Vascular Effects of Thrombin

Abstract

The proteolytic enzyme thrombin catalyzes the con version of fibrinogen to fibrin and activates clotting fac tors that are necessary for prothrombin transformation, fibrin stabilizing Factor XIII, and protein C activation. Thrombin is a potent activator of a variety of cell events and has been shown to evoke a number of physiologic responses in various tissues that are typical of those stim ulated by hormones. 1,2 It triggers several receptor-medi ated processes such as platelet aggregation, secretion, and formation of thromboxane A 2 3,4 and contraction of smooth muscle. 5,6 Furthermore, thrombin causes prolif eration of fibroblasts and osteoblastic cells, chemotaxis of monocytes, mitogenesis of neuroblastoma, and mesangial cells. 7-11 At very low concentrations, it stimu lates isolated frog heart muscle cells via activation of L-type calcium channels, presumably mediated by a sec ond messenger. 12 In the circulation thrombin is rapidly bound to high-affinity binding sites on endothelial cells. [13][14][15] It exerts various effects on these cells, such as release of plasminogen activator, platelet activating fac tor (PAF), endothelin, prostacyclin, and the so-called endothelium-derived relaxant factor (EDRF). 16-25 Pros tacyclin and EDRF cause vasodilation and inhibition of platelet aggregation. Therefore, thrombin may produce biphasic effects on vascular smooth muscle, endothelium-dependent vasodilation, or vasoconstriction. 26,27 The biphasic vascular effects depend on the anatomic origin and type of vessel and the species studied. 28-30 ENDOTHELIUM-DEPENDENT VASODILATIONSeveral endogenous substances such as acetylcho line and bradykinin, as well as the proteolytic enzymes thrombin and trypsin, are able to produce endotheliumdependent vasodilation indirectly mediated by EDRF re leased from the endothelium. The EDRF, which has been characterized as nitric oxide, activates the soluble guanylate cyclase in smooth muscle cells and increases the cyclic guanosine monophosphate (cGMP) level, thereby inducing relaxation of the smooth muscle. 31 Thrombininduced endothelium-dependent relaxation has been demonstrated in isolated rat aorta, in porcine pulmonary and coronary arteries, in canine femoral, pulmonary, basilar, cerebral and saphenous arteries, and in human basilar and internal mammary arteries. 24,[28][29][30][32][33][34][35][36] How ever, in veins with intact endothelium the relaxation was less pronounced, in most cases an increase in tension was observed. 32,34,37,38 In isolated porcine coronary arteries thrombin caused reversible and transient relaxation of prostaglandin F 2α (PGF 2α )-precontracted vessels with in tact endothelium (Fig. 1). The threshold concentration of thrombin to obtain significant relaxation was 0.01 U/ml (about 0.1 nmol/liter). The relaxant effect reached a max imum within 1 to 3 minutes and was gradually attenuated up to the initial tension. When the same thrombin con centration was added to the contracted vessel after the relaxant phase, no response was obtained on the second exp...

Thrombin Is a Distal Mediator of Lipopolysaccharide-Induced Liver Injury in the Rat

“…III. The earliest identified function of thrombin was the cleavage of fibrinogen into fibrin monomers and the That thrombin is a distal link in the chain of events that result in liver injury may prove useful in the cliniactivation of the fibrin-stabilizing factor (factor XIII) and protein C [35]; however, its actions extend beyond cal setting. In experimental studies, drugs that interfere with cellular and soluble mediators have usually those involved directly in coagulation.…”

Antithrombin III inhibits thrombin-induced proliferation in human arterial smooth muscle cells.

“…58 Thrombin plays a crucial role at several levels in the cascade reaction leading to thrombus formation, 9 but it may also regulate many postthrombotic events. 10 Clot-bound thrombin is gradually released into the extracellular matrix of the vascular wall, 11 where it may influence endothelial and leukocyte function 12 and participate in the growth regulation of SMCs.…”

Thrombin receptor activation elicits rapid protein tyrosine phosphorylation and stimulation of the raf-1/MAP kinase pathway preceding delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for an obligate autocrine mechanism promoting cell proliferation induced by G-protein-coupled receptor agonist.

“…In cultured rat aortic smooth muscle (RASM) 1 cells, thrombin has been reported to activate Na ϩ /H ϩ exchange and calcium mobilization (5). An increase in intracellular calcium was required for thrombin-induced expression of c-fos mRNA, a protooncogene associated with cell growth.…”