thromboxane-b2 and Arrhythmias--Cardiac

Nitric oxide (NO) and cyclooxygenase-derived prostaglandins, such as prostacyclin (PGI2), are involved in vascular homeostasis. To better understand the reciprocal role of both NO and PGI2 on myocardial infarction in the rat, we have investigated the cardioprotective effect of nitro-naproxen, isosorbide dinitrate (ISDN), L-arginine, defibrotide and naproxen. In this study, male Wistar rats were treated orally once a day for 5 consecutive days with the compounds under investigation and then, under anesthesia, the animals were subjected to acute myocardial ischemia (30 min) and reperfusion (120 min). Systemic blood pressure, left ventricular pressure and related parameters of cardiac mechanics were recorded. Ventricular arrhythmias and infarct size of the left ventricular wall were also evaluated. Furthermore, cardiac myeloperoxidase (MPO) and plasma creatine phosphokinase (CPK) activities were determined. Defibrotide, nitro-naproxen, ISDN and L-arginine all provided a cardioprotection characterized by significant prevention of arrhythmias with high survival rate of the rats. Infarct size restriction was paralleled by reduction of both cardiac MPO and plasma CK. Cardioprotection of nitro-naproxen, ISDN and L-arginine involve nitrites/nitrates and PGI2-increased in the circulation associated to a reduction of thromboxane B2 (TXB2) in the blood. Defibrotide displays a cardioprotection by increasing PGI2 release and by reducing TXB2 in the blood. Naproxen was devoid a lower protecting activity on myocardial infarction, and PGI2 inhibition may have played a critical role in this context. The results suggested that the increase of both NO and PGI2 brings about a cascade of integrated cellular and molecular events which are of paramount importance in prevention of myocardial ischemic insult.

Topics: Animals; Arginine; Arrhythmias, Cardiac; Cardiotonic Agents; Creatine Kinase; Epoprostenol; Isosorbide Dinitrate; Male; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Naproxen; Nitric Oxide; Peroxidase; Polydeoxyribonucleotides; Random Allocation; Rats; Rats, Wistar; Thromboxane B2

1. The effect of the nitro-derivative of aspirin, NCX4016, was assessed on ischaemic ventricular arrhythmias and myocardial infarct size in anaesthetized pigs in comparison to native aspirin. 2. Pigs were given aspirin (10 mg kg(-1); n=6), low dose NCX4016 (18.4 mg kg(-1); n=6) or high dose NCX4016 (60 mg kg(-1); n=7) orally for 5 days prior to coronary occlusion and reperfusion. None of the interventions had any effect on baseline haemodynamics prior to coronary occlusion in comparison to control pigs (n=9). Aspirin and high dose NCX4016 both prevented the generation of thromboxane A(2) from platelets activated ex vivo with A23187 (30 microM), whereas all three interventions markedly attenuated platelet aggregation in response to collagen in whole blood in comparison to controls. 3. None of the drug interventions had any effect on the incidence of ventricular fibrillation (VF) during myocardial ischaemia (100% in all groups). However, 60 mg kg(-1) NCX4016 significantly attenuated the total number of premature ventricular beats (PVB's) (62+/-16 vs 273+/-40 in control pigs; P<0.05) during the first 30 min of occlusion. The higher dose of NCX4016 also significantly reduced myocardial infarct size (22.6+/-3.7% of area at risk vs 53.0+/-2.8% of area at risk in control pigs; P<0.05). 4. These results suggest that the nitro-derivative of aspirin, NCX4016, is an effective antiplatelet agent, which unlike aspirin also reduces the extent of myocardial injury following ischaemia and reperfusion.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arrhythmias, Cardiac; Aspirin; Coronary Disease; Endothelium, Vascular; Hemodynamics; Leukocytes; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Platelet Aggregation; Swine; Thromboxane B2; Ventricular Fibrillation

To determine the effective plasma levels of CPU-86017 which could suppress the cardiac arrhythmias induced by i.v. ouabain in guinea pigs.. The cardiac arrhythmias and the heart rate were monitored by ECG traces. Blood samples were collected to determine plasma levels using HPLC assay. TXB2 and 6-keto-PGF1 alpha were measured in plasma.. The plasma concentrations of CPU-86017 which were effective to suppress ventricular fibrillation (VF) and heart rate were 0.13-0.23 mg/L and 0.13-0.31 mg/L, respectively. A reduction of TXB2 levels and an elevation of 6-keto-PGF1 alpha levels were observed after CPU-86017 i.v. administration.. The arrhythmia-suppressing and heart rate-slowing effect of CPU-86017 followed a linear relationship with its concentrations in plasma.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Berberine; Chromatography, High Pressure Liquid; Female; Guinea Pigs; Heart Rate; Male; Ouabain; Thromboxane B2

A study was carried out on the effect of aspirin 175 mg/day on the plasma levels of 6 keto PGF 1 alpha and TXB2 in patients with acute myocardial infarction and in patients subjected to coronary artery bypass surgery. Our results showed a fall in the levels of both the prostagladins from day one to day seven and further from seven to day nine in patients with myocardial infarction treated with aspirin 175 mg/day. In patients with myocardial infarction accompanied by arrhythmias the TXB2 levels dominated over the 6 Keto PGF 1 alpha levels. In the group of patients subjected to coronary bypass surgery but after treatment with aspirin 175 mg/day for a period of five days both 6 keto PGF 1 alpha and TXB2 levels fell significantly.

Topics: 6-Ketoprostaglandin F1 alpha; Arrhythmias, Cardiac; Aspirin; Case-Control Studies; Coronary Artery Bypass; Cyclooxygenase Inhibitors; Humans; Myocardial Infarction; Postoperative Care; Thromboxane B2; Time Factors

A study was carried out on the plasma levels of 6 Keto PGF1 alpha and Thromboxane B2 (TXB2) in patients with acute myocardial infarction. Our results showed a generalized increase in the levels after acute myocardial infarction. The 6 Keto PGF1 alpha levels increased twice as compared to control values while the TXB2 levels increased nine times as compared to control values. The prostaglandin levels were found to increase from day 1 to day 3 and further from day 3 to day 7. In most of the patients with uncomplicated myocardial infarction the 6 Keto PGF1 alpha levels were higher than the TXB2 levels. In patients with myocardial infarction accompanied by arrhythmias the TXB2 levels dominated over the 6 Keto PGF1 alpha levels.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arrhythmias, Cardiac; Female; Humans; Male; Middle Aged; Myocardial Infarction; Radioimmunoassay; Thromboxane B2

To examine effects of a new thromboxane synthetase inhibitor, Y-20811, on infarct size, neutrophil accumulation, and arrhythmias, coronary artery was occluded for 90 min and reperfused for 6 h in anesthetized dogs. Y-20811 administered intravenously (i.v.) 30 min before occlusion decreased serum thromboxane B2 (TBX2) formation by 98% 30 min later and by 79% at 6 h after reperfusion. Ventricular fibrillation (VF) developed in 1 of 15 control and 3 of 10 treated dogs during occlusion (p = NS), whereas after reperfusion it occurred in 7 of 14 control and none of seven treated dogs (p < 0.05). The number of arrhythmias during the first hour of reperfusion was significantly reduced in treated dogs (134 +/- 74 beats/min in control vs. 14 +/- 4 beats/min in treated dogs, p < 0.05). Hemodynamics, area at risk, and collateral flow to the ischemic region were similar for the two groups. The extent of myocardial necrosis was 28.0 +/- 10.0% (n = 7) of the area at risk in control dogs and 27.6 +/- 6.2% (n = 7) in treated dogs (p = NS). The relation between the ratio of myocardial necrosis to area at risk and collateral flow was similar. The degree of neutrophil accumulation did not differ but correlated with infarct size (r = 0.85). Thus, Y-20811 reduced reperfusion arrhythmias but failed to limit infarct size and neutrophil accumulation after coronary artery occlusion/reperfusion in dogs.

Topics: Animals; Arrhythmias, Cardiac; Coronary Circulation; Coronary Disease; Dogs; Female; Hemodynamics; Imidazoles; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Neutrophils; Thromboxane B2; Thromboxane-A Synthase

The role of platelets in reperfusion arrhythmias (RA) and the efficacy of quercetin (Que) in preventing the arrhythmias were investigated in anesthetized rats. Platelet count (PC) was performed, the ultrastructure of platelets was scrutinized, and the levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (Keto-PGF1 alpha) in plasma were determined by radioimmunoassay (RIA). The pretreatment with Que (5 mg.kg-1) 2 min prior to reperfusion inhibited RA. Que remarkably improved the ultrastructural deviation of platelet, inhibited the platelet aggregation and thromboxane A2 (TXA2) formation, and increased the prostacyclin (PGI2) generation and the ratio of PGI2/TXA2. The decrease in PC and increase in TXB2 level in plasma indicated the participation of platelets in the arrhythmogenic activity of ischemia and reperfusion. The results showed that Que produced a protective effect against RA probably through inhibiting the platelet aggregation, TXA2 formation and increasing the PGI2 generation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Blood Platelets; Male; Myocardial Reperfusion Injury; Platelet Aggregation; Platelet Count; Quercetin; Rats; Rats, Wistar; Thromboxane B2

To determine the effect of dietary fish oil supplementation on myocardial dysfunction following ischemia-reperfusion, independent of plasma and blood cells, Sprague-Dawley rats were fed fish oil-rich nonpurified diet or butter-enriched diet for 5 d. Myocardial content of long-chain and (n-3) polyunsaturated fatty acids was greater in the fish oil-fed rats (P < 0.01), whereas (n-6) fatty acid content was lower compared with controls (P < 0.01). Platelet aggregation in fish oil-fed rats was also inhibited. Hearts from all rats were subjected to 15 min of global ischemia and 10 min of reperfusion. In hearts of control rats, ischemia-reperfusion resulted in a marked decrease in force of cardiac contraction, increase in coronary perfusion pressure, appearance of ventricular arrhythmias and release of creatine kinase and thromboxane B2 in the coronary effluent. Dietary fish oil supplementation attenuated myocardial dysfunction induced by ischemia-reperfusion, as indicated by smaller change in force of cardiac contraction (-77% vs. -89%, P < 0.05) and coronary perfusion pressure (+37% vs. +71%, P < 0.001). Concomitantly, release of creatine kinase as well as thromboxane B2 in coronary effluent was lower (P < 0.01). Ventricular arrhythmias occurred less frequently in hearts from fish oil-fed rats. Thus, short-term dietary fish oil supplementation attenuates myocardial dysfunction caused by ischemia-reperfusion by a direct effect on the heart independent of blood and plasma components.

Topics: Analysis of Variance; Animals; Arrhythmias, Cardiac; Coronary Circulation; Creatine Kinase; Fish Oils; Food, Fortified; Heart; Heart Rate; Lipid Peroxidation; Male; Malondialdehyde; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Phospholipids; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Thromboxane B2

Ubiquinone 6.2, 12.5 or 2.5 mg.kg-1 respectively twice iv 24 h and 30 min before coronary artery ligation, ameliorated the ischemic arrhythmia in conscious rats, and there was a close positive correlation between the ubiquinone concentration in myocardium and plasma and its anti-arrhythmic effect. Ubiquinone iv 3.1, 6.2, and 12.5 mg.kg-1 increased, while 25 mg.kg-1 decreased 6-keto-PGF1 alpha, and 12.5 and 25 mg.kg-1 decreased TXB2, which was in accordance with inhibitory effects on the synthesis of 6-keto-PGF1 alpha and TXB2 in vitro. But the ratio of metabolites of PGI2/TXA2 in vivo was increased in all ubiquinone groups. These results indicated that ubiquinone possesses protective effects on ischemic arrhythmia of conscious rats and the beneficial effects on myocardial ubiquinone content and PGI2/TXA2 seem to contribute to its myocardial protective action.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Coronary Disease; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Microsomes; Myocardium; Rats; Rats, Inbred Strains; Swine; Thromboxane B2; Ubiquinone

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

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

The role of blood platelets in ischemia- and reperfusion-induced arrhythmias and the efficacy of three calcium blocking drugs (verapamil, diltiazem, and nicardipine) in preventing the arrhythmias were investigated. Using anesthetized rats, we measured platelet count (Pc) continuously in vivo with a Technicon autocounter. Thromboxane B2 (TxB2) and 6-keto-PGF1 alpha levels in blood from coronary sinus were determined by radioimmunoassay (RIA). Myocardial ischemia and arrhythmias were monitored from lead I ECG during and after occlusion of the left anterior descending coronary artery (LAD) for 7 min. Ischemia-induced arrhythmias were mainly ventricular ectopic contractions (VECs), whereas reperfusion produced VECs, ventricular tachycardia (VT), and reversible and irreversible ventricular fibrillation (VF). Both ischemia and reperfusion decreased platelet count and increased TxB2 level in blood from the coronary sinus. The effects of the CEBs were determined at two dose levels (0.1 and 0.3 mg/kg). Each calcium entry blocker (CEB), at both dose levels, significantly inhibited ischemia-induced arrhythmias. Verapamil and diltiazem significantly reduced reperfusion-induced VECs, prevented VT and irreversible VF, and reduced the number of animals with reversible VF. Nicardipine in preventing arrhythmias was not very effective at either dose. The CEBs also inhibited both ischemia- and reperfusion-induced decreases in PC with a moderate increase (up to 7%) as compared with levels in sham-operated controls. The CEBs also significantly reduced TxB2 levels in blood from the coronary sinus. These results indicate that ischemia and postischemic reperfusion both induce platelet aggregation in rats. Aggregating platelets release biologically active substances including thromboxane A2 (TxA2) which exacerbates existing ischemia and facilitates generation of arrhythmias. CEBs inhibit platelet aggregation and TxA2 release and enhance PGI2 synthesis, thereby preventing arrhythmias.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Arterial Occlusive Diseases; Blood Platelets; Blood Pressure; Calcium Channel Blockers; Electrocardiography; Heart Rate; Male; Myocardial Reperfusion; Platelet Count; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane B2

The effects of combined thromboxane synthetase inhibition and thromboxane receptor antagonism (TSI/TRA) were studied in conscious and in anesthetized canine models of sudden cardiac death. Administration of the TSI/TRA, R68070 10 mg/kg intravenously (i.v.), decreased thrombin-stimulated thromboxane synthesis and significantly antagonized platelet aggregation in response to the thromboxane-mimetic U46,619. In the conscious canine model, R68070 did not change ventricular refractoriness, did not prevent induction of ventricular arrhythmias by programmed electrical stimulation, and failed to prevent development of spontaneous ventricular fibrillation (VF) in response to ischemia produced at a site remote from the area of previous myocardial infarction (R68070 mortality = 70%, vehicle = 100%, p = NS). In the anesthetized canine model, R68070 prevented development of ischemia in 7 of 11 animals and reduced mortality significantly (R68070 27% and vehicle 73%; p = 0.038). R68070 inhibited thrombus formation in both models (R68070 conscious 7.0 +/- 2.6 mg and vehicle conscious 15 +/- 7.6 mg, p = NS; R68070 anesthetized 5.9 +/- 1.9 mg and vehicle anesthetized 17.7 +/- 4.3 mg; p less than 0.05). The results suggest that inhibition of thromboxane-dependent activity during acute recovery from infarction was able to protect the myocardium from developing ischemia in response to current-mediated intimal damage in a noninfarct-related artery. In the subacute phase of recovery from infarction, when the underlying myocardial substrate is susceptible to electrical derangement induced by transient ischemia, thromboxane inhibition in itself was unable to prevent ischemia-induced sudden cardiac death. Although R68070 may delay onset of ischemia due to thrombotic occlusion of the coronary artery, there does not appear to be an antiarrhythmic/antifibrillatory action to be derived from interfering with the synthesis or receptor-mediated action of thromboxane. Furthermore, R68070 does not alter the electrophysiologic properties of the heart which would result in an antiarrhythmic or antifibrillatory action.

Topics: Adenosine Diphosphate; Animals; Arachidonic Acid; Arachidonic Acids; Arrhythmias, Cardiac; Collagen; Coronary Disease; Death, Sudden; Disease Models, Animal; Dogs; Electric Stimulation; Electrophysiology; Female; Heart Rate; Male; Pentanoic Acids; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: Arrhythmias, Cardiac; Blood Viscosity; Coronary Disease; Dinoprost; Heart Conduction System; Humans; Nucleotides, Cyclic; Platelet Aggregation; Prognosis; Thrombosis; Thromboxane B2

The occurrence of early life threatening arrhythmias in the ischemic myocardium has been associated with local generation of thromboxane (TX). Antiarrhythmic agents are typically classified according to the fundamental mechanism involved in restoring normal rhythm but identifying those agents also capable of suppressing TX formation offers a means of improving the rationale of antiarrhythmic therapy. Accordingly, representative antiarrhythmic agents from classes I-IV were evaluated in the present study for their ability to suppress TX formation from intact rat platelets, in vitro. Agents from class I, II and IV achieved significant reductions in TX levels as compared to a reference TX inhibitor, dazoxiben. The IC-50 value for dazoxiben was 1.5 X 10(-6) M. Nicardipine and flecainide, being the most active of the antiarrhythmic agents tested, had IC-50's of 5 X 10(-6) and 1 X 10(-5) M respectively. Verapamil and propranolol had values of 1 X 10(-5) and 5 X 10(-5) M respectively; labetalol and quinidine were 5 X 10(-5) M, and phenytoin and diltiazem were approximately 1 X 10(-4) M. These data suggest a subsidiary antiarrhythmic property of these particular agents as related to their ability to suppress TX generation in the ischemic myocardium and implies these agents may be preferred in the treatment of early life threatening arrhythmias resulting as an initial response to myocardial ischemia.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Platelets; In Vitro Techniques; Male; Rats; Rats, Inbred SHR; Thromboxane B2

Ten weeks old male Sprague-Dawley rats were used. One mg/kg of a calfskin type III collagen was injected into a tail vein under pentobarbital anesthesia, and the electrocardiogram (ECG) was recorded via leads I, II and III for 10 min. Abnormal ECG patterns, i.e., ST-T changes and incidence of arrhythmia, were shown after collagen injection, and some rats suffered cardiac arrest. Oral administration of (E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (CV-4151), a thromboxane synthetase inhibitor, at the dose of 10 mg/kg two hr before the collagen injection made the ST-T changes small, and it reduced the incidence of cardiac arrest. The effect of CV-4151 was greater than that of 30 mg/kg of ticlopidine with the same type of treatment. Neither CV-4151 nor ticlopidine had any affect on collagen-induced decreases in the blood platelet count. However, plasma thromboxane (TX) B2 level in the CV-4151-treated group was very low in comparison with those in both the control and ticlopidine-treated groups at 10 min after the collagen injection. These findings indicate that TXA2 may contribute, at least partly, to the collagen-induced ECG changes and indicate that CV-4151 might be a favorable agent for the prevention of TXA2-mediated cardiac ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Collagen; Coronary Disease; Electrocardiography; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Humans; Pyridines; Rats; Rats, Inbred Strains; Thiophenes; Thromboxane B2; Ticlopidine

Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 micrograms kg-1 as an i.v. bolus - 15 min prior to coronary occlusion - followed by an infusion of 0.05 micrograms kg-1 min-1. Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and delta R% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. Molsidomine protected the treated animals from early (10 min) post-ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post-occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). In molsidomine treated dogs: mean aortic pressure and the rate-pressure product were lowered 10 min after the start of the drug; immediate post-occlusion (3 min) ST segment changes (0.82 +/- 0.52 vs 1.52 +/- 0.78 mV, P less than 0.025) and delta R% changes (37 +/- 50 vs 90 +/- 84%, P less than 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml-1. The time-action curve of the antifibrillatory effect of molsidomine parallels those at the level of post-ischaemic electrocardiographic changes.

Topics: Adenosine Diphosphate; Animals; Arrhythmias, Cardiac; Cardiac Output; Coronary Disease; Dogs; Electrocardiography; Heart Rate; Heart Ventricles; Molsidomine; Oxadiazoles; Platelet Aggregation; Sydnones; Thromboxane B2; Vascular Resistance

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 effects of the antithrombotic drug nafazatrom (BAY g 6575) were investigated in chloralose-anaesthetized greyhounds subject to coronary artery occlusion and reperfusion. Pretreatment with nafazatrom 10 mg/kg p.o. did not significantly reduce the number of extrasystoles or the incidence of ventricular fibrillation (VF) during the first 30 min occlusion of the left anterior descending coronary artery. However, the incidence of VF resulting from release of a 40-min coronary artery occlusion was markedly reduced (from 88% in the controls to 14% in the nafazatrom group). Both thromboxane B2 (TxB2) and 6-keto PGF1 alpha (breakdown products of TxA2 and prostacyclin respectively) were released from the acutely ischaemic myocardium in control dogs. Nafazatrom did not alter the release of TxB2 but the concentrations of 6-keto PGF1 alpha were elevated in blood draining from both the ischaemic and normal regions of the myocardium. The pronounced anti-fibrillatory effect of nafazatrom during reperfusion of the ischaemic myocardium may be related to the ability of this drug to elevate prostacyclin concentrations in the coronary circulation.

Topics: 6-Ketoprostaglandin F1 alpha; Anesthesia; Animals; Arrhythmias, Cardiac; Coronary Disease; Dogs; Epoprostenol; Female; Fibrinolytic Agents; Male; Perfusion; Prostaglandins; Pyrazoles; Pyrazolones; 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

Timolol (50 micrograms kg-1), administered intravenously to chloralose-anaesthetized open-chest greyhounds 30 min prior to occlusion of the left anterior descending coronary artery, reduced heart rate and mean arterial blood pressure. This dose caused a 20 fold increase in the dose of isoprenaline required to increase heart rate by 25 beats min-1. During the first 30 min of myocardial ischaemia the number of extrasystoles in the timolol-treated dogs (327 +/- 179) was less than in the control group (888 +/- 168) and none of the dogs that received timolol fibrillated. The haemodynamic changes induced by coronary artery occlusion (decreased cardiac output and stroke volume, increased peripheral vascular resistance) were similar in both control and timolol-treated dogs as were the increases in PCO2 and decreases in PO2 and pH in blood draining from the ischaemic myocardium. Timolol did not alter the release during myocardial ischaemia, of either thromboxane B2 or prostacyclin (measured as 6-keto PGF1 alpha). Reperfusion-induced ventricular fibrillation occurred in 7 out of 8 control dogs and in 5 out of 10 timolol-treated dogs. The overall survival following occlusion and reperfusion was improved by 10% to 50% by timolol.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Blood Gas Analysis; Blood Pressure; Coronary Disease; Coronary Vessels; Dogs; Female; Heart Rate; Hemodynamics; Male; Perfusion; Thromboxane B2; Thromboxanes; Timolol

Acute coronary artery occlusion in anaesthetized open-chest greyhounds led to early release of thromboxane B2 (TxB2) into venous blood draining the ischaemic region. No release occurred from the remainder of the left ventricular wall (coronary sinus sampling). TxB2 release and ventricular ectopic activity were positively correlated (r = 0.863) 2 min post-occlusion. Aspirin (3 mg/kg i.v.) suppressed both local TxB2 release and ectopic activity and prevented ventricular fibrillation. It is suggested that TxB2 release is a factor contributing to early post-infarction arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Aspirin; Coronary Disease; Dogs; Myocardium; Thromboxane B2; Thromboxanes