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)

Cavinton was introduced into the clinical practice some twenty years ago in Hungary for the treatment of cerebrovascular disorders and related symptoms. Since then, its active ingredient, vinpocetine, beside its therapeutical utilization, has become a reference compound in the pharmacological research of cognitive deficits caused by hypoxia and ischaemia as well as in the cellular and biochemical investigations related to cyclic nucleotides. In this review a survey is given on the experimental data obtained with vinpocetine and an attempt is made to outline the drug's mechanism of action. Early experiments with vinpocetine indicated five main pharmacological and biochemical actions: (1) selective enhancement of the brain circulation and oxygen utilization without significant alteration in parameters of systemic circulation, (2) increased tolerance of the brain toward hypoxia and ischemia, (3) anticonvulsant activity, (4) inhibitory effect on phosphodiesterase (PDE) enzyme and (5) improvement of rheological properties of the blood and inhibition of aggregation of thrombocytes. Later studies in various laboratories confirmed the above effects and clearly demonstrated that vinpocetine offers significant and direct neuroprotection both under in vitro and in vivo conditions. Evidence has been obtained that neuroprotective action vinpocetine is related to the inhibition of operation of voltage dependent neuronal Na(+)-channels, indirect inhibition of some molecular cascades initiated by the rise of intracellular Ca(2+)-levels and, to a lesser extent, inhibition of adenosine reuptake. Vinpocetine has been shown to be selective inhibitor of Ca(2+)-calmodulin dependent cGMP-PDE. It is assumed that this inhibition enhances intracellular a GMP levels in the vascular smooth muscle leading to reduced resistance of cerebral vessels and increase of cerebral flow. This effect might also beneficially contribute to the neuroprotective action.
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PMID:[Mechanism of action of vinpocetine]. 908 41

The influence of the atrial natriuretic factor (ANF) on heart-cell communication was investigated in cell pairs isolated from the ventricle of cardiomyopathic hamsters (BIO TO-2; 11 months old), and the results were compared with controls (F1B) of same age. The results indicated that ANF (10(-8) M) added to the bath caused a decline in junctional conductance (gj) of 48 +/- 2% (n = 15) within 90 s. The effect of ANF was suppressed by HS-142-1, a specific antagonist of guanylyl cyclase ANF receptor. Moreover, the decline in gj elicited by ANF was related to the synthesis of cyclic guanosine monophosphate (cGMP). Indeed, dibutyryl-cGMP (10(-4) M) decreased gj by 80 +/- 3.5% (n = 15) within 90 s, and zaprinast, a selective inhibitor of cGMP phosphodiesterase, enhanced the effect of ANF on gj. The possible relationship between ischemia, ANF release, and impairment of cell coupling is discussed.
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PMID:Atrial natriuretic factor reduces cell coupling in the failing heart, an effect mediated by cyclic GMP. 967 24

Several signal transduction pathways have been implicated in the mechanism of protection induced by ischemic preconditioning (PC). For example, stimulation of a variety of G-protein coupled receptors results in stimulation of protein kinase C (PKC) which has been suggested to act as common denominator in eliciting protection. PC also significantly attenuated cAMP accumulation during sustained ischemia, suggesting involvement of an anti-adrenergic mechanism. The aim of this study was to evaluate the beta-adrenergic signal transduction pathway (as evidenced by changes in tissue cAMP and cAMP- and cGMP-phosphodiesterase) during the PC protocol as well as during sustained ischemia. Isolated perfused rat hearts were preconditioned by 3 x 5 min global ischemia (PC1,2,3) interspersed by 5 min reperfusion, followed by 25 min global ischemia. Tissue cAMP- and cGMP-PDE activity as well as cAMP and cGMP levels were determined at different time intervals during the PC protocol and sustained ischemia. Tissue cAMP increased with each PC ischemic event and normalized upon reperfusion, while PDE activity showed the opposite, viz a reduction during ischemia and an increase during reperfusion. Except for PC1, tissue cGMP showed similar fluctuations. Throughout 25 min sustained ischemia, cAMP- and cGMP-PDE activities were higher in PC than in nonpreconditioned hearts, associated with a significantly lesser accumulation in cAMP and higher cGMP levels in the former. Fluctuations in cyclic nucleotides during preconditioning were associated with concomitant changes in PDE activity, while the attenuated beta-adrenergic response of preconditioned hearts during sustained ischemia may partially be due to increased PDE activity.
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PMID:Role of cyclic nucleotide phosphodiesterases in ischemic preconditioning. 977 98

To profile gene expression patterns involved in ischemic preconditioning, we monitored global gene expression changes by DNA microarray analysis of 3200 rat-specific genes and by real-time quantitative polymerase chain reaction in rat hearts. Forty-nine genes with altered expression were found after ischemia/reperfusion as compared to control non-ischemic hearts and 31 genes were characteristic for classic preconditioning followed by ischemia/reperfusion as compared to ischemia/reperfusion without preconditioning. Genes with altered expression due to ischemia and/or preconditioning included those controlling protein degradation, stress responses, apoptosis, metabolic enzymes, regulatory proteins, and several unknown cellular functions. Metallothionein, natriuretic peptides, coagulation factor VII, cysteine proteinase inhibitor, peroxisome proliferator activator receptor gamma and myosin light chain kinase genes were previously suspected to be related to several cardiovascular diseases, however, most of these genes have not previously been shown to be related to myocardial ischemia/reperfusion. Some genes were observed to change specifically in response to preconditioning: oligoadenylate synthase, chaperonin subunit epsilon, a cGMP phosphodiesterase (PDE9A1), a secretory carrier membrane protein, an amino acid transporter, and protease 28 subunit. None of these genes has previously been shown to be involved in the mechanism of preconditioning.
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PMID:Effect of classic preconditioning on the gene expression pattern of rat hearts: a DNA microarray study. 1258 34

The free radical peroxynitrite (ONOO-) is formed in biological systems from the reaction of nitric oxide (NO) with superoxide (O2-) and can react with protein and nonprotein thiol groups to produce tissue injury. However, these pathologic actions of (ONOO-) may have been overemphasized, in that (ONOO-) has vasorelaxant properties through activation of soluble guanylate cyclase; inhibits leukocyte-endothelial cell interactions; and reduces ischemia-reperfusion injury in the heart, lung, and liver. It has been reported that tolerance develops to the vasodilator actions of (ONOO-) and that (ONOO-) impairs vascular function. However, little, if anything, is known about responses to (ONOO-) in the hindlimb circulation of the cat. To better understand the effects of (ONOO-) on responses to vasoactive agonists and the mechanism by which (ONOO-) induces vasodilation, the effects of short-term exposure to (ONOO-) were investigated under constant-flow conditions in the hindlimb vascular bed of the cat. In these studies, direct intraarterial injections of (ONOO-) produced dose-dependent decreases in hindquarters perfusion pressure. The vasodilator responses to (ONOO-) were rapid in onset, were short in duration, and could be repeated without exhibiting tachyphylaxis. Vasodilator responses to (ONOO-) were not changed in the presence of inhibitors of nitric-oxide synthase, cyclooxygenase, or K+-ATP (adenosine triphosphate-sensitive potassium) channels. Furthermore, responses to (ONOO-) were enhanced in duration by the type 5-cGMP (cyclic guanosine monophosphate) phosphodiesterase inhibitor zaprinast, whereas rolipram, a type 4-cGMP phosphodiesterase inhibitor, was without effect. Repeated administration of (ONOO-) had no significant effect on responses to vasoconstrictor or to vasodilator agents including acetylcholine. These results show that (ONOO-) has significant vasodilator activity in the hindlimb vascular bed of the cat and suggest that the response is mediated by a cGMP- dependent mechanism. The results of experiments with repeated injections of (ONOO-) indicate that (ONOO-) does not impair vasoconstrictor and endothelium-dependent or endothelium-independent vasodilator responses. Furthermore, tolerance did not develop with repeated short-term exposure to (ONOO-). Moreover, the results of experiments with inhibitors suggest that responses to (ONOO-) are not dependent on K-ATP (adenosine triphosphate-sensitive potassium) channel activation, increased NOS activity, or the formation of products in the cyclooxygenase pathway. The results of these studies are consistent with the hypothesis that (ONOO-) is rapidly converted in the hindlimb circulation to a substance that has the properties of an NO donor. These studies suggest that under physiologic conditions, the cytotoxic effects of (ONOO-) on a short-term basis may have been overemphasized.
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PMID:Analysis of vasodilator responses to peroxynitrite in the hindlimb vascular bed of the cat. 1804 2

The distribution of cyclic GMP, cyclic AMP and related enzymes in the vertebrate retina, together with factors regulating their levels, are described. Photo-receptor cells in retinas from all species examined contain very high levels of cyclic GMP and high activities of both guanylate cyclase and cyclic GMP phosphodiesterase. In more proximal regions of the retina, cyclic GMP is found at concentrations similar to that of brain. Guanylate kinase and GDP kinase, enzymes involved in GMP metabolism, also have increased activities in photoreceptor cell layers although their pattern of distribution does not exactly parallel that of cyclic GMP. The concentration of cyclic AMP is fairly uniform throughout the retina and at a level similar to that found in other areas of the CNS. However adenylate cyclase has an uneven distribution with particularly high activity in the inner plexiform layer. Cyclic nucleotide levels in retina may be modified by several factors. Light decreases both cyclic nucleotides in rod-dominant retinas, although we have not observed similar changes in cone-dominant retinas. Anoxia or ischemia elevates cyclic AMP and decreases cyclic GMP, similar to other areas of CNS, while incubation of retina in Ca(++)- free media markedly increases cyclic GMP levels, an effect opposite that seen in brain tissue. Depolarization of retina with high K(+) causes a modest elevation of cyclic AMP but has no effect on cyclic GMP, which is also significantly different from the response in brain. Cyclic AMP levels in retina however, can be elevated by dopamine which is an effect similar to that in striatum. These data indicate that there are probably multiple cyclic GMP and cyclic AMP systems in retina, some of which may be unique to this tissue.
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PMID:Localization and roles of cyclic nucleotide systems in retina. 2048 44