Adrenoceptor Hyporeactivity Is Responsible for Escherichia coli Endotoxin-Induced Acute Vascular Dysfunction in Humans

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 22; no. 1; pp. 95 - 100
• Main Authors: Pleiner, Johannes, Heere-Ress, Elisabeth, Langenberger, Herbert, Sieder, Anna E, Bayerle-Eder, Michaela, Mittermayer, Fritz, Fuchsjäger-Mayrl, Gabriele, Böhm, Johannes, Jansen, Burkhard, Wolzt, Michael
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.01.2002; Hagerstown, MD Lippincott
• Subjects: Adrenergic alpha-Agonists - pharmacology; Adult; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; Dose-Response Relationship, Drug; Double-Blind Method; Endotoxemia - metabolism; Endotoxemia - physiopathology; Endotoxins - pharmacology; Heart Rate - drug effects; Humans; Male; Medical sciences; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Norepinephrine - pharmacology; Phenylephrine - pharmacology; Proteins - metabolism; Regional Blood Flow - drug effects; Regional Blood Flow - physiology; RNA, Messenger - metabolism; Skin - blood supply; Vasoconstriction; Vasoconstrictor Agents - pharmacology; Human; Enzyme; Pathogenesis; Septicemia; Cardiovascular disease; Endotoxin; Nitric-oxide synthase; Vascular disease; Toxin; α-Adrenergic receptor; Nitric oxide; Atherosclerosis; Oxidoreductases
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/hq0102.101818

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 N-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.