In neonatal pulmonary hypertension, the pulmonary arteries fail to adapt to extrauterine life and remain thick walled. In a previous study on normal neonatal resistance arteries, perfusion myography and confocal microscopy showed that responses to agonist stimulation were related to wall structure. We hypothesized that in hypertensive resistance pulmonary arteries, an enhanced response to contractile and relaxant agonist stimulation would be associated with an increased wall thickness and abnormal postnatal cytoskeletal remodeling of smooth muscle cells (SMC). Pulmonary arteries (110-140 microm external diameter) from normal piglets and those exposed to chronic hypobaric hypoxia from birth or from 3 d of age were mounted on a perfusion myograph. Lumen diameter and SMC nuclear positions were tracked after addition of KCl, the thromboxane mimetic U46619, and bradykinin. After fixation in situ, SMC dimensions were measured using confocal and electron microscopy. In all hypertensive animals, wall thickness and SMC density were increased and SMC length/width ratio decreased. After hypoxic exposure for 3 d, arteries from animals exposed from birth showed a greater and faster contractile response than controls, but arteries from piglets first exposed at 3 d of age did not, though both showed similar structural appearance. Increase of exposure to 11 d elicited an enhanced response and further cytoskeletal remodeling. All vessels relaxed fully to bradykinin. SMC remodeling and reactivity appear to be influenced by the age at onset and the duration of the hypoxic insult.