15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Arrhythmias--Cardiac

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

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

The purpose of this investigation was to provide a detailed analysis of the effects of the thromboxane antagonist L655,240 (0.3 mg/kg i.v.) on early ischemia- and reperfusion-induced arrhythmias in a canine model of coronary artery occlusion. In a dose that abolished the pulmonary response to U46619, L655,240 attenuated markedly the severity of those arrhythmias that resulted from reperfusion of the myocardium; survival from the combined occlusion-reperfusion insult was increased from 10% in control animals to 70% in dogs administered L655,240. Drug intervention did not significantly alter the total number of arrhythmias during the period of ischemia, but a detailed analysis of the different types of arrhythmia that occurred during this period showed that L655,240 significantly reduced those arrhythmias in phase 1a (0-10 min of occlusion) without affecting the later phase 1b arrhythmias. This was particularly shown in the marked reduction in the number of salvos (couplets and triplets) during this period. Neither those arrhythmias occurring later in the ischaemia period (phase 1b) nor the total number of single ectopics and salvos or the incidence and duration of ventricular tachycardia was modified by L655,240. These results reveal that thromboxane antagonism protects especially against reperfusion-induced ventricular fibrillation and against early (phase 1a) ischemia-induced arrhythmias, possibly implicating a role for thromboxane in the genesis of these cardiac rhythm disturbances.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anesthesia; Animals; Arrhythmias, Cardiac; Blood Gas Analysis; Coronary Circulation; Dogs; Hemodynamics; In Vitro Techniques; Indoles; Myocardial Reperfusion; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Reperfusion Injury; Thromboxanes

Substances shifting the balance between thromboxane (TX) and prostacyclin (PGI2) in favour of PGI2 could be of therapeutic value for arrhythmia treatment. This seems to be independent of the pathogenetic mechanism. The TX receptor antagonist BM 13177, the lipoxygenase inhibitor esculetin were effective in ouabain and aconitine induced arrhythmias while the PGI2 formation stimulating substance nafazatrom was only effective in aconitine induced arrhythmia. BM 13177 and esculetin could also counteract the arrhythmogenic effect of PAF. TX synthetase inhibition by HOE 944 was ineffective or partially effective, resp..

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Anti-Arrhythmia Agents; Arachidonic Acids; Arrhythmias, Cardiac; Epoprostenol; Guinea Pigs; Heart; Iloprost; Ouabain; Prostaglandin Endoperoxides, Synthetic; Reference Values; Sulfonamides

The balance between the eicosanoids seems to be involved in the biochemical regulation of cardiac rhythm. Under several pathophysiological conditions thromboxane (TX) could be an important factor for the genesis of cardiac arrhythmias. Shifting the balance between the arrhythmogenic TX and the antiarrhythmic prostacyclin (PGI2) in favour of PGI2 by substances influencing the arachidonic acid cascade might by useful for the treatment of arrhythmias. PAF induced toxic arrhythmogenicity seems to be mediated by TX. Therefore the suppression of TX influence can antagonize these arrhythmias, too.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arrhythmias, Cardiac; Epoprostenol; Fatty Acids, Unsaturated; Guinea Pigs; Male; Platelet Activating Factor; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred Strains; Sulfonamides; Thromboxanes