thromboxane-a2 and Arrhythmias--Cardiac

Topics: Arrhythmias, Cardiac; Arteriosclerosis; Biomarkers; Cholesterol, VLDL; Coronary Restenosis; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Hyperlipidemias; Hypertension; Liver; Reference Values; Thrombosis; Thromboxane A2

The causes of ventricular arrhythmias in the acute setting of coronary artery disease (myocardial ischaemia and reperfusion) may be approached using two paradigms. One, the electrophysiological paradigm (disturbance of ionic homeostasis, electrogenesis, and conduction) has not been addressed in detail here. Instead, we have focused on the concept of a chemical paradigm of arrhythmogenesis. Many endogenous chemical substances (derived from the myocardium, nerves, blood plasma, platelets, leucocytes, and endothelium) accumulate in the ischaemic tissue or are produced during reperfusion and many of these have been suggested to modulate ventricular arrhythmias. Some substances may be arrhythmogenic and others may be antiarrhythmic. Together they determine whether or not arrhythmias occur. Potentially arrhythmogenic substances include potassium, catecholamines, cAMP, histamine, 5-HT, lysophosphatidylcholine, palmitylcarnitine, platelet activating factor, prostaglandins, leukotrienes, thromboxane A2, angiotensin II, endothelin, opioids, protons, calcium, and free radicals. We have considered each of these, with the objective of evaluating which are important in arrhythmogenesis in acute ischaemia and reperfusion. Two alternative models of arrhythmogenesis are possible in the context of the chemical paradigm: a series model (where one substance or its effects determines the arrhythmogenicity of another) and a parallel model (where numerous substances operate independently to cause ventricular arrhythmias). It is not yet clear which model is most appropriate; a combination of the two is possible, so a working prototype has been constructed which accommodates both. A set of criteria (hitherto lacking) for establishing whether a substance is sufficient and necessary for arrhythmogenesis is proposed. Some generalisations are given on approaches to establishment of these criteria for putative arrhythmogenic substances. Finally, we have considered how arrhythmogenic drug development may be influenced by using the chemical paradigm as an alternative to the electrophysiological paradigm of arrhythmogenesis.

Topics: Acute Disease; Arrhythmias, Cardiac; Calcium; Endothelins; Free Radicals; Humans; Myocardial Ischemia; Myocardial Reperfusion Injury; Potassium; Thromboxane A2

Increased levels of the major metabolites of thromboxane (TxA2) and prostacyclin (PGI2) are found in venous blood draining the ischaemic region of the myocardium of dogs subjected to acute coronary artery occlusion. This suggests that these arachidonic acid derivatives are released under conditions of myocardial ischaemia and may be considered as mediators of some of the consequences of coronary blood flow reduction, including arrhythmogenesis. The present experimental evidence suggests that thromboxane release is detrimental both in the early stages of ischaemia and in reperfusion since the severity of both ischaemia and reperfusion-induced arrhythmias is reduced by selective inhibition of thromboxane synthesis or by thromboxane receptor blockade. Since the local administration of prostacyclin (or iloprost) or the promotion of local prostacyclin production (with nafazatrom) reduces the severity of ischaemia and reperfusion-induced arrhythmias, it is suggested that prostacyclin may act as a local, endogenous antiarrhythmic agent. The conclusion thus far from these experimental studies suggests that the prostacyclin-thromboxane balance is one important factor involved in determining the severity of ischaemia and reperfusion-induced arrhythmias but that the mechanisms have not as yet been clearly defined.

Topics: Animals; Arrhythmias, Cardiac; Coronary Circulation; Coronary Disease; Eicosanoic Acids; Epoprostenol; Humans; Myocardium; Thromboxane A2; Thromboxane-A Synthase

We have recently reported that left atrial injections of the thromboxane A(2) (TXA(2)) mimetic, (5Z)-7-[(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxy-1-octenyl]-2 -oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid (U46619), induced ventricular arrhythmias in the anesthetized rabbit. Data from this study led us to hypothesize that TXA(2) may be inducing direct actions on the myocardium to induce these arrhythmias. The aim of this study was to further elucidate the mechanism responsible for these arrhythmias. We report that TXA(2)R is expressed at both the gene and protein levels in atrial and ventricular samples of adult rabbits. In addition, TXA(2)R mRNA was identified in single, isolated ventricular cardiac myocytes. Furthermore, treatment of isolated cardiac myocytes with U46619 increased intracellular calcium in a dose-dependent manner and these increases were blocked by the specific TXA(2)R antagonist, 7-(3-((2-((phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid (SQ29548). Pretreatment of myocytes with an inhibitor of inositol trisphosphate (IP(3)) formation, gentamicin, or with an inhibitor of IP(3) receptors, 2-aminoethoxydiphenylborate (2-APB), blocked the increase in intracellular calcium. In vivo pretreatment of anesthetized rabbits with either gentamicin or 2-APB subsequently inhibited the formation of ventricular arrhythmias elicited by U46619. These data support the hypothesis that TXA(2) can induce arrhythmias via a direct action on cardiac myocytes. Furthermore, these arrhythmogenic actions were blocked by inhibitors of the IP(3) pathway. In summary, this study provides novel evidence for direct TXA(2)-induced cardiac arrhythmias and provides a rationale for IP(3) as a potential target for the treatment of TXA(2)-mediated arrhythmias.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arrhythmias, Cardiac; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; Calcium; Cells, Cultured; Fatty Acids, Unsaturated; Heart Atria; Heart Ventricles; Hydrazines; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Male; Myocytes, Cardiac; Rabbits; Receptors, Thromboxane A2, Prostaglandin H2; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Thromboxane A2; Vasoconstrictor Agents

Experiments were conducted in the anesthetized rabbit to investigate mechanisms for arrhythmias that occur after left atrial injection of the thromboxane A(2) (TxA(2)) mimetic U-46619. Arrhythmias were primarily of ventricular origin, dose dependent in frequency, and TxA(2) receptor mediated. The response was receptor specific since arrhythmias were absent after pretreatment with a specific TxA(2) receptor antagonist (SQ-29548) and did not occur in response to another prostaglandin, PGF(2alpha). Alterations in coronary blood flow were unlikely the cause of these arrhythmias because coronary blood flow (as measured with fluorescent microspheres) was unchanged after U-46619, and there were no observable changes in the ECG-ST segment. In addition, arrhythmias did not occur after administration of another vasoconstrictor (phenylephrine). The potential involvement of autonomic cardiac efferent nerves in these arrhythmias was also investigated because TxA(2) has been shown to stimulate peripheral nerves. Pretreatment of animals with the beta-adrenergic receptor antagonist propranolol did not reduce the frequency of these arrhythmias. Pretreatment with atropine or bilateral vagotomy resulted in an increased frequency of arrhythmias, suggesting that parasympathetic nerves may actually inhibit the arrhythmogenic activity of TxA(2). These experiments demonstrate that left atrial injection of U-46619 elicits arrhythmias via a mechanism independent of a significant reduction in coronary blood flow or activation of the autonomic nervous system. It is possible that TxA(2) may have a direct effect on the electrical activity of the heart in vivo, which provides significant implications for cardiac events where TxA(2) is increased, e.g., after myocardial ischemia or administration of cyclooxygenase-2 inhibitors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anesthesia; Animals; Arrhythmias, Cardiac; Blood Flow Velocity; Coronary Circulation; Heart Rate; Male; Rabbits; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Vasoconstrictor Agents

Pretreatment with tetramethylpyrazine (TMP, 12 mg/kg/day), a drug originally derived from the rhizomes of Ligusticum wallichii, significantly reduced the incidence of ischemia-induced ventricular tachycardia (VT) and fibrillation (VF) from 100% and 50% of control hearts to 41% (p < 0.05) and 0% (p < 0.05), respectively, in the ischemic rat heart. TMP also diminished the incidence of reperfusion-induced VT and VF from 100% and 100% of control hearts to 33% (p < 0.05) and 41% (p < 0.05), respectively. Pretreatment with TMP produced a slight, but significant increase of 6-keto-PGF1 alpha and a decrease of TXB2 production during aerobic perfusion. Ischemia and reperfusion markedly increased the release of 6-keto-PGF1 alpha and TXB2. Pretreatment with TMP significantly enhanced the release of 6-keto-PGF1 alpha and diminished TXB2 outflow following left coronary artery occlusion and reperfusion.

Topics: Animals; Arrhythmias, Cardiac; Epoprostenol; Heart; Male; Myocardial Ischemia; Pyrazines; Rats; Rats, Sprague-Dawley; Thromboxane A2

To identify the arrhythmogenic and the antiarrhythmic eicosanoids, cultured, spontaneously beating, neonatal rat cardiac myocytes were used to examine the effects of various eicosanoids added to the medium superfusing the cells at different concentrations on the contraction of the myocytes. Superfusion of the myocytes with the prostaglandins (PGD2, PGE2, PGF2 alpha) or the thromboxane (TXA2)-mimetic, U 46619, induced reversible tacharrhythmias characterized by an increased beating rate, chaotic activity and contractures. These effects are concentration-dependent. PGF2 alpha and U 46619 were much more potent than PGD2 or PGE2 in the production of tachyarrhythmias. Prostacyclin (PGI2) induced a marked reduction in the contraction rate of the cells with a slight increase in the amplitude of the contractions and showed a protective effect against the arrhythmias induced by PGF2 alpha and TXA2 (U 46619). PGE1 exerted a dose-dependent dual effect on the contraction of the myocytes. At low concentrations (< 2 microM), PGE1 reduced the contraction rate of the cells with an increase in the amplitude of the contractions and effectively terminated the tachyarrhythmias induced by arrhythmogenic agents, such as isoproterenol, ouabain and U 46619. At higher concentrations (> 5 microM), PGE1 caused cell contractures and chaotic activity. In contrast, the lipoxygenase products [leukotriene (LT) B4, LTC4, LTD4 & LTE4] of arachidonic acid (AA) had no significant effect on the myocyte contractions. The eicosanoids derived from eicosapentaenoic acid (EPA), including both the cyclooxygenase products (PGD3, PGE3, PGF3 alpha, TXB3) showed lesser effects on the contraction of the myocytes. The lipoxygenase products (LTB5, LTC5, LTD5 & LTE5), as with the AA metabolites showed little effect on the contraction of cardiac myocytes. The arrhythmias induced by the arrhythmogenic prostaglandins and thromboxane A2 could be suppressed by the nonmetabolizable AA analog eicosatetraynoic acid (ETYA) or free AA and EPA, indicating a distinction in the effect on cardiac arrhythmia between the precursor fatty acids (AA & EPA) themselves and their metabolites. In conclusion, the major arrhythmogenic eicosanoids are the cyclooxygenase products of AA, whereas those products of EPA are much less or not effective; PGE1, PGI2, ETYA and EPA have antiarrhythmic effects.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Arachidonic Acid; Arrhythmias, Cardiac; Cells, Cultured; Dinoprost; Dinoprostone; Eicosanoids; Eicosapentaenoic Acid; Epoprostenol; Heart; Heart Rate; Lipoxygenase; Myocardial Contraction; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Thromboxane A2

1. The effects of the 5-HT2 antagonist, ICI 170,809 and the thromboxane A2 antagonist, ICI 192,605, given alone and in combination (n = 12 per group), were examined in anaesthetized rats. Haemodynamics and arrhythmias induced by permanent coronary artery occlusion or by reperfusion after 5 min of ischaemia were monitored. 2. In a study on reperfusion-induced arrhythmias, the only significant effect of ICI 170,809 (1 mg kg-1, i.v.) was a reduction in the number of ventricular premature beats (VPBs). ICI 192,605 (1 mg kg-1 min-1, i.v.) did not alter reperfusion-induced arrhythmias. However, in combination, when compared with controls, these drugs caused significant reductions in the incidence of ventricular tachycardia (VT), 100% to 58%; ventricular fibrillation (VF), 92% to 33%; and the mortality due to sustained VF, 67% to 17%. There was also a significant reduction in the number of VPBs following reperfusion. 3. In a second study with lower doses of drugs, ICI 170,809 (0.3 mg kg-1) and ICI 192,605 (0.3 mg kg-1 min-1) had no significant effects on reperfusion-induced arrhythmias either alone or in combination. 4. A third study examined the effects of the higher doses of the drugs on ischaemia-induced arrhythmias. Neither drug alone, nor in combination, altered the incidence of ischaemia-induced VT, VF, the mortality, or the number of VPBs. 5. These results indicate that, in contrast to the administration of either drug alone, combined administration of a 5-HT2 antagonist and a thromboxane A2 antagonist caused marked suppression of reperfusion-induced but not ischaemia-induced arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Dioxanes; Drug Combinations; Hemodynamics; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Quinolines; Rats; Rats, Wistar; Serotonin Antagonists; Thromboxane A2

We investigated the effects of (2R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propionamide D-tartrate (Ro 22-9194), a novel class I antiarrhythmic agent, on myocardial ischemia- and reperfusion-induced arrhythmias in dogs. The incidence of ventricular fibrillation induced by reperfusion after a 30-min coronary ligation was significantly reduced by an i.v. infusion of Ro 22-9194 (10 mg/kg for 5 min before and an additional 20 mg/kg for 30 min during coronary ligation: total, 30 mg/kg) from 73% in the vehicle-treated group to 13%. Ro 22-9194 (20 and 30 mg/kg) also dose-dependently reduced the incidence of ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, after coronary reperfusion. Other class I antiarrhythmic agents, mexiletine (15 mg/kg) and disopyramide (7.5 mg/kg), did not inhibit the development of ventricular fibrillation. In in vitro studies, Ro 22-9194, but neither mexiletine nor disopyramide (approximately 10(-3) M), inhibited thromboxane A2 synthase and arachidonic acid-induced aggregation of human platelets (IC50: 1.2 x 10(-5) M and 3.4 x 10(-5) M, respectively). Furthermore, Ro 22-9194 (30 mg/kg) attenuated the increase in venous thromboxane B2 concentrations in the local coronary vein during coronary ligation in dogs. A thromboxane A2 synthase inhibitor, OKY-046 (2.5 mg/kg administered for 5 min before coronary ligation) also showed no evident increases in thromboxane B2 concentrations as well as an antifibrillatory effect. Venous 6-keto-prostaglandin F1 alpha concentrations were not affected by either Ro 22-9194 or OKY-046. These results demonstrate that, unlike mexiletine and disopyramide, Ro 22-9194 protects against reperfusion-induced fatal ventricular arrhythmias in dogs. They also suggest that, in addition to the class I antiarrhythmic effect, the thromboxane A2 synthase inhibitory activity may contribute to the antiarrhythmic properties of Ro 22-9194.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cyclooxygenase Inhibitors; Disopyramide; Dogs; Enzyme Inhibitors; Female; Humans; Male; Methacrylates; Mexiletine; Myocardial Ischemia; Myocardial Reperfusion Injury; Platelet Aggregation; Pyridines; Thromboxane A2; Thromboxane-A Synthase

During i.v. infusion of rose bengal (48 mg/kg/h), the proximal portion of the rat left coronary artery was illuminated from the outside of the myocardium by green light (540 nm) to produce a transluminal thrombus subsequent to endothelial damages. The primary endothelial damages within the illuminated vascular portion, which resulted from the photochemical reaction between the dye and green light, and the subsequent formation of transluminal platelet-rich thrombus, were easily revealed by both light and electron microscopy. The establishment of the thrombus was accompanied in all cases by the occurrence of ventricular arrhythmias due to myocardial ischaemia. The times required to initiate ventricular premature beats (VPBs) and ventricular tachycardia (VT) were 381 +/- 96 s and 444 +/- 114 s (mean +/- SEM, n = 10), respectively. Pretreatment of the rat with acetylsalicylic acid (3 and 10 mg/kg, i.v.) before the initiation of illumination had no effect on the times required to exhibit the first VPBs and VT, the incidences of both types of arrhythmias were not reduced, and the thrombus was finally formed. On the other hand, pretreatment with Y-20811, a novel thromboxane A2 synthetase inhibitor (0.3, 1 and 3 mg/kg, i.v.), delayed the onset of both VPB and VT in a dose-dependent manner. The incidences of VPBs and VT were significantly reduced at 1 and 3 mg/kg, and the thrombus formation was prevented. The formation of a transluminal thrombus in the left coronary artery by the present technique was highly reproducible and could be functionally evaluated by the occurrence of ventricular arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Aspirin; Coronary Thrombosis; Histocytochemistry; Imidazoles; Male; Myocardium; Photochemistry; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Thromboxane A2; Thromboxane-A Synthase; Ventricular Function

The effect of KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl) ethylidene]-6,11-dihydrodibenz[b,e] oxepine-2-carboxylate monohydrate, CAS 127166-41-0), a novel thromboxane A2 (TxA2) receptor antagonist, on collagen-induced coronary ischemia was studied in guinea-pigs. Under pentobarbital anaesthesia, intravenous injection (i.v.) of collagen (1 mg/kg) induced abnormal ECG changes such as ST-T changes, elevation of T-wave arrhythmia and cardiac arrest in severe cases. The changes of ECG (leads I, II and III) were recorded for 10 min following collagen injection. KW-3635 (25-50 mg/kg p.o.) remarkably improved the collagen-induced ischemic ECG changes. The effect of KW-3635 was more potent than those of daltroban, isbogrel and ticlopidine. Neither nifedipine nor propranolol had any effect. The plasma thromboxane B2 level in the KW-3635-treated animals was lower in comparison with those in both the control and daltroban-treated animals. These results suggest that TxA2 may play a role in this model of coronary ischemia and that KW-3635 is effective in the treatment of ischemic heart disease.

Topics: Animals; Arrhythmias, Cardiac; Benzimidazoles; Benzoxepins; Collagen; Coronary Disease; Cyclooxygenase Inhibitors; Electrocardiography; Guinea Pigs; Heart Arrest; Male; Nifedipine; Phenylacetates; Propranolol; Sulfonamides; Thromboxane A2; Thromboxane B2; Thromboxanes; Ticlopidine

The effects of alterations in platelet activity on arrhythmias, haemodynamics and extent of necrosis during coronary ligation for 30 min were assessed in rabbits. Reduction of platelet counts to less than 1% of control by intravenous injection of platelet antiserum (1 ml kg-1 i.v.) reduced the volume of necrosed tissue from 23 +/- 2% to 15 +/- 1%, P less than 0.01 (expressed as % of total LV) and attenuated the hypotensive effect of ischaemia. Pretreatment with the platelet activating factor (PAF) antagonist BN 52021 also attenuated the hypotension and necrosis caused by coronary ligation 23 +/- 2% vs 14 +/- 1%, P less than 0.01. Pretreatment with the thromboxane antagonist CGS 13080 attenuated the hypotensive response to ischaemia but had only a very small effect on the area of necrosis. Administration of PAF at 10 min following coronary ligation markedly increased the volume of necrosed tissue 36 +/- 2%, P less than 0.01 and caused VF and haemodynamic collapse in 10 out of 12 animals. Pretreatment with platelet antiserum or the PAF antagonist BN 52021 reversed this effect of PAF. Pretreatment with CGS 13080 attenuated the marked hypotensive effect of PAF but failed to reverse its necrotic or arrhythmogenic effects. These findings indicate that platelet activation contributes to the necrosis and hypotension following coronary ligation and that platelet-activating factor may contribute to this. The ameliorating effects of platelet antiserum or BN 52021 support the concept that inhibition of platelet activity may have a useful role in the treatment of acute myocardial infarction.

Topics: Animals; Arrhythmias, Cardiac; Blood Platelets; Diterpenes; Ginkgolides; Hypotension; Imidazoles; Immune Sera; Lactones; Myocardial Infarction; Necrosis; Platelet Activating Factor; Platelet Activation; Pyridines; Rabbits; Thromboxane A2; Thromboxane-A Synthase

The effect of high- and low-density lipoproteins separated from human serum on the postischemic reperfusion arrhythmias was investigated. The hearts were perfused by working heart mode with Krebs Henseleit bicarbonate buffer containing arachidonic acid (1 microgram/ml) for 5 minutes. Whole heart ischemia was induced by the use of a one-way ball valve, and hearts were perfused for 15 minutes followed by 20 minutes of reperfusion. Physiologic concentrations of high- and low-density lipoproteins were constantly infused through the atrial route during ischemic perfusion. Coronary effluent was collected via pulmonary artery cannulation for subsequent radioimmunoassay of thromboxane B2 and 6-keto-prostaglandin F1 alpha, the major stable metabolites of thromboxane A2 and prostacyclin, respectively. The incidence of ventricular arrhythmias during reperfusion was 6/6 (100%), 1/6 (17%), and 6/6 (100%) in control, high-density lipoprotein and low-density lipoprotein infusion groups, respectively. There was no significant difference in coronary flow among the three groups throughout the perfusion. Both thromboxane B2 and 6-keto-prostaglandin F1 alpha increased significantly during ischemia compared with preischemic values in all groups of hearts. However, the ratio of these two parameters varied in control and low-density lipoprotein infusion groups during ischemia, while there was no significant change in the high-density lipoprotein infusion group. These results provide the possibility that arachidonate metabolites may be involved in the regulation of ischemia-reperfusion arrhythmias and that high-density lipoprotein that was infused during ischemia markedly inhibits the incidence of ischemia-reperfusion-induced ventricular arrhythmias, due in part at least, to stabilizing the arachidonate metabolites during ischemic perfusion.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arrhythmias, Cardiac; Blood Pressure; Coronary Circulation; Electrocardiography; Epoprostenol; Hemodynamics; Humans; In Vitro Techniques; Lipoproteins, HDL; Lipoproteins, LDL; Male; Myocardial Reperfusion Injury; Rats; Rats, Inbred Strains; Regional Blood Flow; Thromboxane A2; Ventricular Function, Left

Isolated hearts, excised from spontaneously hypertensive male rats treated orally with cicletanine, a new furopyridine anti-hypertensive drug, were subjected to 30 min of global ischemia followed by 10 min of reperfusion. The effect of cicletanine on reperfusion-induced arrhythmias in relation to 6-keto-PGF1 alpha and thromboxane (TXB2) release was studied. After 30 min of global ischemia, the incidence (total) of ventricular fibrillation (VF) and ventricular tachycardia (VT) was reduced by 2-week pretreatment of the rats with 30 and 100 mg/kg of cicletanine (VF, 33% at 30 mg/kg and 25% at 100 mg/kg vs. 91% in untreated rats; VT, 42% at 30 mg/kg and 42% at 100 mg/kg vs. 100% in untreated rats), while lower doses of cicletanine (3 and 10 mg/kg) failed to reduce the incidence of reperfusion-induced rhythm disturbances. Reperfusion of the ischemic myocardium resulted in a fivefold increase of 6-keto-PGF1 alpha and TXB2 release in the perfusion effluent of fibrillated hearts but not in the perfusion effluent of nonfibrillated hearts. Cicletanine failed to influence the reperfusion-stimulated release of 6-keto-PGF1 alpha and TXB2. These results indicate that the anti-arrhythmic effect of cicletanine in the reperfused myocardium is not related to PGI2 and thromboxane A2 release.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Diuretics; Epoprostenol; Male; Myocardial Reperfusion Injury; Myocardium; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane B2

We studied the effects of a thromboxane A2 synthetase inhibitor (RS-5186), a thromboxane A2 antagonist (ONO-3708), a 5-lipoxygenase inhibitor (AA-861) and a peptidoleukotriene antagonist (ONO-1078) on infarct size, polymorphonuclear leukocyte infiltration, gross myocardial hemorrhage and arrhythmias in the canine coronary occlusion (2 hour)-reperfusion model (5 hour). The infarct size and risk area were determined by a double staining technique. Thirty minutes prior to occluding the coronary arteries, dogs were randomly assigned to one of the following five groups: the thromboxane A2 synthetase inhibitor group (n = 11) receiving RS-5186 10 mg/kg i.v., the thromboxane A2 antagonist group (n = 12) receiving continuous intravenous infusion of ONO-3708 1 microgram/kg/min, the lipoxygenase inhibitor group (n = 11) receiving AA-861 3 mg/kg i.v., the peptidoleukotriene antagonist group (n = 11) receiving continuous intravenous infusion of ONO-1078 1 microgram/kg/min and the vehicle control group (n = 15). Except for ONO-3708, all the other drugs reduced the infarct size (RS-5186: 26.3 +/- 2.4% of risk area (mean +/- SEM), AA-861: 21.8 +/- 1.3%, ONO-1078: 22.5 +/- 4.4% vs control: 54.0 +/- 6.4%, p less than 0.01 respectively) as well as reducing the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of infarct size, AA-861: 5.1 +/- 2.4%, ONO-1078: 5.2 +/- 2.5% vs control: 22.3 +/- 3.9%, p less than 0.01 respectively). RS-5186 and AA-861 reduced the intensity of polymorphonuclear leukocyte infiltration into the infarcted area, however, neither ONO-3708 nor ONO-1078 had any significant influence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Benzoquinones; Cardiomyopathies; Chromones; Coronary Disease; Dogs; Hemorrhage; Lipoxygenase Inhibitors; Male; Myocardial Infarction; Myocardium; Neutrophils; Quinones; SRS-A; Thiophenes; Thromboxane A2; Thromboxane-A Synthase

1. Increased local thromboxane (Tx) formation has been considered to be a contributing factor in digitalis-induced arrhythmias. 2. A potent Tx synthetase inhibitor (TxSI), UK 38,485 (0.1, 1.0 or 10.0 mg/kg per h, administered intravenously) and a Tx receptor antagonist (TxRA), ICI 185,282 (1, 2 or 10 mg/kg bolus and 1, 2 or 10 mg/kg per h, administered intravenously) were tested for their ability to reduce digoxin-induced arrhythmias in anaesthetized guinea-pigs. 3. Electrocardiograms, mean blood pressure, heart rate and arrhythmias were recorded, starting 30 min before digoxin administration and continued for 60 min afterwards. 4. ICI 185,282, at the doses used, significantly delayed the time of onset of arrhythmias, and reduced the incidence of ventricular fibrillation, mortality and arrhythmia score. In contrast, UK 38,485 was found to be effective on all measured variables only at the dose rate of 1.0 mg/kg per h, except for time required for the development of arrhythmias. These protective effects of both TxSI and TxRA were not found to be dose-dependent. 5. Arterial blood pressure and heart rate changes caused by either UK 38,485 or ICI 185,282 infusions did not have any marked effects on digoxin-induced arrhythmias. 6. These data suggest that endogenously released TxA2 and prostaglandin endoperoxides may play an important role in digoxin-induced arrhythmias in guinea-pigs.

Topics: Anesthesia; Animals; Arrhythmias, Cardiac; Blood Pressure; Digoxin; Dioxanes; Dioxins; Dose-Response Relationship, Drug; Electrocardiography; Female; Guinea Pigs; Imidazoles; Male; Thromboxane A2; Ventricular Fibrillation

The effects of the new thromboxane A2 (TXA2) synthetase inhibitor sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b]thiophene)carboxylate (RS-5186), 10 mg/kg i.v., on infarct size, polymorphonuclear leukocytes (PMNs) infiltration, gross myocardial hemorrhage and ventricular arrhythmias were studied using a canine coronary occlusion (2 h)-reperfusion (5 h) model. Infarct size (IS) and risk area (RA) were determined by a dual staining technique. 60 min before coronary occlusion dogs were randomly assigned to either the RS-5186 treated group (n = 11) or the control group (n = 15). RS-5186 reduced infarct size (RS-5186: 26.3 +/- 2.4% of RA (mean +/- SEM) vs control: 50.7 +/- 5.9%, p less than 0.01), and also reduced the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of IS vs control: 22.4 +/- 4.0%, p less than 0.01). The drug also decreased the intensity of PMNs infiltration into the infarcted area (p less than 0.05). However, RS-5186 had no significant influence on the incidence of ventricular arrhythmias. These results suggest that the new thromboxane A2 synthetase inhibitor RS-5186 might be useful in salvaging ischemic myocardium.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Coronary Vessels; Dogs; Hemodynamics; In Vitro Techniques; Male; Neutrophils; Risk Factors; Thiophenes; Thromboxane A2; Thromboxane-A Synthase

Prostaglandin plasma levels are elevated in patients with transient myocardial ischemia. We measured 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane (B2(TXB2) in venous blood of 32 patients with myocardial infarction on the first, third, and seventh days. TXB2 and 6-keto-PGF1 alpha levels in these patients (up to 117 +/- 237 pg/ml and 96 +/- 105 pg/ml mean +/- SD, respectively) differed significantly from levels in normal control subjects (10 +/- 12 pg/ml and 4 +/- 7 pg/ml mean +/- SD, respectively) (p less than 0.01). Prostaglandin values remained elevated from day 1 through day 7. In most patients, 6-keto-PGF1 alpha levels prevailed over those of TXB2. In a subgroup suffering from cardiac arrhythmias, the ratio of 6-keto-PGF1 alpha/TXB2 was inverse. It is concluded that prostaglandin generation is increased for at least 7 days after myocardial infarction. A disturbed ratio of 6-keto-PGF1 alpha/TXB2 in favor of the latter might be associated with cardiac arrhythmias in myocardial infarction.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Adult; Aged; Arrhythmias, Cardiac; Epoprostenol; Female; Humans; Male; Middle Aged; Myocardial Infarction; Prostaglandins; Thromboxane A2; Thromboxane B2

The administration of the thromboxane synthetase inhibitor UK38485, 3 mg/kg i.v. 30 min prior to occlusion of the LAD in chloralose-anaesthetized dogs reduced the number of extrasystoles that occurred in the first 30 min of ischaemia from 832 +/- 158 in controls to 193 +/- 126 (P less than 0.01). VF induced by the release of the occlusion after 40 min was also markedly reduced from seven out of nine in controls to two out of seven in the drug group. UK38485 did not alter blood gases or haemodynamics prior to LAD occlusion and the changes in PO2, PCO2 and pH in blood draining from the ischaemic myocardium during occlusion were similar in control and drug-treated dogs. The haemodynamic changes induced by coronary artery occlusion were attenuated by UK38485. This drug also prevented the thromboxane release that normally occurs during acute myocardial ischaemia but did not suppress prostacyclin release. These results provide further evidence in support of the hypothesis that thromboxane is arrhythmogenic during acute myocardial ischaemia and is a particularly important contributory factor in reperfusion-induced VF.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Arteries; Blood; Carbon Dioxide; Coronary Vessels; Dogs; Female; Hemodynamics; Hydrogen-Ion Concentration; Ligation; Male; Oxygen; Perfusion; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Ventricular Fibrillation

Coronary artery spasm was virtually unknown not long ago, but the intense, ongoing interest it has generated in the past decade has produced a number of specific diagnostic techniques and therapeutic approaches, as well as considerable insight into mechanisms of coronary vascular tone and various coronary syndromes. There is growing evidence that coronary artery spasm is involved in unstable angina, stable angina, myocardial infarction, and sudden death. It is by no means a benign process and is associated with significant morbidity or mortality if misdiagnosed or untreated. It seems clear that what started as a mere clinical curiosity involving a minority of patients with the so-called Prinzmetal's variant angina is snowballing into a major arena for research, diagnosis, and treatment in the field of ischemic coronary artery disease.

Topics: Arrhythmias, Cardiac; Calcium; Calcium Channel Blockers; Coronary Vasospasm; Death, Sudden; Electrocardiography; Humans; Prostaglandins; Thromboxane A2