Species variation in the effect of glycoprotein IIb/IIIa antagonists on inhibition of platelet aggregation.
Differences exist between platelets of different species in their reaction to pharmaceutical agents, such as inhibitors of platelet aggregation. Understanding these differences is critical in the interpretation of data from experimental animal models of thrombosis. Platelet aggregation, essential in the hemostatic process, requires that fibrinogen (fgn) bind to activated platelets. Analogs of Arginine-Glycine-Aspartic acid-Phenylalanine (RGDF), a peptide sequence of fgn, block fgn binding to its receptor known as glycoprotein (GP) IIb/IIIa on activated platelets and prevent aggregation. We studied the inhibition resulting from Arginine-Glycine-Aspartic acid-Serine (RGDS) and two analogs of RGDF, (SC-46749 and SC-47643) on aggregation of human, rat, guinea pig, dog, and rhesus monkey platelets in vitro using ADP as the agonist. The inhibitory potency of RGDS, SC-46749, ad SC-47643 was species dependent. The rank order of potency was rhesus monkey, dogs, and human followed by guinea pig and rat. In order to study the relative inactivity of the compounds in rat platelets compared to human, we diluted rat platelet-rich plasma (PRP) to yield platelet levels approximating that of humans. Platelet inhibition was not significantly changed in diluted rat PRP nor did changing concentration appear to affect activity in human PRP. Our data suggest that the platelet response of some species may better represent human response with regard to inhibition of GP IIb/IIIa by (RGDX) analogs.
Panzer-Knodle
S
S
Department of Cardiovascular Diseases Research, Searle, Skokie, Illinois 60077.
Taite
B B
BB
Mehrotra
D V
DV
Nicholson
N S
NS
Feigen
L P
LP
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004285:Dogs; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013045:Species Specificity
D006146:Guanidines; D009842:Oligopeptides; D010980:Platelet Membrane Glycoproteins; C062178:arginine-glycine-aspartate-O-methyltyrosine amide; C070872:8-guanidinooctanoyl-Asp-2-(4-methoxyphenyl)ethylamide; D001224:Aspartic Acid; D000244:Adenosine Diphosphate; C046617:arginyl-glycyl-aspartyl-serine