Endothelium-derived relaxing factor reduces platelet adhesion to bovine endothelial cells.

Abstract

The adhesion of thrombin-stimulated human blood platelets to either the endothelial surface of intact bovine aorta or cultured bovine aortic endothelial cells was studied to determine the role of endothelium-derived relaxing factor in the regulation of platelet adhesion. Endothelial cells and platelets were pretreated with indomethacin to prevent the formation of prostaglandins. The adhesion of thrombinstimulated platelets to endothelial cells was reduced by superoxide dismutase and bradykinin. The inhibitory effect of both drugs was abolished by hemoglobin and was absent in strips of bovine aorta where the endothelial cells had been removed by scraping. It is suggested that the effects of bradykinin are mediated by the release of endothelium-derived relaxing factor, which is protected from destruction by superoxide dismutase, and that endothelium-derived relaxing factor contributes to the nonadhesive properties of the vascular endothelium.Unstimulated or stimulated blood platelets do not easily adhere either to the intact endothelium (1) or to the surface of intact confluent monolayers of cultured endothelial cells (2)(3)(4). This nonthrombogenicity appears to be an intrinsic property of the endothelial cell (EC) plasma membrane. In addition to providing a physical barrier between the blood and thrombogenic subendothelial structures, ECs possess both anticoagulant and antiplatelet properties. The anticoagulant properties are expressed in (i) the synthesis and release of a heparin sulphate that promotes the ability of plasma antithrombin III to inactivate thrombin rapidly (5, 6), (ii) the production of thrombomodulin (7), and (iii) the synthesis of plasminogen activator (8). The antiplatelet properties of the EC surface have been variously attributed to (i) a netnegative charge on the endothelial surface (9), (ii) the presence of an ectoplasmic ATPase that metabolizes aggregatory nucleotides released from aggregating platelets (10), (iii) the synthesis and release of the antiaggregatory prostanoid prostacyclin (11), and (iv) the intracellular concentration of 13-hydroxyoctadecadienoic acid, a lipoxygenase product of linoleic acid (12). The relative contribution of these factors to the nonthrombogenic nature of the EC plasma membrane presently is unknown.Thromboresistance appears to be unrelated to prostacyclin release, since inhibition of prostacyclin production in cultured ECs does not increase the adhesion of either unstimulated or stimulated platelets (1, 3), although concentrations of prostacyclin higher than those normally released at the EC surface are highly effective in preventing platelet adhesion (1,3,4,13). In addition to releasing prostacyclin,

Selective anti‐platelet aggregation synergism between a prostacyclin‐mimetic, RS93427 and the nitrodilators sodium nitroprusside and glyceryl trinitrate

“…This same group (Radomski et al, 1987b) also found that NO inhibited adhesion of platelets to surfaces, including collagen fibrils, an effect mediated by increased platelet cyclic GMP and not shared by physiological concentrations of prostacyclin, which only elevated cyclic AMP. Similar findings have been reported by Sneddon et al (1988b) for platelet adhesion to vascular endothelium. Together, these data suggest existence of a homeostatic process by which vascular prostacyclin (PGI2) and NO, released together by a coupled mechanism, may attenuate localized platelet reactivity (de Nucci et al, 1988).…”

“…Thus, RS93427 (via elevation of platelet cyclic AMP; see Mills & MacFarlane, 1977;Moncada & Vane, 1979) prevents the plateletplatelet aggregation process that amplifies the initial stimulus of adhesion of platelets to collagen. This adhesion process would itself be inhibited by GTN and NaNp via prior conversion to NO (Radomski et al, 1987b;Sneddon et al, 1988b) (Born & Cross, 1962). In addition to directly inducing the platelets to stick to one another (i.e., aggregate), it also induces a secondary aggregation response due to release of aggregation-inducing arachidonate metabolites and platelet granular contents (Willis, 1978).…”

Inhibition of Nitric Oxide Synthesis Increases Focal Ischemic Infarction in Rat

“…Another mechanism through which NO would be neuroprotective relates to the fact that NO facili tates platelet disaggregation (Radomski et a!., 1987a,b;Sneddon and Vane, 1988) and reduces the formation of microthrombi. That platelet-activated microthrombosis may produce or enhance focal ce rebral infarction under controlled experimental con ditions has been demonstrated (Fieschi et a!., 1975;Furlow and Bass, 1976;Dietrich et a!., 1986Dietrich et a!., , 1987.…”

Impairment of Endothelium-Dependent Relaxation by Diesel Exhaust Particles in Rat Thoracic Aorta.

“…Inhaled nitric oxide gas reverses pulmonary hypertension (27), reverses pulmonary vasoconstriction (28), improves lung function in affected patients and increases ventilation-perfusion ratios (29). In addition, nitric oxide inhibits platelet aggregation (13 -15), platelet (30,31) and leukocyte (16)(17)(18) adhesion on endothelial cells and vascular albumin leakage (19,20). Thus, nitric oxide seems to contribute greatly to maintaining physiological functions in the lung.…”