7-oxoprostaglandin-i2 and Angina-Pectoris

Therapeutic application of prostaglandin I2 (PGI2) is rendered difficult by its instability. The 7-oxo-derivative synthesized by Kovács et al. [8] proved to be stable in aqueous solution. Both drugs were tested in experimental model angina in anesthetized thoracotomized dogs with critical stenosis of the left anterior descending coronary artery, in which drug-induced reduction of ischemic ST-segment elevation evoked by frequency loading was estimated [10]. Both drugs markedly reduced blood pressure (BP) even if given by intravenous infusion for 60 min in a total dose of 20 micrograms/kg for PGI2 and 250 micrograms/kg for 7-oxo-PGI2-Na. BP returned to normal soon after infusion and did not substantially change. After a latency of 90-120 min, a 40-50% reduction of ischemia-induced ST-segment elevation appeared in the epi-, endo-, and intramyocardial ECG. Intracoronary infusion of PGI2 in 1 microgram/kg and 7-oxo-PGI2-Na in 25 micrograms/kg total dose minimized systemic actions, but a delayed protective effect appeared, due probably to some nonvasoactive metabolite of these substances. Although both substances exert a potent platelet-aggregation-inhibiting action, serial ex vivo determination of ADP aggregation at different times has shown a dissociation of antiaggregatory action from the protection, this dissociation reaching its maximum when antiaggregatory action was already over.

Topics: Angina Pectoris; Animals; Cardiac Pacing, Artificial; Coronary Circulation; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Epoprostenol; Female; Hemodynamics; Male; Platelet Aggregation

Earlier we have shown in the dog model mimicking angina on effort a delayed antiischaemic effect of PgI2 and its stable analogue 7-oxo-PgI2-Na, appearing only when the drug induced marked vasodilatation was over [1]. In the present experiments we could show that the protective effect appears at a time when the blood pressure returned to normal and in addition the marked platelet aggregation inhibitory effect has also faded away. In the rat 7-oxo-PgI2 could substantially diminish vasopressine induced T-wave elevation in the ECG if given 2 hours before administration of vasopressin. In addition it could moderate the vasopressin induced metabolic changes appearing as diminution of the myocardial CP and ATP-level and increase of the myocardial lactate content. A similar metabolic protection was found in the heart of rats pretreated with 7-oxo-PgI2 2 hours before taking myocardial samples and exposing them for 1 minute to ischaemia by incubation in Ringer solution. It is concluded that a direct metabolic and hemodynamic effect could be at least partly responsible for the late antiischaemic effect of 7-oxo-PgI2. This effect was also present in the early phase of experimental myocardial infarction in conscious rats if animals were pretreated with 7-oxo-PgI2 2 hours before occlusion. However treatment did not increase survival rate and failed to reduce the incidence and severity of arrhythmias.

Topics: Adenine Nucleotides; Angina Pectoris; Animals; Disease Models, Animal; Dogs; Epoprostenol; Female; Heart; Lactates; Male; Myocardial Infarction; Myocardium; Phosphocreatine; Rats; Rats, Inbred Strains; Vasopressins