heme oxygenase pathway. Reperfusion of ischemic myocardium resulted in significant accumulation of radiolabeled inositol phosphate, inositol bisphosphate, and inositol triphosphate. Isotopic incorporation of [3H] inositol into phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-bisphosphate was increased significantly during reperfusion. Reperfusion of the ischemic heart prelabeled with [14C] arachidonic acid resulted in modest increases in [14C] diacylglycerol and [14C] phosphatidic acid. Pretreatment of the heart with L-arginine significantly reversed this enhanced phosphodiesteratic breakdown during ischemia and early reperfusion. However, at the end of the reperfusion the inhibitory effect of L-arginine on the phosphodiesterases seems to be reduced. In L-arginine treated hearts, SOD activity was progressively decreased with the duration of reperfusion time. The results suggests for the first time that NO plays a significant role in transmembrane signaling in the ischemic myocardium. This signaling appears to be on- and off- nature, and linked with SOD content of the tissue. The signaling is transmitted via cGMP and opposes the effects of phosphodiesterases by inhibiting the ischemia/reperfusion-induced phosphodiesteratic breakdown. Our results also suggest that NO activates heme oxygenase which further stimulates the production of cGMP presumably by CO signaling. Thus, NO not only potentiates cGMP mediated intracellular signaling, it also functions as a retrograde messenger for CO signaling in heart.
 ...
PMID:Nitric oxide--a retrograde messenger for carbon monoxide signaling in ischemic heart. 873 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>