Document Detail


Combined inhibition of nitric oxide and vasodilating prostaglandins abolishes forearm vasodilatation to systemic hypoxia in healthy humans.
MedLine Citation:
PMID:  21486803     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We tested the hypothesis that nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute independently to hypoxic vasodilatation, and that combined inhibition would reveal a synergistic role for these two pathways in the regulation of peripheral vascular tone. In 20 healthy adults, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) responses to steady-state (SS) isocapnic hypoxia (O₂ saturation ~85%). All trials were performed during local α- and β-adrenoceptor blockade (via a brachial artery catheter) to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatory mechanisms. The individual and combined effects of NO synthase (NOS) and cyclooxygenase (COX) inhibition were determined by quantifying the vasodilatation from rest to SS hypoxia, as well as by quantifying how each inhibitor reduced vascular tone during hypoxia. Three hypoxia trials were performed in each subject. In group 1 (n = 10), trial 1, 5 min of SS hypoxia increased FVC from baseline (21 ± 3%; P < 0.05). Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min to inhibit NOS during continuous SS hypoxia reduced FVC by -33 ± 3% (P < 0.05). In Trial 2 with continuous NOS inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (20 ± 3%), and infusion of ketorolac for 5 min to inhibit COX during continuous SS hypoxia reduced FVC by -15 ± 3% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). In group 2 (n = 10), the order of NOS and COX inhibition was reversed. In trial 1, five minutes of SS hypoxia increased FVC from baseline (by 24 ± 5%; P < 0.05), and infusion of ketorolac during SS hypoxia had minimal impact on FVC (-4 ± 3%; NS). In Trial 2 with continuous COX inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (27 ± 4%), and infusion of L-NAME during continuous SS hypoxia reduced FVC by -36 ± 7% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). Our collective findings indicate that (1) neither NO nor PGs are obligatory to observe the normal local vasodilatory response from rest to SS hypoxia; (2) NO regulates vascular tone during hypoxia independent of the COX pathway, whereas PGs only regulate vascular tone during hypoxia when NOS is inhibited; and (3) combined inhibition of NO and PGs abolishes local hypoxic vasodilatation (from rest to SS hypoxia) in the forearm circulation of healthy humans during systemic hypoxia.
Authors:
Rachel R Markwald; Brett S Kirby; Anne R Crecelius; Rick E Carlson; Wyatt F Voyles; Frank A Dinenno
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural     Date:  2011-02-21
Journal Detail:
Title:  The Journal of physiology     Volume:  589     ISSN:  1469-7793     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-04-18     Completed Date:  2011-08-09     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1979-90     Citation Subset:  IM    
Affiliation:
Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Vascular Physiology Research Group, Colorado State University, Fort Collins, CO 80523-1582, USA.
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-Antagonists / administration & dosage
Analysis of Variance
Anoxia / blood,  physiopathology*
Blood Flow Velocity
Blood Gas Analysis
Blood Pressure
Carbon Dioxide / blood
Cyclooxygenase Inhibitors / administration & dosage*
Enzyme Inhibitors / administration & dosage*
Female
Forearm / blood supply*
Heart Rate
Hemoglobins / metabolism
Humans
Hydrogen-Ion Concentration
Infusions, Intra-Arterial
Ketorolac / administration & dosage
Male
NG-Nitroarginine Methyl Ester / administration & dosage
Nitric Oxide / metabolism*
Nitric Oxide Synthase / antagonists & inhibitors*,  metabolism
Oxygen / blood
Prostaglandins / metabolism*
Regional Blood Flow
Respiratory Rate
Time Factors
Ultrasonography, Doppler, Pulsed
Vasodilation / drug effects*
Young Adult
Grant Support
ID/Acronym/Agency:
AG022337/AG/NIA NIH HHS; HL087952/HL/NHLBI NIH HHS; HL095573/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adrenergic beta-Antagonists; 0/Cyclooxygenase Inhibitors; 0/Enzyme Inhibitors; 0/Hemoglobins; 0/Prostaglandins; 10102-43-9/Nitric Oxide; 124-38-9/Carbon Dioxide; 50903-99-6/NG-Nitroarginine Methyl Ester; 66635-83-4/Ketorolac; 7782-44-7/Oxygen; EC 1.14.13.39/Nitric Oxide Synthase
Comments/Corrections
Comment In:
J Physiol. 2011 May 1;589(Pt 9):2111-2   [PMID:  21532030 ]

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