THAPSIGARGIN STIMULATES INCREASED NO ACTIVITY IN HYPOXIC HYPERTENSIVERAT LUNGS AND PULMONARY-ARTERIES

This study addressed the controversy of whether endothelium-derived ni tric oxide (NO) activity is increased or decreased in the hypertensive pulmonary vasculature of chronically hypoxic rats. Thapsigargin, a re ceptor-independent Ca2+ agonist and stimulator of endothelial NO produ ction, was used to compare NO-mediated vasodilation in perfused lungs and conduit pulmonary artery rings isolated from adult male rats eithe r kept at Denver's altitude of 5,280 ft (control pulmonary normotensiv e rats) or exposed for 4-5 wk to the simulated altitude of 17,000 ft ( chronically hypoxic pulmonary hypertensive rats). Under baseline condi tions, thapsigargin (10(-9)-10(-7) M) caused vasodilation in hypertens ive lungs and vasoconstriction in normotensive lungs. Whereas the sust ained vasodilation in hypertensive lungs was reversed to vasoconstrict ion by the inhibitor of NO synthase N-omega-nitro-L-arginine (L-NNA; 1 0(-4) M), a transient vasodilation to thapsigargin in acutely vasocons tricted normotensive lungs was potentiated. As measured by a chemilumi nescence assay, the recirculated perfusate of hypertensive lungs accum ulated considerably higher levels of NO-containing compounds than did normotensive lungs, and thapsigargin-induced stimulation of NO-contain ing compounds accumulation was greater in hypertensive than in normote nsive lungs. Similarly, low concentrations of thapsigargin (10(-10)-10 (-9) M) caused greater endothelium-dependent L-NNA-reversible relaxati on of hypertensive than of normotensive pulmonary artery rings. The in creased sensitivity of hypertensive arteries to thapsigargin-induced r elaxation was eliminated in nominally Ca2+-free medium and was not mim icked by ryanodine, a releaser of intracellular Ca2+. These results wi th thapsigargin, which acts on endothelial cells to stimulate Ca2+ inf lux and a sustained rise in intracellular Ca2+ concentration, support the idea that pulmonary vascular endothelium-derived NO activity is in creased rather than decreased in chronic hypoxia-induced pulmonary hyp ertension in rats.