Selective anti-platelet aggregation synergism between a prostacyclin-mimetic, RS93427 and the nitrodilators sodium nitroprusside and glyceryl trinitrate.
1. Citrated platelet-rich plasma from human donors was used to examine turbidometrically the platelet aggregation response to collagen (2.5 micrograms ml-1) and ADP (1.6 microgram ml-1). 2. With collagen as an aggregating agent, the limited (35% maximal inhibition) inhibitory effects of glyceryl trinitrate (GTN, 0.78-50 micrograms ml-1) were markedly potentiated by threshold (3.3-10 ng ml-1) concentrations of RS93427, an orally active prostacyclin-mimetic. Almost complete inhibition of aggregation could then be produced. 3. A threshold concentration of RS93427 (3.3 ng ml-1) similarly potentiated the ability of sodium nitroprusside (NaNp, 0.78-10 micrograms ml-1) to inhibit collagen-induced platelet aggregation. There was an 8 fold reduction in the IC25 concentration of NaNp. 4. Threshold concentrations of the nitrodilators were also able to potentiate the anti-aggregatory effects of RS93427 (0.03-30 ng ml-1) on collagen-induced platelet aggregation. With threshold concentrations of either GTN (6.3-25 micrograms ml-1) or NaNp (0.3-1.3 microgram ml-1), the mean IC50 concentration of RS93427 was reduced 4 or 6 fold, respectively, while the IC25 concentration was reduced 6 or 10 fold, respectively. 5. No similar synergistic interactions were seen between RS93427 and the nitrodilators when ADP was used as an aggregating agent. 6. In spontaneously hypertensive rats, the dose-response for the hypotensive response to bolus doses of RS93427 was not altered by concomitant steady state infusion of a threshold dose (1 micrograms kg-1 min-1) of GTN. 7. Possible therapeutic implications of these findings are discussed.
Willis
A L
AL
Institute of Biological Sciences, Syntex Research, Palo Alto, CA 94305.
Smith
D L
DL
Loveday
M
M
Fulks
J
J
Lee
C H
CH
Hedley
L
L
VanAntwerp
D
D
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D011464:Epoprostenol / Q000494:pharmacology*; D005260:Female; D005292:Ferricyanides / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors; D051381:Rats; D011918:Rats, Inbred SHR
D001952:Bridged-Ring Compounds; D005292:Ferricyanides; D010975:Platelet Aggregation Inhibitors; C050064:RS 93427-007; D009599:Nitroprusside; D000244:Adenosine Diphosphate; D011464:Epoprostenol; D005996:Nitroglycerin