doi: 10.1161/hq0102.101818
© 2002 American Heart Association, Inc.
Vascular Biology |
Adrenoceptor Hyporeactivity Is Responsible for Escherichia coli Endotoxin–Induced Acute Vascular Dysfunction in Humans
From the Department of Clinical Pharmacology (J.P., E.H.-R., H.L., A.E.S., M.B.-E., F.M., G.F.-M., J.B., B.J., M.W.) and the Department of Dermatology (E.H.-R., B.J.), University of Vienna, Vienna, Austria.
Correspondence to Dr Michael Wolzt, Department of Clinical Pharmacology, Allgemeines Krankenhaus Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail Michael.Wolzt{at}univie.ac.at
Impaired response to catecholamines contributes to the altered hemodynamics in sepsis, which has been attributed to excessive NO formation. We have studied the systemic hemodynamic and local forearm responses and inducible NO synthase (iNOS) expression during experimental endotoxemia in humans. Escherichia coli endotoxin (lipopolysaccharide [LPS]) was administered at doses of 1 or 2 ng/kg to healthy volunteers. In 10 subjects, the systemic pressor effect of phenylephrine was assessed before and after the administration of LPS. In 9 further subjects, forearm blood flow responses to intra-arterial noradrenaline, acetylcholine, glyceryl trinitrate, and NG-monomethyl-L-arginine (L-NMMA) were studied at baseline and after LPS administration. Peripheral blood was collected and analyzed for iNOS mRNA and protein. Four hours after LPS, the response of systolic blood pressure (P<0.0005) and heart rate (P<0.05) to phenylephrine was significantly reduced. In the forearm, noradrenaline-induced vasoconstriction was also reduced by 
50% (P<0.01), but L-NMMA responsiveness was unchanged. iNOS mRNA or protein was not increased. Marked vascular adrenoceptor hyporeactivity is detectable in the absence of increased NO activity or iNOS expression in endotoxemia, arguing against major involvement of vascular iNOS activity in the acute systemic vasodilation to LPS.
Key Words: inducible nitric oxide synthase • nitric oxide • sepsis • lipopolysaccharide • adrenoceptors
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