title: Preservation of serotonin-mediated contractility in adult sheep pulmonary arteries following long-term high-altitude hypoxia.
abstract: Long-term hypoxia (LTH) can increase serotonin (5-HT) signaling as well as extracellular calcium entry in adult rodent pulmonary arteries (PA), and 5-HT is associated with pulmonary hypertension. Because LTH, 5-HT, and calcium entry are related, we tested the hypothesis that LTH increases 5-HT-mediated PA contractility and associated calcium influx through L-type Ca2+ channels, nonselective cation channels (NSCC), and reverse-mode sodium-Ca2+ exchange. We performed wire myography and confocal calcium imaging on pulmonary arteries from adult ewes that lived near sea level or were maintained at high-altitude (3801 m) for ∼110 days. LTH did not increase the arterial medial wall thickness, nor did it affect the potency or efficacy for 5-HT-induced PA contraction. Ketanserin (100 nM), a 5-HT2A antagonist, shifted the 5-HT potency to a far greater extent than 1 μM GR-55562, a 5-HT1B/D inhibitor. These influences were unaffected by LTH. The rank order for reducing 5-HT-induced PA contraction in normoxic animals was extracellular calcium removal≈10 mM Ni2+≈10 μM verapamil≈10 μM nifedipine with 50 μM SKF 96365>30 μM KB-R7943≈100 μM flufenamic acid≈10 μM nifedipine≈100 μM Gd3+> 100 μM La3+>500 μM Ni2+≈10 μM diltiazem≈50 μM 2-APB≈100 μM LOE 908. Contraction was not reduced by 100 μM spermine or 30 μM SN-6. LTH increased the effects of KB-R7943 and mitigated those of nifedipine but did not affect calcium responses in imaging studies. Overall, in adult sheep, arterial structure and 5-HT2A and 5HT1B/D functions are preserved following LTH while the role of NSCC-related calcium-dependent contraction is increased. These elements indicate preservation of PA contractility in LTH with minimal functional changes.
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, Loma Linda University Medical Center, Loma Linda, California, USA.
authors.forename: Demosthenes G
authors.initials: DG
authors.lastname: Papamatheakis
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Vemulakonda
authors.forename: Quintin
authors.initials: Q
authors.lastname: Blood
authors.forename: Ravi
authors.initials: R
authors.lastname: Goyal
authors.forename: Monica
authors.initials: M
authors.lastname: Rubalcava
authors.forename: Kurt
authors.initials: K
authors.lastname: Vrancken
authors.forename: Allison
authors.initials: A
authors.lastname: Bennett
authors.forename: Antoinette
authors.initials: A
authors.lastname: Dawson
authors.forename: Noah J
authors.initials: NJ
authors.lastname: Osman
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Blood
authors.forename: William J
authors.initials: WJ
authors.lastname: Pearce
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Longo
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wilson
mesh_terms: D000532:Altitude Sickness / Q000503:physiopathology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D018613:Microscopy, Confocal; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D009213:Myography; D009532:Nickel / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D012756:Sheep; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000502:physiology; D013096:Spermine / Q000494:pharmacology; D050052:TRPC Cation Channels / Q000187:drug effects; D050053:TRPM Cation Channels / Q000187:drug effects; D013997:Time Factors
chemical_list: D001549:Benzamides; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011725:Pyridines; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D019831:Sodium-Calcium Exchanger; D050052:TRPC Cation Channels; D050053:TRPM Cation Channels; C103477:3-(3-(dimethylamino)propyl)-4-hydroxy-N-(4-(4-pyridinyl)phenyl)benzamide; D013096:Spermine; D012701:Serotonin; D009532:Nickel; D007650:Ketanserin; D002118:Calcium