Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151814 (coronary occlusion)
 3,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin converting enzyme (ACE) inhibitors enhance contractile function of myocardium "stunned" by a brief episode of coronary artery occlusion, yet their mechanism(s) of action remain unresolved. In addition to possible hemodynamic effects, ACE inhibitors may stimulate the synthesis of cardioprotective prostaglandins. Furthermore, the beneficial effects of ACE inhibitors that contain a sulfhydryl group may be due in part to the ability of thiol compounds to act as nonspecific antioxidants or direct scavengers of cytotoxic oxygen-derived free radicals. To investigate this question we compared the effects of (1) the sulfhydryl-containing ACE inhibitor zofenopril, (2) the sulfhydryl-containing stereoisomer of captopril (SQ 14,534) with essentially no ACE inhibitor properties, (3) the nonsulfhydryl-containing ACE inhibitor enalaprilat, and (4) solvent alone, given at the time of reperfusion, on recovery of contractile function after 15 minutes of coronary occlusion in the anesthetized open-chest dog. Segment shortening in control animals remained depressed or "stunned" after reperfusion, recovering to only -5 +/- 12% of baseline preocclusion values at 3 hours after reperfusion. In contrast, all three treatment agents attenuated postischemic dysfunction: segment shortening was restored to 33 +/- 12%, 54 +/- 6%, and 83 +/- 5% of baseline values at 3 hours after reflow in dogs treated with SQ 14,534 (p less than 0.05), zofenopril (p less than 0.01), and enalaprilat (p less than 0.01), respectively (all vs control value). These improvements in segment shortening did not appear to be the result of altered oxygen supply or demand after reperfusion, inasmuch as no significant differences in systemic hemodynamic parameters or myocardial blood flow were observed among the groups. In the second phase of the study, we found that the improved contractile function associated with enalaprilat treatment could largely be reversed by infusion of the potent cyclooxygenase inhibitor indomethacin: segment shortening was reduced from 69 +/- 12% at 2 hours after treatment/reperfusion to 38 +/- 12% at 2 hours after indomethacin infusion (p less than 0.01 vs 2 hours after reperfusion). Infusion of indomethacin had no effect, however, on the improved contractile function associated with zofenopril treatment. We therefore conclude that sulfhydryl- versus nonsulfhydryl-containing agents enhance contractile function of stunned myocardium by different mechanisms of action: enalaprilat attenuates postischemic dysfunction at least in part by a prostaglandin-mediated mechanism, whereas the salutary effects of zofenopril and SQ 14,534 may be due in part to the antioxidant properties of the sulfhydryl moiety.
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PMID:Angiotensin converting enzyme inhibitors improve contractile function of stunned myocardium by different mechanisms of action. 185 Jan 88

This study evaluated the effects of transient coronary occlusion on the diameter of a nonischemic vessel or a nonischemic coronary segment proximal to the site of occlusion. Awake mongrel dogs chronically instrumented with dimension crystals, Doppler flow probes, and distal pneumatic occluders on the circumflex coronary arteries were subjected to transient 2-minute circumflex occlusions (n = 9) under constant heart rate (120 beats/min). Left ventricular end-diastolic pressure increased by 60% (from 10 +/- 1 to 16 +/- 2 mm Hg), and dP/dt decreased by 8% (from 2,048 +/- 130 to 1,885 +/- 110 mm Hg/sec); systemic hemodynamics were unaltered. Epicardial coronary diameter proximal to the site of occlusion decreased by 4.37% (from 3.62 +/- 0.25 to 3.46 +/- 0.29 mm, p less than 0.05). Constriction began 15-20 seconds after the onset of ischemia and progressed to maximum in 1-2 minutes. Combined alpha- and beta-receptor blockade (n = 8) with phentolamine (2 mg/kg) and propranolol (1 mg/kg) or cyclooxygenase inhibition (n = 5) with indomethacin (7.5 mg/kg) did not attenuate the ischemia-induced vasoconstriction response. Transient 2-minute occlusion of the left anterior descending coronary artery (n = 6) also elicited significant epicardial vasoconstriction in the circumflex coronary artery in the first minute (from 3.88 +/- 0.31 to 3.81 +/- 0.31 mm, p less than 0.05); the constriction was attenuated subsequently by an increase (25.5%) in circumflex flow. When left anterior descending occlusion was repeated (n = 6) with circumflex flow held constant, the ischemia-induced circumflex constriction was augmented; diameter decreased 3.7% (from 3.83 +/- 0.29 to 3.69 +/- 0.29 mm, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ischemia-induced epicardial vasoconstriction. A potential mechanism for distant myocardial ischemia. 197 33

We have previously reported that inhibition of thromboxane synthesis results in an improvement in postischemic function in stunned myocardium of dogs. The purpose of the present study was to investigate further the mechanism by which thromboxane synthesis inhibition improves recovery of function in stunned myocardium (15 minutes of coronary occlusion and 3 hours of reperfusion) in barbital anesthetized dogs. The recovery of regional myocardial wall function (percent segment shortening, % SS) following treatment with two doses (0.5 and 10 mg/kg) of a thromboxane receptor blocker, BM 13.505, given prior to coronary occlusion, was not different from that of a control group (3-hour % SS of pretreatment control, PTC, 12 +/- 11) throughout reperfusion (3-hour % SS of PTC with BM 13.505: 0.5 mg/kg 14 +/- 10; 10 mg/kg, 27 +/- 9). In contrast, the specific thromboxane synthetase inhibitor, dazmegrel (3.0 mg/kg), significantly improved % SS throughout reperfusion (3-hour % SS of PTC, 66 +/- 8). In addition, while dazmegrel produced a marked decrease in thromboxane, 6-keto-PGF1 alpha was significantly increased in coronary venous blood throughout the occlusion and reperfusion period. The cyclooxygenase inhibitor, indomethacin, had no beneficial effect on functional recovery (3-hour % SS of PTC, 5 +/- 6), attenuated the dazmegrel induced shunting to prostacyclin, and completely prevented the beneficial effects of dazmegrel on functional recovery (3-hour % SS of PTC, 17 +/- 12). Thus, a redirection to endogenous cardioprotective prostanoids, such as prostacyclin, appears to be responsible for the beneficial effect of thromboxane synthesis inhibition on postischemic recovery in stunned myocardium whereas thromboxane does not appear to be an important mediator of the stunning phenomenon.
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PMID:Prostaglandin redirection by thromboxane synthetase inhibition. Attenuation of myocardial stunning in canine heart. 229 41

The anti-ischemic effects of nafazatrom (10 mg/kg intraduodenally) have been studied in a canine model of myocardial infarction. Nafazatrom was given 30 min before and 2 h after occlusion of the left anterior descending coronary artery (LAD). Effects were compared with those after intravenous indomethacin (10 mg/kg) treatment. Infarct size was measured at 6 h of coronary occlusion by postmortem tetrazolium staining. Myocardial ischemia was reduced after nafazatrom administration, whether related to total left ventricle (18 +/- 3.3 vs. 30.7 +/- 4.8%; p less than 0.05) or to the LAD vessel area at risk for infarction (51.4 +/- 4.0 vs. 82.5 +/- 4.5%; p less than 0.01). Salvage with nafazatrom occurred in the subepicardial and endomural tissues without lateral protection. Indomethacin had no effects on infarction. The LAD occlusion-induced hemodynamic consequences were reduced at 15 min by nafazatrom and remained unchanged by indomethacin. During the following experimental course, no differences were noted between the groups. At 6 h, blood flow in the nonoccluded circumflex artery increased by 12.6 +/- 3.2 ml/min (p less than 0.05) following nafazatrom treatment. Thus, nafazatrom reduced ischemia by a mechanism unrelated to changes in hemodynamics. Most likely, this was due to 5-lipoxygenase inhibition. This may shift arachidonic acid metabolism to cyclooxygenase products and prevent release of deleterious lipoxygenase products by neutrophils during ischemic injury.
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PMID:Effects of nafazatrom and indomethacin on experimental myocardial ischemia in the anesthetized dog. 241 12

The present study was undertaken to determine whether the baroreflex control of renal sympathetic nerve activity (RSNA) was attenuated by an acute coronary artery occlusion and if so, what was the role played by cardiac prostaglandins in this attenuation. Arterial pressure was lowered with an infusion of sodium nitroprusside before and during a 5- to 10-min occlusion of the left circumflex coronary artery. The protocol was repeated 30 min after indomethacin (5 mg/kg) had been given. In addition, this study was carried out in a group of vagotomized dogs and in a group of thoracic-sympathectomized dogs. In intact dogs, coronary occlusion reduced the slope of the mean arterial pressure-RSNA relationship by 75% from -7.7 +/- 1.8% change in RSNA per millimeter Hg before indomethacin treatment. After indomethacin, there was no inhibition of the baroreflex slope during coronary occlusion. The reduction in the slope during coronary occlusion was abolished in dogs that were vagotomized but preserved in thoracic-sympathectomized dogs. In this latter group, indomethacin inhibited the attenuation of the slope during coronary occlusion. These data provide strong support for the notion that some cyclooxygenase product (most likely a prostaglandin) is released during coronary ischemia and stimulates or sensitizes cardiac vagal afferent endings, which, in turn, attenuate the baroreflex-mediated increase in RSNA during lowered arterial pressure.
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PMID:Baroreflex inhibition during coronary occlusion is mediated by prostaglandins. 275 Sep 61

Platelets are suggested to exacerbate ischemia-induced myocardial injury, which has led to the study of various antiplatelet therapies including thromboxane synthetase inhibitors (TXSI). Two such agents, benzylimidazole and OKY-046, reduce infarct size commensurate with a diminution in serum thromboxane B2 formation in anesthetized dogs subjected to 90 minutes of coronary artery occlusion followed by 5 hours of reperfusion. In contrast, platelet depletion with specific antiserum does not reduce infarct size but prevents the cardioprotection afforded by the TXSI. Platelet-derived prostaglandin endoperoxides (PGG2 and PGH2), which cannot be converted to thromboxane A2 in the inhibited platelet, can be transformed to PGE2 and PGD2 in plasma and to PGI2 by the blood vessel wall. These prostaglandins are considered "cardioprotective." Consequently, a low dose of aspirin (3-5 mg/kg) given 24 hours before coronary occlusion was used to selectively block the platelet cyclooxygenase enzyme. Aspirin, by itself, does not reduce infarct size, but it suppresses the myocardial salvage induced by OKY-046. Thus, TXSI reduce infarct size by platelet-dependent, aspirin-sensitive mechanism that depends on the redirection of platelet-derived PGG2 and PGH2 to protective metabolites, rather than inhibition of thromboxane A2 per se. Moreover, myocardial salvage induced by the TXSI is accompanied by a reduction in neutrophil accumulation in the myocardium, as indicated by the levels of the neutrophil-specific myeloperoxidase enzyme. Platelet depletion or pretreatment with aspirin prevents the TXSI-induced suppression of neutrophil accumulation. Consequently, it is proposed that the prostaglandin-mediated protective effects of TXSI can be resolved, at least in part, in terms of a braking action on neutrophil activation to prevent leukocyte-dependent tissue injury.
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PMID:Thromboxane synthetase inhibitors reduce infarct size by a platelet-dependent, aspirin-sensitive mechanism. 312 73

To determine the relative importance of arachidonic acid pathway products on vulnerability to ventricular fibrillation (VF), we examined the effects of synthesis inhibitors and a receptor blocker acting in the cyclooxygenase (C) and lipoxygenase (L) pathways on VF thresholds in a feline model of coronary occlusion. Thresholds for the induction of VF wer measured before and after a 5-minute coronary occlusion in drug-treated animals and control subjects. Animals were treated with BW755c, a dual L and C inhibitor, CGS-8515, and L inhibitor, FPL-55712, a leukotriene receptor blocker, or sulfinpyrazone, a C inhibitor. BW755c, CGS-8515, and FPL-55712 all prevented an otherwise significant fall in VF threshold during coronary occlusion (p less than 0.01) independent of an effect on effective refractory period, heart rate, or blood pressure. In contrast, sulfinpyrazone, the only compound devoid of an effect on the L pathway, did not protect against an occlusion-related fall in VF threshold. BW755c and CGS-8515 inhibited the synthesis of L and C metabolites coincident with their protection against VF (p less than 0.01). We conclude that agents that antagonize the effects of L products protect against enhanced ventricular vulnerability during acute ischemia, whereas C inhibition alone may not afford this protection.
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PMID:Modulation of arachidonic acid metabolites and vulnerability to ventricular fibrillation during myocardial ischemia in the cat. 314 41

Endothelial damage or removal abolishes the dilation of epicardial coronary arteries induced by increments in flow through these arteries in vitro. Therefore, we tested whether or not the release of a cyclooxygenase product from endothelial cells in vivo is the mechanism of this flow-dependent dilation. In eight conscious dogs, instrumented to register the external diameter of two epicardial branches--anterior descending and circumflex--of the left coronary artery, increments in coronary flow increased and reductions in coronary flow decreased the diameter of the left circumflex epicardial artery by 182 +/- 11 micron/100% change in flow. When mean coronary flow in one epicardial branch was kept constant by a distal, flow-limiting stenosis during the application of flow-augmenting stimuli (temporal coronary occlusion or 80-400 micrograms/kg adenosine i.v.), no dilation of this artery was observed. Cyclooxygenase inhibition (suppressing the bradykinin-induced elevation of plasma 6-keto-PGF1 alpha) by indomethacin (5 mg/kg) or by diclofenac (10 mg/kg) increased smooth muscle tone in both epicardial arteries, but did not modify the flow-diameter relation (181 +/- 10 and 179 +/- 9 microns/100% change in flow, respectively). It is concluded that a tonic, instantaneous influence of coronary flow on the smooth muscle tone of the epicardial coronary arteries exists in vivo. It is unlikely that prostacyclin or another prostanoid is a mediator of this endothelium-mediated influence of flow on smooth muscle tone.
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PMID:Flow-dependent, endothelium-mediated dilation of epicardial coronary arteries in conscious dogs: effects of cyclooxygenase inhibition. 608 75

Over the last few years methods have been developed to assess appearance of thrombin during blood clotting in a clinical setting. This can be achieved either by measurement of the specific thrombin markers or by analysis of the thrombin generation kinetics. Thrombin markers rise following coronary occlusion and, surprisingly, their plasma levels become further increased during and after thrombolytic treatment with streptokinase or tissue-plasminogen activator. In myocardial infarction enhanced thrombin generation extends over the weeks, well beyond the acute phase of the disease. It indicates increased risk to a patient and might call for more anticoagulation or angioplasty. The benefit of aspirin as conjunctive treatment for thrombolysis has been clearly demonstrated. The well-founded concept is that aspirin exerts its anti-thrombotic action through inhibition of platelet cyclooxygenase. Recent evidence indicates that antithrombotic effects of aspirin might be explained, partly at least, by its inhibition of thrombin formation. Indeed, in both healthy subjects and survivors of myocardial infarction, aspirin, either at a single dose of 500 mg or at a dose of 300 mg per day administered over two weeks, effectively inhibits thrombinogenesis. Such response to aspirin is blunted in hypercholesterolemia. Subjects with high serum cholesterol levels might profit less than others from the anti-thrombotic action of aspirin.
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PMID:Thrombin generation in myocardial infarction and hypercholesterolemia: effects of aspirin. 857 30

Well-developed coronary collateral vessels contain an abundant muscular media and can undergo active vasomotion. However, early after coronary occlusion, coronary collateral vessels are thin walled with little smooth muscle, suggesting that vasomotor capability might be limited. Consequently, this study determined whether newly developed coronary collateral vessels have active vasomotor activity and whether endothelial function in these newly developed vessels is impaired. Retrograde blood flow was measured as an index of coronary collateral blood flow approximately 2 wk after embolic occlusion of the anterior descending coronary artery of dogs. Agonists were administered into the left main coronary artery to reach collaterals originating from the left coronary system. Baseline retrograde blood flow was 25.1 +/- 2.7 ml/min and increased to 36.7 +/- 3.7 ml/min after nitroglycerin (6 micrograms.kg-1.min-1, P < 0.05). Cyclooxygenase blockade with indomethacin (5 mg/kg i.v.) decreased retrograde collateral blood flow to 16.8 +/- 2.3 ml/min (P < 0.05). Subsequent administration of acetylcholine increased retrograde flow to 29.4 +/- 3.7 ml/min (P < 0.05), indicating intact endothelium-mediated vasodilation. Inhibition of nitric oxide synthase with NG-nitro-L-arginine further decreased coronary collateral retrograde flow to 12.0 +/- 2.8 ml/min (P < 0.05) and markedly blunted the response to acetylcholine. These findings demonstrate substantial vasomotor capability even early during coronary collateral development and indicate that both nitric oxide and cyclooxygenase-dependent endothelial mechanisms are intact.
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PMID:Vasomotor responses of newly developed coronary collateral vessels. 877 88


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