title: Combined inhibition of nitric oxide and vasodilating prostaglandins abolishes forearm vasodilatation to systemic hypoxia in healthy humans.
abstract: 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.affiliation: Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Vascular Physiology Research Group, Colorado State University, Fort Collins, CO 80523-1582, USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Markwald
authors.forename: Brett S
authors.initials: BS
authors.lastname: Kirby
authors.forename: Anne R
authors.initials: AR
authors.lastname: Crecelius
authors.forename: Rick E
authors.initials: RE
authors.lastname: Carlson
authors.forename: Wyatt F
authors.initials: WF
authors.lastname: Voyles
authors.forename: Frank A
authors.initials: FA
authors.lastname: Dinenno
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage; D000704:Analysis of Variance; D001783:Blood Flow Velocity; D001784:Blood Gas Analysis; D001794:Blood Pressure; D002245:Carbon Dioxide / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005542:Forearm / Q000098:blood supply*; D006339:Heart Rate; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000097:blood / Q000503:physiopathology*; D007261:Infusions, Intra-Arterial; D020910:Ketorolac / Q000008:administration & dosage; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D011453:Prostaglandins / Q000378:metabolism*; D012039:Regional Blood Flow; D056152:Respiratory Rate; D013997:Time Factors; D018617:Ultrasonography, Doppler, Pulsed; D014664:Vasodilation / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D011453:Prostaglandins; D002245:Carbon Dioxide; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester; D020910:Ketorolac