iloprost and Myocardial-Ischemia

A growing body of evidence suggests that oxygen radicals can mediate myocardial tissue injury during ischaemia and, in particular, during reperfusion. This review focuses on the role of neutrophil as a mediator of myocardial damage. Upon reperfusion, neutrophils accumulate and produce an inflammatory response in the myocardium that is responsible, in part, for the extension of tissue injury associated with reperfusion. It has shown that the inhibition of neutrophil accumulation and adhesion is associated with decreased infarct size. This strongly suggests that myocardial cells at risk region undergo irreversible changes upon reperfusion and accumulation of neutrophils. Several pharmacological agents (ibuprofen, allopurinol, prostacyclin, and prostaglandin E analogues) protect the myocardium from reperfusion injury. In addition, the mechanisms by which these agents act and directions of research that may lead to therapeutically useful approaches are also discussed in this review.

Topics: Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Epoprostenol; Free Radical Scavengers; Humans; Ibuprofen; Iloprost; Myocardial Ischemia; Myocardial Reperfusion Injury; Neutrophils; Prostaglandins E, Synthetic; Reactive Oxygen Species

During heart transplantation, weaning from cardiopulmonary bypass may be particularly laborious as a result of superimposed acute right ventricular dysfunction in the setting of pre-existing pulmonary hypertension. Research in recent years has focused on inhaled vasodilatory treatment modalities which selectively target the pulmonary circulation.. We present a series of eight patients in whom inhaled iloprost, a synthetic prostacyclin analog, was used to treat pulmonary hypertension and right ventricular dysfunction detected by transesophageal echocardiography during a heart transplant procedure. In addition to conventional inotropic support, 20 mug of inhaled iloprost was administered via nebulized aerosol for a 20-min period. Complete sets of hemodynamic measurements were obtained before inhalation and during and after cessation of the inhalation period.. Inhaled iloprost decreased the transpulmonary gradient at the end of the inhalation period relative to baseline (8.2 +/- 1.6 mmHg vs. 11.2 +/- 0.9 mmHg, P < 0.05). The mean pulmonary artery pressure to systemic artery pressure ratio decreased over this period (0.24 +/- 0.07 vs. 0.44 +/- 0.09, P < 0.05). A statistically significant decrease in the pulmonary vascular resistance to systemic vascular resistance ratio was also observed (0.10 +/- 0.02 vs. 0.19 +/- 0.02, P < 0.05). Improved indices of right ventricular function were observed in echocardiographic monitoring.. During heart transplantation procedures, episodes of pulmonary hypertension can be successfully treated with inhaled iloprost administration, without untoward side-effects or significant systemic impact.

Topics: Administration, Inhalation; Adult; Blood Pressure; Cardiomyopathy, Dilated; Female; Heart Rate; Heart Transplantation; Humans; Iloprost; Male; Middle Aged; Myocardial Ischemia; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Right

To determine whether the prostacyclin analog iloprost plays a beneficial role in crystalloid cardioplegia in isolated working rat hearts, 20 isolated rat hearts were studied after sustaining 90 min of cardioplegic arrest under hypothermia (20 degrees C). The findings indicated that thromboxane A2 (TXA2) levels in coronary effluent were increased during reperfusion. Iloprost (12 nm/l) inhibited the release of TXA2 and improved the recovery of cardiac hemodynamics after ischemia. These data demonstrated that cardiac-derived TXA2 appeared to mediate reperfusion injury after prolonged aortic clamp or cardiac transplantation and iloprost cardioplegic infusion resulted in the inhibition of release of cardiac-derived TXA2 and in a better preservation of cardiac function after ischemic arrest.

Topics: Animals; Cardiac Output; Heart; Heart Arrest, Induced; Iloprost; In Vitro Techniques; Male; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Thromboxane B2; Ventricular Function, Left; Ventricular Function, Right

The aim of this study was to investigate the effect of Iloprost (Schering AG), a stable prostacyclin analogue, on the intensity of thiobarbituric acid-reactive substances (TBARS), conjugated diene and hydroperoxide production in ischaemic dog myocardium. Adult male mongrel dogs were divided into groups as follows: A = sham/operated group, B = control animals, and C = Iloprost-supplemented group. The drug was administered as a single intravenous bolus at a dose of 10 micrograms/kg. Partial heart ischaemia was induced by occlusion of the left descending coronary artery. After 3 h ischaemia the dogs were killed, their hearts were removed and the levels of the above-mentioned peroxidation products were assayed. The concentrations of TBARS, conjugated dienes and hydroperoxides were significantly increased not only in the ischaemic region, but also in the border zone and in the "normally" perfused region of the heart. A considerable decrease of these products was observed in the Iloprost-treated group. A direct effect of Iloprost on the heart cell membranes is postulated.

Topics: Animals; Dog Diseases; Dogs; Iloprost; Lipid Peroxidation; Male; Myocardial Ischemia; Thiobarbituric Acid Reactive Substances; Vasodilator Agents

The modification of cardioprotective actions of iloprost by K(+)-channel blockade was studied in ischemic rabbit hearts. Glibenclamide, a blocker of ATP-dependent K(+)-channels, prevented coronary vasodilation mediated by the prostacyclin mimetic iloprost. In contrast, the cardioprotective effects of iloprost which were determined from prevention of ischemia induced rise in left ventricular enddiastolic pressure and loss of cytosolic troponin T in hearts made globally ischemic for two hours were not affected by glibenclamide. It is concluded that the cardioprotective action of iloprost can be separated from ist coronary vasodilator effect mediated by opening KATP(+)-channels.

Topics: Adenosine Triphosphate; Animals; Glyburide; Heart; Iloprost; Myocardial Ischemia; Perfusion; Potassium Channel Blockers; Potassium Channels; Rabbits; Vasodilation

To investigate the effects of alterations of nitric oxide (NO) and prostacyclin (PGI2) availability on platelet-mediated electrophysiological effects during myocardial ischaemia.. Transmembrane action potentials and electrograms were recorded from isolated, Langendorff-perfused guinea-pig hearts during normal perfusion, global myocardial ischaemia and reperfusion during infusion of washed human platelets. Experiments were performed in the presence of 100 microM NG-nitro-L-arginine methyl ester (L-NAME), 30 microM L-arginine, 10 microM haemoglobin, 100 microM sodium nitroprusside and 2.3 nM iloprost, or using hearts obtained from DL-lysine monoacetylsalicylate (Aspisol, 50 mg.kg-1 i.p.)-treated animals.. Perfusion with L-NAME and haemoglobin increased perfusion pressure by 33% (P = 0.0017) and 23% (P = 0.0026) while sodium nitroprusside and iloprost reduced it (17%, P = 0.0004, and 24%, P = 0.0006). In the absence of platelets, these compounds had no effect on arrhythmogenesis, but in the presence of platelets L-NAME reduced the onset time of ventricular tachycardia during ischaemia from 19.4 (s.e.m. 2.0) min to 12.9 (2.1) min, P = 0.04 and accentuated the ischaemia-induced reduction of action potential duration at 95% repolarization (APD95): 95(6) vs. 115(5) ms, P < 0.05 at 25 min. Sodium nitroprusside in the presence of platelets attenuated the ischaemia-induced reduction in APD95, while iloprost in the presence of platelets was antiarrhythmic (ventricular fibrillation 25 vs. 75%, P = 0.04) and attenuated the reduction in APD95 during ischaemia 115(4) vs. 94(4) ms, P < 0.05 at 20 min. Infusion of platelets into hearts obtained from DL-lysine-monoacetylsalicylate-treated guinea-pigs accentuated the ischaemia-induced reduction in APD95 (94(4) vs. 119(7) ms, P < 0.05 at 20 min) and this was reversed by sodium nitroprusside (117(7) ms, P < 0.05 at 20 min). L-NAME and haemoglobin had no effect on the aggregatory responses of the platelets to 5 microM ADP and 4 micrograms.ml-1 collagen, while sodium nitroprusside and iloprost ablated the responses to ADP and reduced the responses to collagen (maximum height of the aggregatory response reduced by 75 and 84%, respectively, both P = 0.03.). Inhibition of NO and PGI2 synthesis exacerbates the reduction in cardiac action potential duration associated with platelet activation during ischaemia, while provision of exogenous NO and PGI2 attenuates the reduction in cardiac action potential duration. Provision of exogenous NO and PGI2 (as iloprost) was associated with inhibition of platelet reactivity.

Topics: Action Potentials; Adenosine Diphosphate; Animals; Arginine; Blood Platelets; Collagen; Epoprostenol; Guinea Pigs; Heart; Hemoglobins; Iloprost; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroprusside; Perfusion; Platelet Aggregation Inhibitors; Vasodilator Agents

Ischaemic injury was produced in the dog heart by occluding the left anterior descending coronary artery just below the second diagonal branch for the duration of 3 h. A prostacyclin analogue, ZK 36374 (Iloprost) was administered (10 micrograms/kg) just before the coronary artery occlusion. During 3 h occlusion ATP levels in the ischaemic area declined from 65.4 +/- 7.1 mM/g protein in sham-operated group to 31.5 +/- 5.2 microM/g protein in no-drug group and to 44.1 +/- 5.0 microM/g protein in Iloprost group. Creatine phosphate decreased from 112 +/- 14 microM/g protein, to 81 +/- 10 microM/g protein in no-drug group and to 95 +/- 12 microM/g protein in Iloprost group. The energy charge (ATP + 0.5 ADP/ATP + ADP + AMP) decreased slightly but not significantly in no-drug and Iloprost group. Three hours of LAD occlusion produced a significant fall in SOD activity in the ischaemic heart in comparison to the non-ischaemic and Iloprost-treated hearts.

Topics: Adenine Nucleotides; Animals; Dog Diseases; Dogs; Iloprost; Male; Myocardial Ischemia; Myocardium; Phosphocreatine; Superoxide Dismutase; Time Factors; Vasodilator Agents

The effects of intravenous administration of iloprost, a prostacyclin analogue, on myocardial energy metabolism and myocardial blood flow (MBF) were examined in anesthetized open-chest dogs subjected to 60 min of myocardial ischemia by coronary ligation. Iloprost administration at levels of 0.1 or 0.2 micrograms/kg/min was started 30 min before the commencement of ischemia and continued throughout the 90 min observation period. Since systolic aortic pressure in the iloprost 0.2 micrograms/kg/min group showed significantly lower values than that in the control group, whereas no clear effect was observed with the lower concentration (0.1 micrograms/kg/min), this latter group was further investigated. This 0.1 microgram/kg/min dose of iloprost lacked influence on MBF in both ischemic and nonischemic areas but did result in a significantly higher value for high energy phosphate contents in the ischemic myocardium. Moreover, myocardial mitochondrial respiratory function in the ischemic area was significantly improved. These results indicate that iloprost brought about preservation of myocardial energy metabolism without alteration of coronary perfusion, suggesting that it may exert a direct cardioprotective effect.

Topics: Animals; Coronary Circulation; Dogs; Energy Metabolism; Female; Iloprost; Male; Myocardial Ischemia

Effects of iloprost, which is a stable prostacyclin analogue, on the ischemic myocardium were examined in the open-chest dog heart in terms of biochemical parameters. Ischemia was initiated by ligating the left anterior descending coronary artery. When the coronary artery was ligated for 3 min, the levels or glycogen, fructose-1,6-diphosphate (FDP), adenosine triphosphate and creatine phosphate decreased, and the levels of glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), lactate, adenosine diphosphate and adenosine monophosphate increased. During ischemia, therefore, energy charge potential was significantly decreased from 0.89 +/- 0.01 to 0.82 +/- 0.01, and ([G6P] + [F6P])/[FDP] and [lactate]/[pyruvate] ratios were significantly increased from 1.75 +/- 0.30 to 29.05 +/- 5.70 and 13 +/- 3 to 393 +/- 112, respectively. Iloprost (0.1, 0.3, or 1 microgram.kg-1) was injected intravenously 5 min before the onset of ischemia. Iloprost (0.1, 0.3, and 1 micrograms.kg-1) reduced the ischemia-induced decrease in energy charge potential to 94, 74, and 86%, respectively, the increase in ([G6P] + [F6P])/[FDP] to 38, 29, 32%, respectively, and the increase in [lactate]/[pyruvate] to 67, 45, 65%, respectively. These results suggest that iloprost lessens the myocardial metabolic derangements produced by ischemia, and the most potent effect was obtained at the dose of 0.3 microgram.kg-1.

Topics: Adenosine Diphosphate; Animals; Dogs; Energy Metabolism; Female; Fructosediphosphates; Glucose-6-Phosphate; Glucosephosphates; Glycogen; Heart; Hemodynamics; Iloprost; Lactates; Male; Myocardial Ischemia; Phosphocreatine

Molsidomine, a donor of nitric oxide, is a drug used in the treatment of ischaemic heart disease. Iloprost, a stable analogue of prostacyclin, is a cardioprotective agent in dogs, cats and rats but not in men. We have studied an interaction between molsidomine and iloprost in protecting against consequences of the "no-reperfusion" myocardial ischaemia. In ten control open-chest cats the left descending coronary artery (LDCA) was ligated at a site of its branching. This procedure caused 80% of mortality and the survival time was 40.9 +/- 8.6 min. The death of cats was preceded by continuous premature ventricular contractions (PVC) which appeared 2.1 +/- 0.3 min after LDCA and occurred with frequency of 7.3 +/- 0.6 per min. Molsidomine at a dose of 20 micrograms/kg i.v. given to ten cats before LDCA was neither cardioprotective nor it influenced the rate of mortality while iloprost at a dose of 2 micrograms/kg i.v. opposed the outcome of LDCA as alluded by the elongation of the survival time to 66.6 +/- 7.6 min and the delay of the onset of PVC to 9.1 +/- 1.9 min; also the frequency of PVC fell to 3.6 +/- 0.4 per min, however, the LDCA-induced mortality (60%) was not significantly different from that in control animals (80%). On the other hand, in ten cats with LDCA which were pretreated with a mixture of molsidomine and iloprost there was observed a significant reduction of the LDCA-induced mortality (down to 20%) and a two fold increase in the survival time. Thereby, we conclude that molsidomine permitted enhancing the cardioprotective potency of iloprost.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Cats; Drug Synergism; Female; Heart Ventricles; Iloprost; Male; Molsidomine; Myocardial Contraction; Myocardial Ischemia

The potential therapeutic value of a new prostacyclin analogue, (4z, 16s)-4,5,18,18,19,19-hexadehydro-16,20-dimethyl-delta 6(9a)- 9-(O)-methano-PGI1 (KP-10614), was studied in acute myocardial infarction in rats. Myocardial infarction was induced by ligation of the left coronary artery and ischemic injury was followed up to 4 h. The infarct size, evaluated by the area unstained by 2,3,5-triphenyltetrazolium chloride, reached 41.1 +/- 1.4% of the left ventricle at 4 h. KP-10614 (3 ng/kg/min x 4 h) reduced the infarct size at 4 h significantly (26.5 +/- 2.9%). At the same dose, KP-10614 inhibited ADP-induced ex vivo platelet aggregation significantly (21.5 +/- 4.0% of the control aggregation), but did not alter the arterial blood pressure or heart rate. To assess the role of platelets in myocardial infarction, circulating platelets were reduced by about 95% with rabbit antiserum to rat platelets. In platelet-depleted rats, the infarct size decreased significantly to 24.1 +/- 4.6% of the left ventricle at 4 h. These results suggest that platelets play an important role in expression of myocardial ischemic injury resulting from coronary artery occlusion in rats, and the ability of KP-10614 to decrease the infarct size appeared to be attributable, at least in part, to the inhibition of platelet aggregation or cellular metabolic effects produced by platelets at the site of tissue injury.

Topics: Animals; Blood Platelets; Epoprostenol; Fibrinolytic Agents; Hemodynamics; Iloprost; Leukocyte Count; Male; Molecular Structure; Myocardial Infarction; Myocardial Ischemia; Platelet Aggregation; Rats; Rats, Sprague-Dawley