High-dose heparin impairs nitric oxide pathway and vasomotion in rats.
BACKGROUND
Platelet-activating effects have been reported with high-dose heparin in acute thrombotic disorders. Recent studies have shown that increased platelet aggregation is due to reduced nitric oxide (NO) production in endothelial cells cultured in the presence of high-dose heparin. The aim of this study was to determine whether heparin can affect the NO pathway and the regulation of the vascular tone in vivo.


RESULTS
Anesthetized and mechanically ventilated Sprague-Dawley rats were treated with high-dose heparin. After 4 hours, the endothelial constitutive NO synthase (ecNOS) protein content in the aorta decreased (36% reduction, P<0.05), as detected by immunoblotting, and NO-dependent vascular reactivity was impaired. In fact, the increase in mean arterial blood pressure after inhibition of ecNOS with NG-nitro-L-arginine methyl ester (30 mg/kg) was smaller in heparin-treated animals than in controls (+26. 9+/-4.8 versus +48.3+/-9.1 mm Hg, P<0.05), and further infusion of the biological ecNOS substrate L-arginine (0.5 g/kg) was ineffective in reversing systemic vasoconstriction (-1% versus 28% vasodilatation, P<0.001).


CONCLUSIONS
High-dose heparin can significantly affect vascular reactivity in vivo by downregulation of ecNOS protein expression.
Bachetti
T
T
Salvatore Maugeri Foundation for Care and Research, Cardiovascular Pathophysiology Research Center, Gussago, Italy.
Pasini
E
E
Clini
E
E
Cremona
G
G
Ferrari
R
R
D000818:Animals; D001011:Aorta / Q000201:enzymology; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006493:Heparin / Q000008:administration & dosage* / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects*
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D006493:Heparin; D001120:Arginine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester