Administration of a potent antagonist of protease-activated receptor-1 (PAR-1) attenuates vascular restenosis following balloon angioplasty in rats.
Human platelets possess two distinct thrombin-activated receptors, PAR-1 (protease-activated receptor-1) and PAR-4, whereas human vascular smooth muscle cells possess only PAR-1. Although such thrombin receptors have been studied extensively in vitro, their physiological roles are still rather ill-defined. We have now employed a potent, selective PAR-1 antagonist, RWJ-58259, to probe the in vivo significance of PAR-1 in thrombosis and vascular injury. RWJ-58259 was examined in two thrombosis models in guinea pigs: the arteriovenous (A-V) shunt assay (monitoring thrombus weight) and the Rose Bengal intravascular photoactivation assay (monitoring time to occlusion). Administration of RWJ-58259 (10 mg/kg, total i.v. dose) did not inhibit thrombus formation in either thrombosis model, although local, intrashunt delivery in the A-V shunt model did elicit a modest antithrombotic effect (thrombus weight reduction from 35 +/- 2 to 24 +/- 4 mg). These results are consistent with the presence of more than one thrombin-sensitive receptor on guinea pig platelets, in analogy with human platelets. Indeed, we were able to establish that guinea pig platelets express three thrombin receptors, PAR-1, PAR-3, and PAR-4. We also examined RWJ-58259 in a vascular restenosis model involving balloon angioplasty in rats. Perivascular administration of RWJ-58259 (10 mg) significantly reduced neointimal thickness (77 +/- 5 microm to 45 +/- 5 microm, P < 0.05), clearly demonstrating an important role for PAR-1 in vascular injury. From these results, it is evident that a PAR-1 antagonist is not especially effective for treating platelet-dependent thrombosis; however, it could well be beneficial for treating restenosis attendant to arterial injury.
Andrade-Gordon
P
P
Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477-0776, USA. pandrade@prius.jnj.com
Derian
C K
CK
Maryanoff
B E
BE
Zhang
H C
HC
Addo
M F
MF
Cheung Wm
Damiano
B P
BP
D'Andrea
M R
MR
Darrow
A L
AL
de Garavilla
L
L
Eckardt
A J
AJ
Giardino
E C
EC
Haertlein
B J
BJ
McComsey
D F
DF
D000800:Angioplasty, Balloon; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology / Q000601:surgery; D018929:Cell Culture Techniques; D006083:Graft Occlusion, Vascular / Q000188:drug therapy*; D006168:Guinea Pigs; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors* / Q000502:physiology; D013927:Thrombosis / Q000188:drug therapy; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
D007191:Indazoles; C424723:RWJ 58259; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D014508:Urea