Thrombin-induced endothelium-dependent inhibition and direct activation of platelet-vessel wall interaction. Role of prostacyclin, nitric oxide, and thromboxane A2.

Abstract

BACKGROUND Platelet-vessel wall interaction plays an important role in acute cardiovascular disorders. Thrombin is a potent platelet activator but also has profound effects on the endothelium. Endothelial cells possess antithrombotic activity by releasing nitric oxide and prostacyclin, both potent vasodilators and platelet inhibitors. We studied the role of thrombin as a regulator of platelet-vessel wall interaction in isolated human arteries suspended in organ chambers for isometric tension recording. METHODS AND RESULTS In arteries with endothelium, thrombin (0.01 to 1 U/mL) induced endothelium-dependent relaxations, which were reduced by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10(-4) mol/L) and/or indomethacin (10(-5) mol/L). Human platelets (75,000/microL) evoked only marginal contractions in arteries with endothelium (3 +/- 3% of the contraction to KCl 100 mmol/L; NS), which were markedly enhanced by endothelial removal (22 +/- 4%; P < .05). Thrombin (1 U/mL) did not affect the response to platelets in arteries with (6 +/- 5%; NS) but induced a huge contraction in rings without endothelium (53 +/- 6%; P < .01 versus control without endothelium). The potent contraction to thrombin-activated platelets (1000 to 75,000/microL) in arteries without endothelium was markedly inhibited by the thromboxane A2 synthetase/receptor antagonist ridogrel (10(-5) mol/L; P < .005 versus control) and the single-acting thromboxane receptor blocker SQ-30741 (10(-7) mol/L; P < .01 versus control). CONCLUSIONS Thus, thrombin directly stimulates platelets to release thromboxane A2, inducing potent vasoconstriction, which is prevented by the simultaneous thrombin-induced release of prostacyclin and nitric oxide from endothelial cells. In arteries devoid of functional endothelial cells, as occurs in patients with coronary artery disease, a combined inhibition of thromboxane production and action provides a potent therapeutic tool to interfere with the thrombin-induced activation of platelet-vessel wall interaction.

Different Types of Vasocontractile Responses to Noradrenaline in the Presence of Platelets with Platelet Activating Factor.

“…In In contrast, PGI2 and nitric oxide derived from vascular endothelium function entirely as antithrombotics (Vanhoutte et al ., 1985;Zimmerman et al, 1985;Yang et al ., 1994).…”

“…Vascular endothelial dysfunction accompanied by platelet activation develops very often in pathological conditions and/or diseases such as atherosclerosis, hypertension, vasculitis, col lagen disease, and disseminated intravascular coagulation (Vanhoutte et al ., 1985;Zimmerman et al,1985;Yang et al, 1994;Gerritsen et al, 1996) . Since mechanisms of abnormal platelet-blood vessel interactions causing vascular damage differ in vascular diseases, it seems to be very important to elucidate their mechanisms for the sake of preventing individual angiopathies.…”

“…It is generally accepted that abnormalities in platelet-blood vessel interaction very often cause vascular endothelial dysfunction and/or vascular thrombosis (Vanhoutte at al., 1985;Crowley at al., 1994;Yang et al, 1994). Furthermore, among sub stances liberated from platelets stimulated by platelet agonists there are several vasoactive agents participating in blood vessel contractility (Witte et al, 1978;Kaplan at al ., 1979;Brash 1985;Bossant at al., 1990;Henson 1990).…”

“…Furthermore, among sub stances liberated from platelets stimulated by platelet agonists there are several vasoactive agents participating in blood vessel contractility (Witte et al, 1978;Kaplan at al ., 1979;Brash 1985;Bossant at al., 1990;Henson 1990). Some vasoactive substances released from activat ed platelets are closely affected by the agonists (Vanhoutte et al, 1985;Yang at al., 1994).…”

Platelet Aggregation and Vasoconstriction Related to Platelet Cyclooxygenase and 12-Lipoxygenase Pathways

“…Many thrombotic angiopathies are known to involve abnormalities of platelet-blood vessel wall interaction (1,2), and it is generally accepted that abnormal interaction between platelets and the vascular endothelium leads to vascular endothelial dysfunction. Thrombotic mechanisms, whether arterial, venous, or mixed, vary widely among patients (3)(4)(5)(6), but most involve pathophysiologic conditions among platelets, the vascular endothelium, and the coagulation and fibrinolytic systems.…”