Effects of enprostil on cardiovascular and respiratory parameters in the dog, and on hematologic parameters in the rat, monkey, and human
Johnson, L.G.; Bruno, J.J.; Allely, M.C.; Eglen, R.M.; Chang, K.; Yang, D.; Alps, B.J.; Rosenkranz, R.P.; Strosberg, A.M.
Arzneimittel-Forschung 39(11): 1443-1448
1989
ISSN/ISBN: 0004-4172 PMID: 2515862 Document Number: 339586
The effects of enprostil (methyl (.+-.)-7-[(1R*,2R*,3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy-1-butenyl]-5-oxocyclopentyl]-4,5-heptadienoate) were studied on cardiovascular and respiratory parameters in the dog and on hematologic parameters in the rat, monkey, and human. Anesthetized dogs were instrumented to allow measurement of heart rate, systemic blood pressure, respiratory rate or trachea pressure, and ventricular contractile force after intragastric (i.g.) or intravenous (i.v.) administration of enprostil in the presence or absence of autonomic challenges. The effects of intraduodenal (i.d.) enprostil on arterial and venous PO2, PCO23, and pH; respiratory rate, flow rate, and volume; blood pressure (b.p.); and heart rate were also examined. Enprostil i.v. (0.3-10 .mu.g/kg) significnatly increased tracheal pressure in a dose-dependent manner, but minimally altered b.p., heart rate, and ventricular contractile force. Enprostil i.v. (1-10 .mu.g/kg) significantly inhibited pressor and depressor responses to several autonomic challenge agents at the highest dose level, indicative of a nonspecific inhibitory effect on b.p. responses. Cardiovascular effects of enprostil (1-100 .mu.g/kg i.g.) were absent. Enprostil (10-3,000 .mu.g/kg i.d.) had no noteworthy effects on respiratory parameters in the dog. Platelet aggregation effects of enprostil were studied in vitro using platelet rich plasma (RPR) from the rat, monkey, and human; whole blood clotting time and prothrombin time after oral enprostil were studied in the rat; and ex vivo effects on platelet activation were studied in humans. Enprostil induced platelet aggregation in vitro using rat and human plasma, proabably due to its thromboxane-agonist properties; however, given p.o. it did not affect rat prothrombin time or cause platelet activation as measured by platelet .alpha.-granule proteins in human plasma.