Preservation of serotonin-mediated contractility in adult sheep pulmonary arteries following long-term high-altitude hypoxia

Papamatheakis, Demostehens G., SrilakshmiVemulakonda, Quintin Blood, Ravi Goyal, Monica Rubalcava, Kurt Vrancken, Allison Bennett, Antoinette Dawson, Noah J. Osman, Arlin B. Blood, William J. Pearce, Lawrence D. Longo, and Sean M. Wilson. Preservation of serotonin-mediated contractility in adult sheep pulmonary arteries following long-term high-altitude hypoxia. High Alt. Med. Biol. 12:253-264.-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 Ca ²⁺ channels, nonselective cation channels (NSCC), and reverse-mode sodium-Ca ²⁺ 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 (3801m) 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-HT _2A antagonist, shifted the 5-HT potency to a far greater extent than 1μM GR-55562, a 5-HT _1B/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≈10mM Ni ²⁺≈10μM verapamil≈10μM nifedipine with 50μM SKF 96365>30μM KB-R7943≈100μM flufenamic acid≈10μM nifedipine≈100μM Gd3+>100μM La ³⁺>500μM Ni ²⁺≈10μM diltiazem≈50μM 2-APB≈100μM LOE 908. Contraction was not reduced by 100μM spermine or 30μM 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-HT _2A and 5HT _1B/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.