6-ketoprostaglandin-f1-alpha and Arrhythmias--Cardiac

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

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

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

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

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

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

Multivariate analysis of survival using Cox's proportional hazards model demonstrates that several clinically measurable covariates are determinants of life-threatening arrhythmias following left circumflex coronary artery occlusion-reperfusion in 107 dogs. These are heart rate, ST segment elevation and mean aortic pressure immediately (3 min) following occlusion, and the presence of early (0-10 min) post-occlusion sustained ventricular tachycardia. The risk of occlusion-reperfusion ventricular fibrillation was determined according to Cox's solution based on ST segment elevation, thus enabling quantification of the role of cicletanine. Since cicletanine-treated dogs had reduced mean ST segment elevation at 3 min post-occlusion, lower incidence of early post-occlusion (0-10 min) sustained ventricular tachycardia, and increased endogenous production of prostacyclin, and the latter was inversely correlated with the level of ST segment elevation, it is concluded that such favourable effects on the ischaemic myocardium were contributory to the improved outcome in these experiments. These effects on the ischaemic myocardium obtained in spite of a hypotensive action in the experimental setting might be regarded as desirable and it is therefore suggested that they should be further investigated by pharmacodynamic studies in human subjects.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Coronary Disease; Death, Sudden; Diuretics; Dogs; Electrocardiography; Female; Heart Rate; Heart Ventricles; Male; Perfusion; Pyridines; Statistics as Topic

We examined the hypothesis that endogenous prostaglandins participate in the arrhythmogenic influence of ouabain in guinea pig hearts. Addition of ouabain (10 ng/ml) resulted in a 5-fold increase in the release of 6-keto-prostaglandin F1 alpha in the coronary effluent. Ten of 13 hearts studied (77%) demonstrated arrhythmic activity with a mean time to the onset of arrhythmias of approximately 35 min. The nonsteroidal antiinflammatory drugs indomethacin and acetylsalicylic acid which significantly inhibited the efflux of 6-keto-prostaglandin F1 alpha also reduced the incidence of arrhythmias to 10 of 30 hearts studied. In those hearts in which arrhythmias occurred, the time to onset was significantly increased to approximately 50 and 55 min for acetylsalicylic acid and indomethacin, respectively. In contrast, exogenous prostaglandin F2 alpha (0.1 and 1 ng/ml) and prostacyclin (0.1 and 10 ng/ml) increased the incidence of arrhythmias to 100% (10 of 10 hearts studied) and decreased the time to onset to approximately 10 min. These prostaglandin pretreatments were also able to reverse the protective actions of both acetylsalicylic acid and indomethacin. Other concentrations (10 ng/ml prostaglandin F2 alpha and 1 ng/ml prostacyclin) had no influence either on the incidence of arrhythmias or their time to onset. Prostaglandin E2 (0.1 ng/ml) produced a modest but not significant decrease in the time to onset of arrhythmias although this concentration was significantly effective in reversing the nonsteroidal antiinflammatory drug effects. The inotropic, chronotropic and coronary constricting actions of ouabain were unaffected either by nonsteroidal antiinflammatory drug or prostaglandin pretreatment. These studies suggest that prostaglandins are involved, at least in part, in the arrhythmogenic actions of ouabain in the isolated guinea pig heart.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Coronary Circulation; Dinoprost; Epoprostenol; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Male; Myocardial Contraction; Ouabain; Prostaglandins; Prostaglandins F; Radioimmunoassay

A possible role for endogenous prostaglandins in the toxic electrophysiological effects of the aglycone acetylstrophanthidin was studied in isolated canine Purkinje fiber papillary muscle preparations by standard microelectrode techniques. Acetylstrophanthidin (5 X 10(-8) g/ml) caused a significant increase in 6-keto-prostaglandin F1 alpha release from these preparations. A significant loss of membrane potential and the development of oscillatory afterpotentials was observed, as well. Administration of either of two nonsteroidal antiinflammatory agents, indomethacin (3 X 10(-5) g/ml) or aspirin (5 X 10(-5) g/ml), in the presence of acetylstrophanthidin, abolished the stimulation of 6-keto-prostaglandin F1 alpha release and delayed and attenuated the loss of membrane potential and the development of oscillatory afterpotentials. In addition, indomethacin and aspirin appeared to preserve the electrogenic pumping capacity of Purkinje fiber cells exposed to acetylstrophanthidin. Exposure of Purkinje tissues to acetylstrophanthidin inhibited post-pacing hyperpolarization normally exhibited by these tissues. Both indomethacin and aspirin decreased this inhibition. Addition of prostacyclin (1 ng/ml) after 30 minutes of exposure to acetylstrophanthidin to preparations in which endogenous prostaglandin synthesis had been inhibited, resulted in a significant increase in the amplitude of oscillatory afterpotentials within 2 minutes. These results suggest that the presence of endogenous prostaglandins may play a role in the development of the toxic electrophysiological effects associated with acetylstrophanthidin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Aspirin; Cardiac Pacing, Artificial; Dogs; Female; Heart Conduction System; Heart Ventricles; In Vitro Techniques; Indomethacin; Male; Membrane Potentials; Papillary Muscles; Purkinje Fibers; Strophanthidin; Time Factors; Ventricular Function

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

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

Arrhythmias were produced by ouabain (2.7 X 10(-7) M) in isolated perfused guinea pig hearts. In control hearts the average time to onset of arrhythmias following exposure to ouabain was approximately 35 min. Ligation of the left anterior descending coronary artery significantly shortened the time to arrhythmias to about 15 min. This effect of ligation was attenuated significantly by pretreating the hearts with acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs. In contrast, the protective influence of ASA was reversed by either prostaglandin (PG) E2, PGF2 alpha, or PGI2 (2.8 X 10(-9) M). When PGE2 or PGI2 were present in the absence of ASA, the time to arrhythmias following ouabain administration was significantly shortened. PGF2 alpha had no effect in these experiments. The sensitivity was enhanced significantly by treatment with arachidonic acid. This effect was reduced by treatment with ASA or indomethacin. Prostaglandin production during the experiments was estimated by monitoring release of 6-keto-PGF1 alpha, the hydrolysis product of prostacyclin. Abbreviation of time to arrhythmias by ligation was greatest in hearts that released large amounts of 6-keto-PGF1 alpha and least in those that released low amounts. These results suggest that coronary ligation potentiates the arrhythmogenic effects of ouabain by a mechanism probably mediated by prostaglandin(s).

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Arrhythmias, Cardiac; Aspirin; Coronary Circulation; Coronary Disease; Coronary Vessels; Dinoprost; Dinoprostone; Epoprostenol; Guinea Pigs; Ibuprofen; Indomethacin; Ligation; Male; Ouabain; Perfusion; Prostaglandins; Prostaglandins E; Prostaglandins F; Time Factors

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