Thrombin does not alter vascular hyporeactivity in models of endotoxin-induced septic shock in rats.
1. Hypotension and vascular hyporesponsiveness to vasoconstrictors are observed during endotoxic shock, and are associated with increased production of nitric oxide in the vascular wall. Disseminated intravascular coagulation is another feature of septicaemia. We hypothesized that thrombin generated during disseminated intravascular coagulation might modulate the changes in vascular tone induced by endotoxin. 2. Incubation of rat aortic rings for 4 h with alpha-thrombin (0.003-3.0 NIH units/ml) did not change their reactivity to noradrenaline. Incubation for 4 h with lipopolysaccharide increased the EC50 for noradrenaline, whereas co-incubation of thrombin (0.5 NIH units/ml) with lipopolysaccharide did not alter this hyporeactivity to noradrenaline. 3. In vivo in rats, lipopolysaccharide caused early (1 h) and late (4-6 h) hyporeactivity to noradrenaline. In rats infused with lipopolysaccharide and heparin (1 U min-1 kg-1, 0.4 ml/h) or hirudin (2.2 mg ml-1 kg-1, 0.8 ml/h), vasopressor responses to noradrenaline were not different from those after infusion of lipopolysaccharide alone. Aortic rings taken from rats receiving both anticoagulant treatment and lipopolysaccharide had the same sensitivity to noradrenaline as those obtained from rats receiving lipopolysaccharide alone. 4. Our results suggest that, in vivo, disseminated intravascular coagulation does not modify the early and late effects of lipopolysaccharide on arterial pressure and that, in vitro, thrombin neither induces hyporeactivity to noradrenaline nor modifies lipopolysaccharide-induced hyporeactivity. We propose that thrombin generated during disseminated intravascular coagulation in rats does not play a major role in the alterations of vascular tone observed during endotoxic shock.
Martin
V
V
URA CNRS 600, Laboratoire de Pharmacologie Cellulaire et Moléculaire, Faculté de Pharmacie, Université Louis Pasteur de Strasbourg, France.
Wiesel
M L
ML
Albert
A
A
Beretz
A
A
D000818:Animals; D001011:Aorta; D004211:Disseminated Intravascular Coagulation / Q000503:physiopathology*; D006493:Heparin / Q000494:pharmacology; D006629:Hirudins / Q000494:pharmacology; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000503:physiopathology*; D013917:Thrombin / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*
D006629:Hirudins; D008070:Lipopolysaccharides; D006493:Heparin; D013917:Thrombin; D009638:Norepinephrine