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)

Inhibition of 20-hydroxyeicosatrienoic acid (20-HETE), by pretreatment with pharmacological inhibitors of cytochrome P450 (CYP) omega-hydroxylase, has been shown to reduce infarct size in canines when administered prior to ischemia. However, it is unknown whether these agents reduce infarct size when administered just prior to reperfusion and if the sarcolemmal and/or mitochondrial K(ATP) channels (sK(ATP) and mK(ATP)) contribute to cardioprotection. Therefore, we determined whether specific CYP inhibitors for epoxygenases and omega-hydroxylases are cardioprotective when given either prior to ischemia or prior to reperfusion and furthermore, if selective inhibition of the sK(ATP) by HMR-1098 or mK(ATP) by 5-hydroxydecanoic acid (5-HD) could abrogate this effect. Male Sprague-Dawley rats underwent 30 minutes of ischemia followed by 2 hours of reperfusion. Groups received either miconazole (MIC, non-selective CYP inhibitor, 3 mg/kg), 17-octadecynoic acid (17-ODYA, CYP omega-hydroxylase inhibitor, 0,3 or 3 mg/kg), N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS, CYP omega-hydroxylase inhibitor, 0,4 or 4 mg/kg), N-methanesulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH, CYP epoxygenase inhibitor, 3 mg/kg), or vehicle either 10 minutes prior to ischemia or 5 minutes prior to reperfusion. Rats also received either HMR-1098 (6 mg/kg) or 5-HD (10 mg/kg) 10 minutes prior to reperfusion, with subsets of rats also receiving either MIC or 17-ODYA 5 minutes prior to reperfusion. DDMS and 17-ODYA dose dependently reduced infarct size. Rats treated with MIC, 17-ODYA and DDMS, but not MS-PPOH, produced comparable reductions in infarct size when administered prior to ischemia or reperfusion compared to vehicle. HMR-1098, but not 5-HD, also blocked the infarct size reduction afforded by MIC and 17-ODYA. These data suggest a novel cardioprotective pathway involving CYP omega-hydroxylase inhibition and subsequent activation of the sK(ATP) channel during reperfusion.
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PMID:Cytochrome P450 omega-hydroxylase inhibition reduces infarct size during reperfusion via the sarcolemmal KATP channel. 1557 55

Reactive oxygen species (ROS), as superoxide and its metabolites, have important roles in vascular homeostasis as they are involved in various signaling processes. In many cardiovascular disease states, however, the release of ROS is increased. Uncontrolled ROS production leads to impaired endothelial function and consequently to vascular dysfunction. This review focuses on two clinical conditions associated with elevated ROS levels: ischemia/reperfusion and nitrate tolerance. Injury caused by ischemia/reperfusion is an important limitation of transplantations, and complicates the management of stroke and myocardial infarction. Nitrates, which are used to treat transient myocardial ischemia (angina pectoris), decrease in efficacy in long-term continuous administration. There are several enzyme systems, such as xanthine oxidase, cyclooxygenase, uncoupled endothelial nitric oxide synthase, NAD(P)H oxidase, cytochrome P450 and the mitochondrial electron transport chain, which are responsible for the increased vascular production of superoxide. The contribution of particular ROS producing enzymes and the effect of antioxidant treatment are discussed in both pathological conditions.
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PMID:Endothelial dysfunction and reactive oxygen species production in ischemia/reperfusion and nitrate tolerance. 1563 16

We investigated the expression of 50 cytochrome P450 (CYP) genes in the postischemic reperfused rat liver using a DNA microarray. Thirteen CYPs showed absent expression in all experiments and 2 CYPs were induced by pentobarbital, which was used as an anesthetic. Eight of the remaining 35 CYPs showed significantly decreased expression following ischemia-reperfusion. Monitoring CYP expression may be a powerful approach for elucidation of pathways regulating drug metabolism that may be involved in postischemic reperfusion liver injury.
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PMID:Monitoring expression of cytochrome P450 genes during postischemic rat liver reperfusion using DNA microarrays. 1565 85

The brain's adaptive response to ischemic preconditioning (IPC) is mediated in part via hypoxia inducible factor (HIF)-responsive genes. We previously showed that IPC induces cytochrome P450 2C11 expression in the brain, associated with protection from stroke. Cytochrome P450 2C11 is an arachidonic acid (AA) epoxygenase expressed in astrocytes, which metabolizes AA to epoxyeicosatrienoic acids (EETs). We tested the hypotheses that hypoxic preconditioning (HPC) induces 2C11 expression in astrocytes via HIF-1alpha, and that the P450 epoxygenase pathway contributes to enhanced astrocyte tolerance to ischemia-like injury induced by oxygen-glucose deprivation (OGD). Primary cultured astrocytes were incubated under normoxic or hypoxic conditions for 1, 3, 6, 24, or 48 h, and protein levels of P450 2C11 and HIF-1alpha were measured by Western blotting. Additionally, 2C11 mRNA was measured by Northern blotting, and binding of HIF-1alpha to 2C11 promoter was evaluated using electrophoretic mobility shift assay (EMSA) with 2C11 promoter DNA containing putative HIF-binding sites. Levels of 2C11 mRNA and protein were significantly increased starting at 3 and 6 h of hypoxia, respectively. The increase in 2C11 expression was preceded by an increase in HIF-1alpha protein at 1 h of hypoxia, and EMSA showed a specific and direct interaction between 2C11 promoter DNA and HIF-1alpha in nuclear extracts from astrocytes. HPC and EETs reduced astrocyte cell death, and P450 epoxygenase inhibition prevented protection by HPC. We conclude that HPC induces tolerance in astrocytes, at least in part, via HIF-1alpha-linked upregulation of P450 2C11.
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PMID:Hypoxic preconditioning and tolerance via hypoxia inducible factor (HIF) 1alpha-linked induction of P450 2C11 epoxygenase in astrocytes. 1572 89

Calcium channel blockers (CCBs) comprise a heterogeneous group of compounds with unique structures and pharmacologic characteristics. These agents are employed in the treatment of hypertension, coronary ischemia, and/or supraventricular arrhythmias. CCBs are both substrates for, and in the instance of verapamil and diltiazem inhibitors of, cytochrome P450 3A4. In the case of verapamil and diltiazem, this inhibitory effect increases the likelihood of drug-drug interactions with other compounds similarly metabolized by cytochrome P450 3A4. Much of the debate with reference to a cardiovascular risk for CCBs has been quieted with the advent of sustained-release delivery systems that offer a more gradual rate of drug delivery. The most common side effects with CCBs are vasodilatory in nature and include peripheral edema, flushing, and headache. Despite the potential for side effects with CCBs, their potent blood pressure-lowering effect makes them a prerequisite for blood pressure control in many patients.
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PMID:Calcium channel blocker class heterogeneity: select aspects of pharmacokinetics and pharmacodynamics. 1585 99

Ca(2+) overload in myocardial cells is responsible for arrhythmia. Sodium-calcium exchanger (NCX) inhibitors are more effective than sodium-hydrogen exchanger (NHE) inhibitors with regard to modulation of Ca(2+) overload, because NCX inhibitors can directly inhibit the influx of Ca(2+) into cells. NCX is an attractive target for the treatment of heart failure and ischemia-reperfusion. We have designed and synthesized a series of N-(2-aminopyridin-4-ylmethyl)nicotinamide derivatives, based on compound 5. We have discovered a novel NCX inhibitor (23 h) with an IC(50) value of 0.12 microM against reverse NCX. The inhibitory activities of our NCX inhibitors against cytochrome P450 were also evaluated. The effects on heart failure and the pharmacokinetic profile of compound 23 h are discussed.
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PMID:Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: a potent and orally bioavailable NCX inhibitor. 1591 15

Since the discovery of atrial natriuretic peptide (ANP) more than 20 years ago, numerous studies have focused on the mechanisms regulating ANP secretion. From a physiological standpoint, the most important factor governing ANP secretion is mechanical stretching of the atria, which normally occurs when extracellular fluid volume or blood volume is elevated. In addition, the ability of several vasoconstrictors to increase ANP secretion can be traced to their indirect effects on atrial stretch via increases in cardiac preload or afterload. Whether vasoconstrictors such as angiotensin II and vasopressin have a direct positive or negative effect on ANP secretion has not been determined with certainty. Two paracrine factors derived from endothelial cells play important roles in modulating ANP secretion. Endothelin, a potent vasoconstrictor, stimulates ANP secretion and augments stretch induced ANP secretion. The dramatic increase in ANP release produced by cardiac ischemia appears to be mediated in part by endothelin. Nitric oxide (NO), an important vasodilator, is also produced by endothelial cells and inhibits ANP secretion acting through cyclic GMP as an intracellular messenger. Several recent studies have helped to define the cellular mechanism contributing to regulation of ANP secretion including stretch-activated ion channels, prostaglandins, cytochrome P450, G proteins and cell calcium. A number of steps in the cellular transduction of the ANP signal remain to be resolved. The release of ANP in disease states such as myocardial infarction and heart failure appears to be related to both mechanical and cellular events.
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PMID:Mechanisms of atrial natriuretic peptide secretion from the atrium. 1599 90

Ischemia-reperfusion of the heart and other organs results in the accumulation of unesterified arachidonic acid (AA) via the action of membrane-bound phospholipases, primarily phospholipase A2. AA can be metabolized by the classical cyclooxygenase (COX) and lipoxygenase (LOX) pathways to well-characterized metabolites and their respective cardioprotective end products such as prostacyclin (PGI2) and 12-hydroxyeicosatetraenoic acid (12-HETE). However, it has only been recently recognized that another less well-characterized pathway of AA metabolism, the cytochrome P450 (CYP) pathway, may have important cardiovascular effects. Several lines of data support the possibility that certain CYP metabolites resulting from the hydroxylation of AA such as 20-hydroxyeicosatetraenoic acid (20-HETE) are potent vasoconstrictors and may produce detrimental effects in the heart during ischemia and pro-inflammatory effects during reperfusion. On the other hand, a group of regioisomers resulting from the epoxidation of AA, including 5,6-, 8,9-, 11,12- and 14,15-epoxyeicosatrienoic acid (EETs), have been shown to reduce ischemic and/or reperfusion injury in the heart and vasculature. This review will discuss the detrimental and beneficial actions, including the potential cellular mechanisms responsible as a result of stimulating or inhibiting the two arms of this novel CYP pathway. The therapeutic potential of increasing EET concentrations and/or reducing 20-HETE concentrations will also be addressed.
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PMID:Cytochrome P450 and arachidonic acid metabolites: role in myocardial ischemia/reperfusion injury revisited. 1599 70

The review present the literature data and the authors findings on perspective technologies for design of active chemical and natural compounds based on small molecules for highly specific therapy and correction of a wide variety of pathophysiological conditions in humans, that show overlapping development processes and have common mediators. The following strategies are discussed: chemogenomics strategy using computer screening libraries for generating of small molecule compounds with advantageous properties; strategy of chemokine network that provide control of many processes, from immunosurveillance to inflammation and from viral infections to cancer; strategy of using cytochrome P450 enzymes that guarantee maximum bioavailability of drugs and prevent their interaction and toxic effect; strategy of using superoxide dismutase enzymes (SOD) correcting superoxide anions overproduction in tissue injury and inflammation, from ischemia, organ transplantation to AIDS and cancer; strategy of telomer maintenance directed to anticancer and antiviral therapy as well as to correction of the aging processes; and strategy of short interfering RNAs capable to induce intracellular immunity to antigens of various origin.
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PMID:[Perspective technologies for drug design]. 1630 41

This study examined the role of Kupffer cells in altering the hepatic secretory and microsomal function during ischemia and reperfusion (Is/Rp). Rats were subjected to 60 min of hepatic ischemia, followed by 1 and 5 h of reperfusion. Gadolinium chloride (GdCl3, 7.5 mg/kg body weight, intravenously) was used to inactivate the Kupffer cells 1 day prior to ischemia. Is/Rp markedly increased the serum aminotransferase level and the extent of lipid peroxidation. GdCl3 significantly attenuated these increases. Is/Rp markedly decreased the bile flow and cholate output, and GdCl3 restored their secretion. The cytochrome P450 content was decreased by Is/Rp. However, these decreases were not prevented by GdCl3. The aminopyrine N-demethylase activity was decreased by Is/Rp, while the aniline p-hydroxylase activity was increased. GdCl3 prevented the increase in the aniline p-hydroxylase activity. Overall, Is/Rp diminishes the hepatic secretory and microsomal drug-metabolizing functions, and Kupffer cells are involved in this hepatobiliary dysfunction.
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PMID:The roles of Kupffer cells in hepatic dysfunction induced by ischemia/reperfusion in rats. 1639 73


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