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 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 similar to 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 mu M 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 approximate to 10 mM Ni2+ approximate to 10 mu M verapamil approximate to 10 mu M nifedipine with 50 mu M SKF 96365 > 30 mu M KB-R7943 approximate to 100 mu M flufenamic acid approximate to 10 mu M nifedipine approximate to 100 mu M Gd3+ > 100 mu M La3+ > 500 mu M Ni2+ approximate to 10 mu M diltiazem approximate to 50 mu M 2-APB approximate to 100 mu M LOE 908. Contraction was not reduced by 100 mu M spermine or 30 mu M 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 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.