Inhibition of platelet adhesion to surfaces of extracorporeal circuits by disintegrins. RGD-containing peptides from viper venoms.

Abstract

Previous studies indicate that exposure of fibrinogen receptors associated with glycoprotein lIb/llla complex contributes to platelet loss during cardiopulmonary bypass. Recently, we isolated a number of RGD (Arg-Gly-Asp)-containing, low molecular weight, cysteine-rich peptides from viper venoms. These peptides, which we propose to call "disintegrins," block platelet-fibrinogen interaction and platelet aggregation. We compared the effect of RGDS (Arg-Gly-Asp-Ser) and four disintegrins (echistatin, flavoridin, albolabrin, and bitistatin) on platelet behavior in a membrane oxygenator. During simulated extracorporeal circulation for 2 hours, platelet count decreased to about 30% of initial values. Addition of echistatin (60-200 nM), albolabrin (60-200 nM), bitistatin (60 nM), and flavoridin (45 nM) significantly inhibited platelet loss in the circuit. RGDS (33 /lM) did not show any significant inhibitory effect. ADP-induced platelet aggregation was inhibited in samples of platelet-rich plasma taken from the circuits containing disintegrins. However, echistatin appeared to be a more potent inhibitor of platelet aggregation, whereas albolabrin and flavoridin interfered more selectively with platelet loss from the circuit. Echistatin prevented the accumulation of glycoprotein IlIa on the surface of the circuit. Echistatin (60-200 nM), flavoridin (45 nM), bitistatin (60 nM), and albolabrin (200 nM) significantly inhibited the loss of j-thromboglobulin from platelets into circulating plasma. Electron microscopy studies demonstrated shape change but not degranulation in platelets circulating in the presence of 200 nM echistatin. On the other hand, this peptide (up to 1,000 nM) did not prevent loss of a granules and ,3-thromboglobulin from thrombin-stimulated platelets, although it prevented their aggregation. In conclusion, disintegrins protect platelets in the circuit by preventing their adhesion to surfaces and, therefore, preventing fragmentation of adhered platelets under the shear stress of flowing blood. This study indicates that distintegrins may be potential candidates for platelet protection during cardiopulmonary bypass. (Circulation 1990;82:261-273) Cardiopulmonary bypass involves extensive contact between blood and synthetic surfaces of the membrane oxygenator. Bypass produces thrombocytopenia,1"2 platelet fragmen-

Inhibitory Effects of Salmosin, a Disintegrin, on Posterior Capsular Opacification in vitro and in vivo

“…RGD peptide, as has been previously reported, has a comparatively low level effect on the inhibition of integrin activity and the prevention of PCO (Nishi et al, 1997a). Indeed, the potency of disintegrins is 500±2000 times higher at inhibiting platelet aggregation (Musial et al, 1990;Jia et al, 1997) and 150±300 times higher at inhibiting retinal pigment epithelial cell attachment to the ECM than the small RGD peptides (Yang et al, 1996). Most of the ECM proteins, such as ®bronectin, laminin, The in¯ammatory conditions of anterior chamber (Hogan et al, 1959) (Nagata and Watanabe, 1996): Grade I (no opaci®cation or limited to less than one quadrant of the posterior capsule periphery), Grade II (opaci®cation extending beyond one quadrant of the periphery but not invading the papillary region).…”

L1 Interaction with Ankyrin Regulates Mediolateral Topography in the Retinocollicular Projection

“…In contrast to ventral retinal cells, no effect of ephrinB1-Fc was seen on adhesion of dorsal retinal cells. To demonstrate that ephrinB1-stimulated adhesion of ventral retinal cells was mediated by RGD-dependent integrins, adhesion of WT retinal cells to fibronectin was examined in the presence of echistatin, a competitive disintegrin peptide that blocks RGDbinding integrins (Musial et al, 1990). Echistatin significantly reduced basal adhesion of ventral retinal cells and completely abolished the stimulating effect of ephrinB1 on adhesion ( p Ͻ 0.01) (Fig.…”

Structure and function of RGD peptides involved in bone biology

“…They are developed from snake venoms and directly influence the b 3 subunit of the integrins, blocking their function. Flavoridin belongs to the snake venom family and potently inhibits blood platelet aggregation [40]. Barbourin, a single disintegrin peptide, contains RGD and KGD.…”