Exogenous nitric oxide prevents endotoxin-induced glomerular thrombosis in rats.
Nitric oxide (NO) synthesized from L-arginine is an endogenous vasodilator and inhibitor of platelet adhesion and aggregation. Gram-negative lipopolysaccharide (LPS) can induce NO synthesis, which may mediate the pathophysiologic effects of endotoxemia. In addition, our previous studies suggested that LPS-induced NO may protect against thrombosis in rats. In the present study, male Sprague-Dawley rats given LPS (0.1 mg/kg) i.p. increased their urinary excretion of NO2 + NO3 (stable end-products of NO) by 4.3-fold. Rats given 10 micrograms/kg/hr i.v. of nitroglycerin (GTN), an exogenous NO donor, showed a similar increase. L-NAME, an inhibitor of NO synthesis, abrogated the increase in urinary NO2 + NO3 in LPS-treated rats but not in rats given GTN. Glomerular thrombosis developed in rats given LPS + L-NAME (thrombosis score = 3.02 +/- 0.4), while those given LPS + L-NAME + GTN were largely protected (thrombosis score = 1.37 +/- 0.5, P < 0.05). Atrial natriuretic peptide (ANP), an NO-independent vasodilator, neither increased urinary NO2 + NO3 nor prevented glomerular thrombosis (thrombosis score = 2.68 +/- 0.5, NS). Hydralazine, another vasodilator without effects on NO or platelets, also failed to prevent glomerular thrombosis in rats given LPS + L-NAME. We conclude that in endotoxemia, the antithrombogenic properties of endogenously synthesized NO are important in preventing alomerular thrombosis. The exogenously NO donor, GTN, can substitute for the antithrombogenic effect of endogenous NO. Clinically, administration of NO synthesis inhibitors to treat endotoxic shock may need to be combined with concomitant administration of exogenous NO donors to prevent microvascular thrombosis.
Westberg
G
G
Department of Medicine, Veterans Administration Medical Center, Minneapolis, Minnesota.
Shultz
P J
PJ
Raij
L
L
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000633:toxicity; D001794:Blood Pressure; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
D008070:Lipopolysaccharides; D009569:Nitric Oxide; D001120:Arginine; D005996:Nitroglycerin; D019331:NG-Nitroarginine Methyl Ester