cicaprost and Arrhythmias--Cardiac

A novel carbacyclin derivative (16S)-13,14-dehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro- 6a- carbaprostaglandin-I2 (3-oxa-analogue) has been synthesized in order to find chemically and metabolically stable prostacyclin-mimetics with a potency equal or even superior to PGI2. The 3-oxa-analogue was found to be stabilized against beta-oxidation, a main metabolic degradation step also for chemically stable PGI2-analogues. The compound is orally available and displays a long duration of 4.5-48 h of antiaggregatory and hypotensive action. The 3-oxa-analogue inhibits ADP-induced platelet aggregation with an IC50 of 3.0 nM. Following intravenous application the 3-oxa-analogue lowers diastolic blood pressure in a dose dependent manner, the ED20 being 0.1-0.2 micrograms/kg after injection and less than or equal to 0.05 micrograms/kg/min after infusion respectively. In vivo platelet aggregation is inhibited after i.v. infusion of the 3-oxa-analogue with an IC50 of 0.037 micrograms/kg/min. As compared to Iloprost, the 3-oxa-analogue is 5-12 fold more potent with respect to in vivo hypotensive and anti-aggregatory effects. The results of the present studies indicate that the 3-oxa-analogue has a pharmacological profile comparable to prostacyclin (PGI2) and Iloprost. Due to the fact that the 3-oxa-analogue is chemically and metabolically stable, long term oral treatment can be achieved in clinical conditions in which PGI2 and Iloprost have already been shown to be therapeutically useful principles.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Epoprostenol; Heart Rate; Hydroxyprostaglandin Dehydrogenases; In Vitro Techniques; Liver; Male; Platelet Aggregation; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Receptors, Prostaglandin

Iloprost (ILO) and ZK 96 480 (96 480) are stable prostacyclin (PGI2) analogues with platelet aggregation-inhibiting and hypotensive activities equal or superior to PGI2 which in contrast to PGI2 show longlasting pharmacological effects also after oral application. PGI2 as well as ILO and 96 480 with i.v. infusion at equihypotensive doses in rats after coronary artery ligation reduce ventricular ectopic beats, markedly reduce or abolish the periods of ventricular tachycardia and entirely prevent ventricular fibrilloflutter. Even nonhypotensive doses of the prostanoids attenuate postligation arrhythmias. Catecholamine depletion by reserpine pretreatment also markedly reduced the incidence of arrhythmias. As PGI2 and ILO have previously been shown by others to preserve noradrenaline content of sympathetic nerve terminals in ischemic myocardium, prevention of excessive catecholamine loss from hypoxically compromised sympathetic nerve terminals might be involved in the antiarrhythmic action of PGI2, ILO and 96 480.

Topics: Adenosine Diphosphate; Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiovascular Agents; Epoprostenol; Iloprost; Lidocaine; Platelet Aggregation; Rats; Rats, Inbred SHR; Reserpine