Long-term inhibition of nitric oxide synthesis increases arterial thrombogenecity in rat carotid artery

Abstract

Kubo-Inoue, Mayuko, Kensuke Egashira, Makoto Usui, Masao Takemoto, Kisho Ohtani, Makoto Katoh, Hiroaki Shimokawa, and Akira Takeshita. Long-term inhibition of nitric oxide synthesis increases arterial thrombogenecity in rat carotid artery. Am J Physiol Heart Circ Physiol 282: H1478-H1484, 2002. First published November 29, 2001 10.1152/ajpheart.00739.2001.-Reduced activity of endothelial nitric oxide (NO) may be involved in thrombus formation on atherosclerotic plaques, a major cause of acute coronary syndrome. However, mechanisms of such increase in arterial thrombogenecity have not been fully understood. We previously reported that long-term inhibition of NO synthesis by administration of N G -nitro-L-arginine methyl ester (L-NAME) causes hypertension and activates vascular tissue angiotensin-converting enzyme (ACE) activity. We used this model to investigate the mechanism by which long-term impairment of NO activity increases arterial thrombogenecity. We observed cyclic flow variations (CFVs), a reliable marker of platelet thrombi, after the production of stenosis of the carotid artery in rats treated with L-NAME for 4 wk. The thrombin antagonist argatroban suppressed the CFVs. The CFVs were detected in rats receiving L-NAME plus hydralazine but not in rats receiving L-NAME plus an ACE inhibitor (imidapril). Treatment with the ACE inhibitor imidapril, but not with hydralazine, prevented L-NAME-induced increases in carotid arterial ACE activity and attenuated tissue factor expression. These results suggest that long-term inhibition of endothelial NO synthesis may increase arterial thrombogenecity at least in part through angiotensin IIinduced induction of tissue factor and the resultant thrombin generation. These data provide a new insight as to how endothelial NO exhibits antithrombogenic properties of the endothelium.thrombosis; angiotensin-converting enzyme; tissue factor; thrombin OCCLUSIVE OR NONOCCLUSIVE thrombus formation on atherosclerotic plaque is believed to be of prime importance in the cause of acute coronary syndrome as well as the progression of atherosclerosis. Such thrombus formation is triggered by endothelial dysfunction, by exposure of plaque components or local mediators in the subendothelial layers to blood components after endothelial disruption (plaque rupture), or by systemic blood factors (17,25). Thus any interventions that may reduce the risk of thrombus formation might be expected to improve patient outcomes. The antithrombotic effects of nitric oxide (NO) have been studied mainly in in vitro conditions or in in vivo conditions with acute blockade of NO activity. However, the mechanisms by which long-term impairment of NO activity can increase arterial thrombogenesis are not fully understood.Atherosclerosis has been demonstrated to be associated with endothelial dysfunction, which leads to the abnormal production of NO. Endothelial NO has been shown to regulate vascular tone and to inhibit platelet aggregation, thrombus formation, leukocyte adhesion, and vascular proliferation (3,...

Atrial Fibrillation Increases Production of Superoxide by the Left Atrium and Left Atrial Appendage

“…PAI-1 and tissue factor are prothrombotic molecules that are modulated by redox stimuli. [27][28][29][30][31] Tissue factor activates thrombin, and elevated tissue factor expression is associated with thrombosis in atherosclerosis and sepsis. 32,33 Tissue factor expression is inhibited tissue factor endothelial NO ⅐ production.…”

Augmentation of Pulse Wave Velocity Precedes Vascular Structural Changes of the Aorta in Rats Treated with N.OMEGA.-Nitro-L-Arginine Methyl Ester

“…The fourth group (L + Hyd group) ( n = 10) received L-NAME and hydralazine (L-NAME: 0.7 mg/ml; hydralazine: 0.2 mg/ml; Nacalai Tesque Co.) in its drinking water. These doses of imidapril and hydralazine were chosen based on their previously reported ability to normalize the L-NAME-induced increase in systolic blood pressure (SBP) ( 11 ).…”

Endogenous NO Blockade Enhances Tissue Factor Expression via Increased Ca 2+ Influx Through MCP-1 in Endothelial Cells by Monocyte Adhesion

“…2 Using the same model of long-term inhibition of NO increased arterial thrombogenicity along with upregulated expression of TF. 8 Our study may thus provide a possible mechanism involving MCP-1/CCR2-mediated Ca 2ϩ influx for the increased TF expression in the monocyte-EC interaction in their animal model in vivo. The present study suggests the role of MCP-1/CCR2 in procoagulant activity in the vascular wall, which is critical for the development of early atherosclerosis and the formation of vulnerable plaques.…”

“…7 In vivo studies with a rat model showed that inhibition of NO synthesis by L-NAME increased MCP-1 expression and induced increased arterial thrombogenicity including upregulated expression of TF and the resultant thrombin generation. 2,8 Intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) consists of intracellular mobilization from Ca 2ϩ stores and influx via the plasma membrane. The upregulated expression of TF is inhibited by 1,2-bis(o-amino-5-fluorophenoxy)ethane-N,N,Nc,Nc-tetraacetic acid tetraacetoxymethylester (BAPTA-AM) chelation of Ca 2ϩ in cultured smooth muscle cells, indicating that Ca 2ϩ signaling is involved in the induction of TF gene expression.…”