Cutaneous venous dysfunction studied in vivo in the LPS-treated rabbit: implication of NO in saphenous vein hyporeactivity.
Superficial vein pathology involves both mechanical (hyperpressure and distension) and inflammatory mechanisms. Conflicting results exist about the role of NO in the venous hyporeactivity induced by inflammation. In order to clarify this point, we aimed to investigate the effects of sepsis on cutaneous vein responsiveness in vivo and the possible contributions of constitutive and inducible NOS to the changes of venous contractility. Saphenous vein diameter was recorded by an ultrasonic echo-tracking device in pentobarbital-anaesthetised rabbits. Bacterial lipopolysaccharide (LPS) was administered i.v. at 20 mg/kg/15 min, inducing a progressive fall in mean arterial blood pressure after 2-3 h. The effects of LPS on saphenous vein responsiveness to noradrenaline (2 microg/kg i.v.) were measured simultaneously. In some rabbits, veins were removed for immunochemistry to detect iNOS staining. The venoconstriction to noradrenaline was already significantly reduced at 30 min after LPS (6+/-1% instead of 19+/-1% before LPS) and was completely abolished 3 h after LPS. A reduction of the venoconstriction induced by sumatriptan, a 5-HT(1B/D) agonist, (100 microg/kg, 11+/-1% after saline n=5) was also observed 180 min after LPS infusion (3+/-1%, n=4). The venodilatations induced by acetylcholine or sodium nitroprusside injected locally into the vein were not altered by LPS. When administered 90 min after LPS infusion, the NOS inhibitor L-NAME but not the selective iNOS inhibitor L-NIL (10 mg/kg) induced a recovery of the venoconstriction. Preventive perfusion with L-NAME (10 mg/kg/2 h) reduced the initial hyporeactivity to noradrenaline (30 to 60 min), but accelerated the lethal fall in MAP. L-NIL (10 mg/kg/2 h), to a lesser extent than L-NAME, also reduced the initial hyporeactivity to noradrenaline; in contrast to L-NAME, L-NIL also delayed the complete loss of noradrenaline constriction and improved animal survival. In control animals, neither L-NAME nor L-NIL modified the venoconstriction induced by noradrenaline. iNOS staining was observed in the saphenous vein endothelium after LPS. The experimental model developed in these experiments allows the study of venous responsiveness during sepsis in vivo. Our results show that LPS administration reduces saphenous vein contractility to both adrenergic and serotoninergic constrictor agents. The data suggest that both endothelial and inducible NO are involved in the loss of venous reactivity but these enzymes exert contrasting effects on blood pressure changes.
Vayssettes-Courchay
Christine
C
Division of Angiology, Servier Research Institute, 11 rue des Moulineaux, 92150 Suresnes, France.
Chataigneau
Marta
M
Protin
Cedric
C
Ragonnet
Christophe
C
Verbeuren
Tony J
TJ
D000109:Acetylcholine / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019446:Endotoxemia / Q000209:etiology; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000493:pharmacokinetics; D019001:Nitric Oxide Synthase / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009638:Norepinephrine / Q000008:administration & dosage / Q000493:pharmacokinetics; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000009:adverse effects*; D011817:Rabbits; D012501:Saphenous Vein / Q000187:drug effects / Q000503:physiopathology*; D012867:Skin / Q000098:blood supply* / Q000503:physiopathology*; D018170:Sumatriptan / Q000008:administration & dosage / Q000493:pharmacokinetics; D014657:Vasculitis / Q000150:complications; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
C090663:N(6)-(1-iminoethyl)lysine; D011135:Polysaccharides, Bacterial; D018170:Sumatriptan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D008239:Lysine; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine