Long-term inhibition of nitric oxide synthesis increases arterial thrombogenecity in rat carotid artery.
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 II-induced 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.
Kubo-Inoue
Mayuko
M
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.
Egashira
Kensuke
K
Usui
Makoto
M
Takemoto
Masao
M
Ohtani
Kisho
K
Katoh
Makoto
M
Shimokawa
Hiroaki
H
Takeshita
Akira
A
D000284:Administration, Oral; D000804:Angiotensin II / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002341:Carotid Artery Thrombosis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D007275:Injections, Intravenous; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010875:Pipecolic Acids / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D011517:Prothrombin Time; D051381:Rats; D011921:Rats, Inbred WKY; D013449:Sulfonamides; D013925:Thromboplastin / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000991:Antithrombins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D010875:Pipecolic Acids; D013449:Sulfonamides; D000804:Angiotensin II; D013925:Thromboplastin; D001120:Arginine; C065166:imidapril; D019001:Nitric Oxide Synthase; D007703:Peptidyl-Dipeptidase A; C031942:argatroban; D019331:NG-Nitroarginine Methyl Ester