Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coronary atherosclerosis is the process underlying virtually all the clinical manifestations of ischemic heart disease. When ulcer or fissure in the fibrous cap of the atheroma occur, platelet adhesion to subendothelium, aggregation and further platelet recruitment culminate in thrombus formation. These mechanisms are known to be responsible for most cases of acute events in patients with ischemic heart disease. Inside platelets, aspirin blocks the synthesis of thromboxane A2 by irreversibly inhibiting cyclooxygenase. Aspirin is recommended not only for treatment of patients with acute coronary syndromes (unstable angina, acute myocardial infarction), but also for secondary prevention of vascular events in chronic coronary syndromes. Aspirin prevents myocardial infarction in patients with chronic stable angina and reduces mortality, reinfarction and stroke in survivors of an acute myocardial infarction. Aspirin, alone or in combination with dipyridamole, prevents early and late occlusion of aortocoronary vein grafts. It is useful also in patients undergoing coronary angioplasty. Such benefits extend to all patients regardless of age, sex, history of hypertension or diabetes. Higher daily doses (900-1500 mg) are not more effective than lower doses (75-325 mg). Other antiplatelet drugs are not more effective than aspirin, which has the best risk-to-benefit and cost-to-benefit ratios. Ticlopidine is a reasonable alternative for use in preventing vascular events among patients intolerant to aspirin. Warfarin is an effective antithrombotic alternative to aspirin for secondary prevention after a myocardial infarction. However aspirin is easier to administer and follow-up when compared with warfarin. Warfarin should be preferred in high risk patients with left ventricular dysfunction with or without a mural thrombus, and those with associated atrial fibrillation.
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PMID:[Low-dose aspirin in the long-term treatment of the patient with ischemic heart disease]. 763 59

5-Fluorouracil (5-FU) is a commonly employed chemotherapeutic agent. Among the various toxicities associated with 5-FU, cardiovascular toxicity, consisting principally of acute myocardial ischemia and/or myocardial infarction, has been reported in up to 8.5% of patients treated with this drug. While 5-FU-induced coronary vasospasm has been considered as a potential basis for such clinical toxicity, this hypothesis remains unsubstantiated by laboratory investigation. Accordingly, the present study was designed to investigate the hypothesis that 5-FU induces reversible vasoconstriction of vascular smooth muscle and to study the cellular mechanisms of such vasomotor alterations. To investigate the effects of 5-FU on the vasoreactivity of vascular smooth muscle, 479 exposures were performed in 105 rings of aorta freshly isolated from 23 New Zealand white rabbits. Vasoconstriction was documented in 20 of 86 (23%) rings exposed to 5-FU at 7 x 10(-5) M, 45 of 83 (54%) rings exposed to 5-FU at 7 x 10(-4) M, and 41 of 49 (84%) rings exposed to 5-FU at 7 x 10(-3) M. In each case, 5-FU-induced vasoconstriction was endothelium independent. Pretreatment of rings with 10(-9) M staurosporine, a protein kinase C (PK-C) inhibitor, reduced 5-FU-induced vasoconstriction from 25.0 +/- 6.5 to 2.5 +/- 1.7 mg; staurosporine at a concentration of 10(-8) M abolished 5-FU-induced vasoconstriction. Pretreatment of rings with 10(-7) M phorbol-12,13-dibutyrate, an activator of PK-C, increased the magnitude of 5-FU-induced vasoconstriction 23-fold, from 49.7 +/- 11.1 mg before to 1163.6 +/- 276.4 mg after phorbol-12,13-dibutyrate (P = 0.0002). Neomycin, an inhibitor of phosphoinositide turnover, did not alter the magnitude of 5-FU-induced vasoconstriction. Membrane receptor blockers, including the alpha-adrenergic receptor blocker phentolamine, the beta-adrenergic receptor blocker propranolol, the H1 receptor inhibitor diphenhydramine, the H2 receptor inhibitor cimetidine, the Ca2+ channel blockers verapamil and diltiazem, and the cyclooxygenase inhibitor indomethacin all failed to alter the magnitude of 5-FU-induced vasoconstriction. Furthermore, the 5-FU-related compounds uracil and floxuridine did not produce vasoconstriction. Finally, 5-FU-induced vasoconstriction was abolished by nitroglycerin. These results indicate that (a) 5-FU causes direct, endothelium-independent vasoconstriction of vascular smooth muscle in vitro, (b) this vasomotor response involves activation of PK-C, and (c) this response is independent of vasoactive cell membrane receptors, phosphoinositide turnover, or activation of the cyclooxygenase pathway.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle. 839 84

This study analyzed the effects of the neuropeptides, neurotensin, and human and porcine analogue, neuropeptide Y, in anesthetized open-chest dogs. The left anterior descending coronary artery was cannulated and perfused at constant pressure via a blood reservoir. Flow to the coronary cannula was measured by an electromagnetic flowmeter, and regional segment lengths were measured by sonomicrometer crystals. Neurotensin injected into the coronary cannula resulted in a dose-dependent increase of coronary flow; neuropeptide Y resulted in a decrease of coronary flow. Because these changes in flow were not explained by systemic hemodynamic effects or alterations in regional myocardial function, they were considered to be coronary dilatation or constriction. Coronary dilatation by neurotensin was not prevented by alpha- or beta-adrenoceptor blockade but was completely abolished by indomethacin or by lowering coronary perfusion pressure to 35 mmHg when depressed systolic segment shortening indicated myocardial ischemia. Coronary constriction by neuropeptides Y persisted at coronary perfusion pressure of 35 mmHg and was only attenuated by indomethacin. We conclude that in contrast to systemic effects, coronary vasodilatation by neurotensin is mediated by a prostanoid product of cyclooxygenase. Preactivation of the prostaglandin system may explain why neurotensin lost its coronary dilator effect during myocardial ischemia. Neuropeptide Y may elicit coronary constriction in addition to mechanic reduction of coronary flow resembling severe coronary stenosis.
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PMID:Effects of neurotensin and neuropeptide Y on coronary circulation and myocardial function in dogs. 847 83

After transient episodes of ischemia, benefits of thrombolytic or angioplastic therapy may be limited by reperfusion injury. Angiotensin-converting enzyme inhibitors protect the heart against ischemia/reperfusion injury, an effect mediated by kinins. We examined whether the protective effect of the angiotensin-converting enzyme inhibitor ramiprilat on myocardial ischemia/reperfusion is due to kinin stimulation of prostaglandin and/or nitric oxide release. The left anterior descending coronary artery of Lewis inbred rats was occluded for 30 minutes, followed by 120 minutes of reperfusion. Immediately before reperfusion rats were treated with vehicle, ramiprilat, or the angiotensin II type 1 receptor antagonist losartan. We tested whether pretreatment with the kinin receptor antagonist Hoe 140, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, or the cyclooxygenase inhibitor indomethacin blocked the effect of ramiprilat on infarct size and reperfusion arrhythmias. In controls, infarct size as a percentage of the area at risk was 79 +/- 3%; ramiprilat reduced this to 49 +/- 4% (P < .001), but losartan had little effect (74 +/- 6%, P = NS). Pretreatment with Hoe 140, NG-nitro-L-arginine methyl ester, or indomethacin abolished the beneficial effect of ramiprilat. Compared with the 30-minute ischemia/120-minute reperfusion group, nonreperfused hearts with 30 minutes of ischemia had significantly smaller infarct size as a percentage of the area at risk, whereas in the 150-minute ischemia group it was significantly larger. This suggests that reperfusion caused a significant part of the myocardial injury, but it also suggests that compared with prolonged ischemia, reperfusion salvaged some of the myocardium. Ventricular arrhythmias mirrored the changes in infarct size. Thus, angiotensin-converting enzyme inhibitors protect the myocardium against ischemia/reperfusion injury and arrhythmias; these beneficial effects are mediated primarily by a kinin-prostaglandin-nitric oxide pathway, not inhibition of angiotensin II formation.
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PMID:Paracrine systems in the cardioprotective effect of angiotensin-converting enzyme inhibitors on myocardial ischemia/reperfusion injury in rats. 859 91

We investigated changes in vascular reactivity to endothelin (ET) and local release of ET-like immunoreactivity (ET-LI) induced by myocardial ischemia and reperfusion in a pig model of coronary thrombosis and thrombolysis and studied the possible mechanisms producing the changed vascular reactivity to ET-1. We induced coronary thrombosis by inserting a copper coil into the left anterior descending coronary artery (LAD) and achieved thrombolysis with tissue plasminogen activator (t-PA). Vascular reactivity to ET-1 in the nonischemic and ischemic/reperfused LAD diagonal branches was evaluated in vitro. ET-LI was analyzed in plasma from the great cardiac vein and aorta for estimation of local release. The vasoconstrictor response to ET-1 was enhanced twofold (p < 0.01) in the ischemic/reperfused arteries as compared with the nonischemic arteries. The vasoconstriction induced by the ETB receptor agonist [Ala 1,3,11,15] ET-1 or serotonin was not significantly affected by ischemia/reperfusion. The ETA receptor antagonist BQ-123 reversed the ET-1-induced vascular contraction to a similar degree in ischemic/reperfused and control arteries. The ET-1-induced vasoconstriction of control arteries was not affected by inhibition of nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NNA) or cyclooxygenase with indomethacin. During reperfusion, the myocardial venoarterial plasma concentration difference of ET-LI and blood flow increased, resulting in an increased overflow of ET-LI. Our results demonstrate that coronary thrombosis and thrombolysis evokes enhanced local release of ET-LI during the reperfusion period and increases the vasoconstrictor effects of ET-1 through a mechanism related to ETA receptor activation but unrelated to altered endothelial function. These changes may play a role in the development of ischemic/reperfusion injury and no-reflow phenomenon.
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PMID:Myocardial release of endothelin (ET) and enhanced ET(A) receptor-mediated coronary vasoconstriction after coronary thrombosis and thrombolysis in pigs. 863 92

Both polymorphonuclear (PMN) leukocytes and metabolites of arachidonic acid, especially lipoxygenase products, have been reported to contribute to myocardial damage after coronary artery occlusion and reperfusion. While canine models of myocardial ischemia were used in many of these studies, very little is known about arachidonic acid metabolism by canine PMNs. Moreover, it is unclear whether arachidonic acid metabolites released by canine PMNs affect vascular tone. Therefore, we characterized arachidonic acid metabolism by canine PMNs and determined the effect of these metabolites on vascular tone of isolated canine coronary arteries. Suspensions of canine PMNs were incubated with [14C]arachidonic acid and the calcium ionophore A23187. The incubation media was extracted, and the metabolites resolved by HPLC. 20-Hydroxy-leukotriene B4 (LTB4), 12,20-dihydroxyeicosatetraenoic acid (diHETE), LTB4, 12-hydroxyheptadeclatrienoic acid (HHT), and 12-(S)-hydroxyeicosatetraenoic acid (HETE) were isolated, and their structures confirmed by gas chromatography/mass spectrometry. There was also evidence for the formation of 20-HETE, thromboxane B2 (TXB2), 5-HETE, and several isomers of LTB4. None of the arachidonic acid metabolites that were isolated from incubates of canine PMNs augmented vascular tone, but material migrating with 12,20-diHETE relaxed canine coronary arteries. Authentic 12(S),20-diHETE also produced a concentration-related relaxation of canine coronary artery. 12(R), 20-diHETE was inactive. 20-HETE inhibited A23187-induced PMN aggregation. Thus, arachidonic acid is metabolized in canine PMNs through the cyclooxygenase, lipoxygenases and cytochrome P-450 pathways. Whether these metabolites contribute to myocardial injury remains to be determined.
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PMID:Metabolism of arachidonic acid by canine polymorphonuclear leukocytes synthesis of lipoxygenase and omega-oxidized metabolites. 865 40

Indobufen ((+/-)-2-[p-(1-oxo-2-insoindolinyl)-phenyl]-butyric acid, indo) is a drug inhibiting platelet function by a reversible block of the arachidonic acid metabolism at the level of cyclooxygenase. Since tolerability profile of such drugs is mostly linked to extra-platelet cyclooxygenase inhibition, we prospectively evaluated the extent of platelet and extra-platelet cyclooxygenase inhibition by in vivo administration of indo in comparison with ASA. We assessed the effects of the two drugs on the ex vivo generation of TXB2 and 6-keto-PGF1 alpha in whole blood, as indices of the production of TXA2 and PGI2 (prostacyclin), respectively, either after spontaneous clotting at 37 degrees C for 1 h (Study 1) or after the addition of 2 micrograms/ml collagen (Study 2). Generation of 6-keto-PGF1 alpha in whole blood is a mixed index of platelet and extra-platelet cyclooxygenase activity, deriving from both platelet and white blood cell arachidonic acid metabolization. Fifteen patients with ischemic heart disease and baseline serum TXB2 levels > 300 ng/ml were allocated to receiving one single administration of either indobufen 200 mg (n = 6) or aspirin 500 mg (n = 9). Whole blood prostanoid generation was assessed at 0, 1, 2, 4, 6, 8, 12 and 24 h after drug administration (Study I). Ten healthy male volunteers were allocated to a double-blind, randomized crossover comparison of indo 200 mg b.i.d. vs. ASA 300 mg/d for 7 days (Study 2). Prostanoid generation and whole blood platelet aggregation were performed before and at the end of each study period (Day 0 and Day 7). At each time-point after single dose administration (Study 1), indobufen caused less % inhibition of whole blood 6-keto-PGF1 alpha than of TXB2. At 2 h, TXB2 was reduced to a similar extent after ASA (98 +/- 4%) and indo (97 +/- 6%) (p = N.S.), while inhibition of 6-keto-PGF1 alpha was clearly different ( > 98% after ASA, 81 +/- 2.5% after indo, p < 0.01). After one week of ASA or indo (Study 2) the maximum extent of whole blood platelet aggregation was similarly inhibited (from 17.2 +/- 1.4 ohms to 3.6 +/- 1.3 ohms with ASA; from 18.3 +/- 1.0 ohms to 1.6 +/- 0.7 ohms with indo (p ASA vs. indo = N.S.). Despite equal inhibition of whole blood TX production after collagen (from 49.0 +/- 4.3 ng/ml to 1.1 +/- 0.6 ng/ml with ASA, from 49.8 +/- 1.3 ng/ml to 1.4 +/- 0.6 ng/ml with indo), again, however, 6-keto-PGF1 alpha production was less affected by indo than by ASA (from 409 +/- 30 pg/ml to 37 +/- 13 pg/ml with ASA, inhibition = 91%; from 396 +/- 35 to 318 +/- 40 with indo, inhibition = 20%). These differential effects of indo and ASA might lead to a better platelet selectivity, tolerability and benefit/risk profile of indo vs. ASA, which are worthy of further assessment.
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PMID:A prostacyclin-sparing effect of indobufen vs. aspirin. 870 17

Perfusion of the isolated rabbit heart with 5 x 10(6) human polymorphonuclear leukocytes (PMNL), under recirculating conditions (50 ml) and challenge with A-23187 (0.5 mu M) increased coronary perfusion pressure (CPP) sixfold, accompanied by increased levels of sulfidopeptide leukotrienes (CY-SLT), which had previously shown to correlate linearly with the increase in CPP. Pretreatment (20 min) of isolated rabbit hearts with the prostacyclin (PGI(2)) analogue iloprost (3 nM) resulted in significant protection against the increase in CPP and in almost complete inhibition of 5-lipoxygenase (5-LO) product synthesis. Similarly, pretreatment of isolated rabbit heart with defibrotide (200 mu g/ml), a polydeoxyribonucleotide derivative known to inhibit PMNL activation and enhance PGI(2) production by heart endothelial cells, produced significant protection against the increase in CPP and almost complete inhibition of 5-LO product synthesis. Neither iloprost nor defibrotide affected the A-23187-induced arachidonic acid (AA) metabolism in isolated PMNL alone. Inhibition of rabbit cyclooxygenase by intravenous (i.v.) administration of lysine-acetylsalicylate (60 mg/kg) 2 h before the animals were killed significantly reduced the protection provided by defibrotide, with a parallel fivefold increase in sulfidopeptide LT levels, returning to values in the range observed in control hearts. Control of endogenous modulators of leukocyte-vascular wall interactions such as PGI(2) results in significant changes in sulfidopeptide LT production in an organ model of transcellular metabolism of LT A(4), suggesting a novel mechanism of action for cardioprotective drugs in myocardial ischemia.
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PMID:Vasoconstriction to polymorphonuclear leukocytes in the isolated, perfused rabbit heart: inhibition by prostacyclin mimetics. 885 38

12 volunteers with slightly elevated serum triglyceride levels were given 30 ml fish oil (5.4 g eicosapentaenoic acid and 3.2 g docosahexaenoic acid) daily for 4 weeks. The percentage of eicosapentaenoic acid increased (P < 0.01) and the percentage of linoleic (P < 0.05) and arachidonic acid (P < 0.01) decreased in neutrophil phospholipids. Superoxide generation by neutrophils initiated by phorbol myristate acetate decreased significantly from 48.6 +/- 8.8 to 34.7 +/- 11.1 nmol/10 min/400,000 cells (means +/- SD, P < 0.01, n = 11). Treatment of the cells with the cyclooxygenase inhibitor indomethacin had no significant influence on the decrease in superoxide generation, indicating that cyclooxygenase products were not involved in this effect of fish oil. Neutrophil elastase release did not change significantly, suggesting that neutrophil lysosomal enzyme release and superoxide generation may be under separate control. In conclusion, dietary fish oil decreased superoxide generation by human neutrophils without involvement of the cyclooxygenase pathway and without altering neutrophil lysosomal enzyme release. Dietary fish oil could have beneficial effects in pathological conditions with activated neutrophils, such as ischaemic heart disease.
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PMID:Dietary fish oil decreases superoxide generation by human neutrophils: relation to cyclooxygenase pathway and lysosomal enzyme release. 893 Nov 14

The attenuation of myocardial stunning by the ACE inhibitor ramiprilat is prevented by cyclooxygenase inhibition with indomethacin. In the clinical setting of ischemia/reperfusion however, the cyclooxygenase inhibitor aspirin is widely used to prevent platelet aggregation. The present study therefore investigated whether aspirin in dosages sufficient to inhibit platelet aggregation interferes with the attenuation of myocardial stunning by ramiprilat. Fifteen dogs received either 1 mg/(kg.day) (group I, n = 7) or 10 mg/(kg.day) (group II, n = 8) aspirin orally for 1 week. Both dosages of aspirin inhibited ADP-induced platelet aggregation. The dogs were then anesthetized thoracotomized and subjected to 15 min LCx-occlusion and 4 h reperfusion. Before LCx-occlusion, groups I and II received ramiprilat (20 micrograms/kg, i.v.). Systemic hemodynamics, posterior myocardial blood flow (PMBF, colored microspheres) and wall thickening (PWT, sonomicrometry) of these groups were measured and data compared to placebo-controls (group III, n = 11) and dogs receiving only ramiprilat before LCx-occlusion (group IV, n = 11). Four dogs received 10 mg/(kg.day) aspirin without ramiprilat (group V). Mean aortic pressure was kept constant by an intra-aortic balloon, and heart rate did not change. PMBF was not different between the five groups. Under control conditions and during myocardial ischemia PWT was also not different. At 4 h reperfusion PWT was still depressed in group III (-5 +/- 20% of control) and group V (-23 +/- 6%) whereas PWT recovered to the same extent in groups I (46 +/- 23%), II (50 +/- 15%) and IV (58 +/- 18%) (all P < 0.05 v groups III and V). The attenuation of myocardial stunning by the ACE inhibitor ramiprilat is not prevented by aspirin in dosages which are nevertheless sufficient to inhibit platelet aggregation.
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PMID:Aspirin does not prevent the attenuation of myocardial stunning by the ACE inhibitor ramiprilat. 901 43


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