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)

Primary dysmenorrhea may affect as many as 40 percent of all adult women, temporarily disabling one-tenth of them. The etiology of this condition may be related to excess production of prostaglandins by the endometrium following decline in progesterone levels consequent to corpus luteum regression. It is proposed that increased prostaglandin levels produce increased myometrial contractility and uterine ischemia and sensitization of pain fibers, resulting in pelvic pain. Administration of nonsteroidal anti-inflammatory agents which block the cyclooxygenase enzyme of the arachidonic acid cascade is an effective treatment for primary dysmenorrhea, as is oral contraceptive therapy. Criteria for an ideal prostaglandin synthetase inhibitor are described.
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PMID:Current concepts in the etiology and treatment of primary dysmenorrhea. 354 8

The long-acting antianginal drug molsidomine has been shown experimentally to reduce myocardial infarct size when administered prior to or after cardiac insult. This is due to several drug actions. Dilation of postcapillary capacitance vessels diminishes venous return, preload, heart dimensions, and myocardial oxygen consumption. Relaxation of stenosed conductive coronary arteries increases the perfusion of myocardial areas at risk of infarction due to enhanced collateral circulation. Increased regional blood supply nourishes predominantly subendocardial cardiac muscles as a result of reduction of extravascular coronary pressure, and resistance. The stable heart rate and cardiac contractility favor improved heart performance. The inhibition of platelet aggregation in vivo by molsidomine or its active metabolites, SIN-1 and SIN-1A, is linked to the stimulation of prostacyclin synthesis, inhibition of thromboxane release with induction of thrombosis and vasoconstriction, and enhanced concentrations of cyclic guanosine monophosphate. Dilation of coronary arteries after intracoronary administration of SIN-1, with inhibition of platelet aggregation by restrained release of adenosine diphosphate and stabilization of platelet membranes, facilitates the recanalization of stenosed arteries and reduces coronary muscle tone at the site of thrombosis. Activation of the human fibrinolytic system and drug-induced release of a plasminogen activator favor dysaggregatory effects. The drug's inhibiting actions on lipoxygenase products of arachidonate (e.g., 12-hydroperoxy-eicosatetraenoic acid and leukotrienes) may shift prostaglandin catabolism to cyclooxygenase products (e.g., prostacyclin) that protect against the expansion of ischemia and the induction of coronary spasm. Experimentally, the hemodynamic effectiveness of molsidomine can be antagonized by catecholamines (afterload effects) and dihydroergotamine (preload and afterload effects) respectively. Further clinical investigations will clarify the application of these mechanisms for the therapeutic success of the drug in human myocardial infarction.
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PMID:Molsidomine: alternative approaches to treat myocardial ischemia. 355 58

The involvements of arachidonic acid metabolites in the development of ischemic brain edema and cerebral energy metabolism were investigated on the experimental ischemia and reperfusion model. The level of arachidonic acid in brain tissue increases especially on the ischemic insult, which is rapidly converted to prostaglandins and leukotrienes after the reperfusion. The drugs which modify the arachidonic acid metabolism were administrated to clarify the effect on ischemic brain edema and cerebral energy metabolism. Male stroke resistant spontaneously hypertensive rats (SHRSR) were subjected to incomplete ischemia for two hours by occlusion of both common carotid arteries with vascular clips, and reperfused for two hours. The drugs used are dexamethasone, indomethacin, trapidil and OKY-046. Indomethacin inhibits cyclooxygenase. Dexamethasone inhibits phospholipases by the production of lipocortin. OKY-046 inhibits thromboxane A2 synthetase. Trapidil inhibits thromboxane A2 synthetase and increases the level of 6-keto-PGF1 alpha. These drugs were administered 18 hours before, just after clipping on (1/2) and off (1/2). Brain water content, cerebral ATP and lactic acid levels were examined. In the saline treated group, the cerebral water content was increased after the reperfusion and reached its maximal level after two hours of the reperfusion. The development of brain edema was prevented by the administration of dexamethasone or trapidil, but not by indomethacin and OKY-046. Administration of trapidil or dexamethasone was found to prevent the decrease in ATP and the increase of lactic acid. In the indomethacin administrated group, only the increase of lactic acid was prevented. 6-keto-PGF1 alpha was high in the trapidil administrated group and low in the indomethacin administrated group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Involvement of arachidonic acid cascade in brain edema and cerebral energy metabolism after reperfusion]. 359 3

Nafazatrom is an antithrombic drug that has been shown to have beneficial effects in traumatic shock and organ ischemia. This study evaluated the effect of nafazatrom on cardiovascular, sympathetic, and endocrine consequences to moderate or severe hemorrhagic shock in the conscious rat. Nafazatrom (2 mg/kg, i.v.) had no effect on the blood pressure, heart rate, and circulatory norepinephrine, vasopressin, and leukotriene C4 responses to bleeding. Nafazatrom significantly reduced plasma TXB2 and 6-keto-PGF1 alpha and blocked the increment in these cyclooxygenase metabolites in response to hemorrhage. It is concluded that nafazatrom does not increase survival after moderate hypovolemic hypotension and decreases survival to severe hemorrhage. Nafazatrom does not modify the cardiovascular, sympathetic, and neuroendocrine responses to hypovolemic hypotension.
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PMID:Effects of nafazatrom on cardiovascular, sympathetic, and endocrine responses to hemorrhagic shock in conscious rats. 384 Oct 32

To know the mechanism underlying ischemic brain edema, a time-course analysis of the eicosanoid synthetic capacity of brain microvessels was carried out using unilateral, middle cerebral artery (MCA)-occluded rats. Concomitant with the development of brain edema the synthetic capacity of all products, including cyclooxygenase and lipoxygenase products, increased significantly. Next the effects of 15-hydroperoxyarachidonic acid (15-HPAA) on the synthetic capacity of microvessels were examined. The drug caused a generalized increase of each product, the profile of which was similar to that obtained with ischemic hemispheres, although the ratios of each product differed somewhat among them. The enhanced synthesis of eicosanoids by 15-HPAA was markedly suppressed by radical scavengers such as alpha-tocopherol, hydroquinone, and 1,2-bis(nicotineamide)-propane. Furthermore, the evolution of brain edema was virtually suppressed by the systemic administration of 1,2-bis(nicotineamide)-propane. The above result suggests that the enzyme activity of the arachidonic acid (AA) cascade of microvessels is stimulated by its own products. Such a mechanism will form a vicious cycle that accelerates the accumulation of free radicals within microvessels and thus may play a role in the progressing disruption of the blood-brain barrier (BBB) following ischemia.
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PMID:Alterations of the eicosanoid synthetic capacity of rat brain microvessels following ischemia: relevance to ischemic brain edema. 396 37

Using the rat middle cerebral artery occlusion model, alterations in the eicosanoid synthetic capacity of brain microvessels following ischemia were studied by radiochromatography. Brain microvessels of normal rats predominantly produced hydroxyacids with relatively small amounts of PGD2 and PGE2 from exogenous arachidonic acid. Confirmation that hydroxyacids and prostaglandins were products respectively of lipoxygenase(s) and cyclooxygenase was obtained by experiments using indomethacin and eicosatetraynoic acid. The eicosanoid synthetic capacity of the brain microvessel, especially of hydroxyacids, was significantly enhanced 24 and 72 hours after the onset of ischemia. Because this is the phase of maximum edema in the present model, enhanced eicosanoid production in the brain microvessel may be involved in the mechanisms that underly ischemic brain edema.
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PMID:Ischemic brain edema following occlusion of the middle cerebral artery in the rat. II: Alteration of the eicosanoid synthesis profile of brain microvessels. 396 53

Renal cortical prostaglandin synthesis, particularly by arterioles and glomeruli, is important to preserve renal blood flow (RBF) and glomerular filtration rate (GFR). Glomeruli and arterioles synthesize not only the vasodilatory prostaglandins PGE2 and PGI2, but also the vasoconstrictor, thromboxane A2. The primary renal cortical actions of these prostaglandins are renal vasodilatation and maintenance of GFR (PGE2 and PGI2) or renal vasoconstriction and reduction of GFR (thromboxane A2). Vasodilatory renal prostaglandins are relatively unimportant under normal circumstances but play a modulatory role after ischemia or in the presence of increased concentrations of vasoconstrictor substances such as angiotensin II (ANG II), vasopressin or norepinephrine. ANG II and vasopressin stimulate the synthesis of PGE2 in rat glomerular epithelial and mesangial cells maintained in cell culture. These stimulatory actions of constrictor peptides are dependent upon calcium entry into the cells since removal of extracellular calcium or co-incubation with verapamil or nifedipine block the prostaglandin stimulatory capacity of ANG II or vasopressin. In vivo indomethacin potentiates the actions of ANG II on the kidney, particularly the reduction of RBF and GFR. Isolated rat glomeruli contract in response to ANG II and this contractile effect, which reflects reduction in glomerular filtration surface area, can be potentiated by cyclooxygenase blockade. Conversely, arachidonic acid reduces the glomerular contractile effect of ANG II. The importance of renal prostaglandins in support of RBF and GFR has been studied in dogs after chronic bile duct ligation (CBDL). CBDL dogs have significant increase in renal PGE2 and PGI2 which maintain RBF and GFR since cyclo-oxygenase inhibition resulted in a 50% decrease in both RBF and GFR. Indomethacin, ibuprofen, naproxen, and sulindac sulfide had comparable effects. The pro-drug, sulindac sulfoxide, was tested in normal volunteers and found to spare renal prostaglandin synthesis whereas indomethacin reduced renal synthesis of PGE2 and PGF2 alpha by more than 50%. In vitro, sulindac sulfide is a potent inhibitor of renal prostaglandin synthesis by kidney cells in culture. It is, therefore, concluded that renal prostaglandins play an important vasoregulatory role. Furthermore, sulindac sulfoxide may spare renal cyclo-oxygenase and thereby preserve renal function.
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PMID:Mechanisms of the nephrotoxicity of non-steroidal anti-inflammatory drugs. 659 99

Several of the cyclooxygenase products of arachidonic acid were measured in the cerebral hemispheres of gerbils subjected to transient interruption of the cerebral circulation. The levels of PGD2, PGF2 alpha, PGE2, TXB2, 13, 14-H2-15-keto-PGE2, and the stable nonenzymic product of prostacyclin, 6-keto-PGF1 alpha, were not altered at the end of a 5-min period of ischemia. However, the onset of reperfusion was accompanied by a rapid accumulation of these products. Levels were highest during the initial period of reperfusion, then decreased to approach control levels after 120 min. PGD2, PGF2 alpha, and PGE2 were the predominant metabolites detected. This postischemic accumulation of arachidonic acid metabolites could be blocked by prior administration of inhibitors of cyclooxygenase activity.
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PMID:Accumulation of cyclooxygenase products of arachidonic acid metabolism in gerbil brain during reperfusion after bilateral common carotid artery occlusion. 677 64

Rats were subjected to severe incomplete cerebral ischemia followed by recirculation. The levels of several of the cyclooxygenase products of arachidonic acid were measured at 5 and 15 minutes of ischemia and at 30 minutes of recirculation following 15 minutes of ischemia, PGE2 accumulated during the first 5 min. of ischemia and its level declined at 15 min. and returned to control level at 30 min. of recirculation. TXB2, on the other hand, increased during the whole time course of the experiment and at the end of the post ischemic period its level was 5 times higher than control. Treatment of the animals with indomethacin (4 mg/Kg, i.v.) prior to ischemia reduced the levels of these products without altering the pattern of their changes. During the ischemic period the EEG was isoelectric and the mean recovery time of electrical cortical activity after 15 min. of ischemia was 10.4 +/- 3.5 min. in the control rats. The rats which received indomethacin recovered faster (43. +/- 0.9 min) and were more resistant to the induction of ischemia. We suggest that the reversibility of cortical activity may be correlated to the accumulation of TXB2 during ischemia and recirculation, and inhibition of its synthesis might improve the post-ischemic reflow.
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PMID:The effect of incomplete cerebral ischemia on prostaglandin levels in rat brain. 689 89

We evaluated the consequences of platelet activation within the coronary circulation and determined the contribution of released thromboxanes, the most potent vasoconstrictors known, to the ensuing cardiac ischemia. Human platelets were isolated by sepharose column chromatography from blood of normal donors and added to the crystalloid perfusate of a Langendorff rabbit heart (platelet counts greater than or equal to 10,000/microliters). Following thrombin-induced (1 U/ml) platelet activation, the coronary flow decreased by 30 +/- 10% (mean +/- SEM, P less than 0.02), the mean concentration of thromboxane B2 in the coronary sinus effluent rose to 62 +/- 25 pmol/ml, and immediate, often irreversible cardiac ischemia as monitored by nicotinamide adenine dehydrogenase autofluorescence photography, ensued. However, with high concentrations of the platelet inhibitor and vasodilator, prostaglandin E1 (1.0 mM), the coronary flow increased by 50 +/-= 15%, and the epicardial fluorescence remained unchanged despite a small (10 +/- 3 pmol/ml) increase in coronary sinus thromboxanes. Platelets isolated from donors who ingested aspirin were incapable of thromboxane synthesis (less than 5 pmol/ml) but remained normally responsive to thrombin-induced activation. When these platelets were challenged by thrombin during cardiac perfusion, however, coronary flow and epicardial fluorescence remained unchanged. We conclude that platelet activation within the coronary circulation can induce irreversible cardiac ischemia, which, however, can be prevented by appropriate pharmacologic inhibition of platelet function. Furthermore, the fact that cardiac perfusion was preserved during a thrombin challenge of platelets from aspirin-treated donors establishes a fundamental role for the products of cyclooxygenase activity (e.g., thromboxanes) in the genesis of this form of myocardial ischemia.
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PMID:Mediation of cardiac ischemia by thromboxanes released from human platelets. 704 97


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