Synergistic platelet antiaggregatory effects of the adenylate cyclase activator iloprost and the guanylate cyclase activating agent SIN-1 in vivo.
The aim of our study was to evaluate the platelet antiaggregatory and hemodynamic effects of the stable prostacyclin analog iloprost and the NO-donor SIN-1, an active metabolite of molsidomine. The number of circulating platelets was determined in anesthetized male Wistar rats as a measure of in vivo platelet aggregation. Platelet count decreased from 648 +/- 25 to 476 +/- 15 x 10(3) platelets/microliter and from 578 +/- 36 to 411 +/- 40 (mean +/- SEM) in response to two repetitive injections of collagen (70 micrograms/kg body weight). Treatment with SIN-1 bolus injections (0.3 or 1 mg/kg bw) and/or continuous i.v. infusion of iloprost (0.2 or 0.4 micrograms/kg bw/min) was initiated 15 min before the second collagen bolus. As a single agent, SIN-1 did not influence platelet count. Iloprost at 0.2 micrograms/kg/min reduced platelet aggregation (PA) by 15.5%, and at 0.4 micrograms/kg/min by 27.1% (p = n.s.). When iloprost (0.2 micrograms/kg) and SIN-1 (0.3 mg/kg) were administered simultaneously, PA was suppressed by 56.2%, iloprost at 0.4 micrograms/kg/min and SIN-1 at 0.3 mg/kg were even more effective and inhibited PA synergistically by 64.9% (p < 0.05). A statistically significant decrease in mean arterial blood pressure (MABP) was seen in response to all SIN-1 and iloprost groups. However, the vasorelaxant effect of both agents given simultaneously was not synergistic but less than additive. In conclusion, iloprost and SIN 1 exert synergistic platelet inhibitory effects in vivo. In contrast, the decrease in MABP is less then additive. These results are of major interest for the therapeutic regimen with NO-donors (nitrovasodilators).
Spiecker
M
M
II. Med. Clinic, University of Mainz, Germany.
Darius
H
H
Meyer
J
J
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D016285:Iloprost / Q000494:pharmacology*; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D000067956:Adenylyl Cyclase Inhibitors; D000959:Antihypertensive Agents; D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D006162:Guanylate Cyclase; D016285:Iloprost