PROGRESSIVE LOSS OF VASODILATOR RESPONSIVE COMPONENT OF PULMONARY-HYPERTENSION IN NEONATAL CALVES EXPOSED TO 4,570 M

Severe neonatal pulmonary hypertension (PH) may have both reversible ( vasoconstrictive) and ''fixed'' (vasodilator unresponsive) components. To assess when and to what degree vasodilator unresponsive PH develop ed in the neonate, pulmonary arterial pressures (PAP) and cardiac outp uts (CO) were measured, and total pulmonary resistances (TPR) were cal culated in neonatal calves exposed to chronic hypoxia (CH) (barometric pressure of 430 mmHg = 4,570 m) for 1, 3, 7, and 14 days under both n ormoxic (barometric pressure of 640 mmHg - 1,500 m) and hypoxic condit ions with and without an infusion of the vasodilator acetylcholine (AC h). Studies were done at 4 h and at 2, 4, 8, and 15 days of life in bo th control and CH animals. The fixed component of PH was defined as th at PAP or TPR above the control baseline value which remained in CH an imals after an infusion ACh at 1,500 m. Small pulmonary arteries were also examined histologically in an attempt to correlate relative chang es in the reversible and fixed elements of PH with alterations in vess el structure. Chronic exposure to 4,570 m altitude prevented the norma l postnatal fall in PAP and TPR observed in control animals. Instead, PAP, TPR, and the structure of small pulmonary arteries initially rema ined similar to those of the 4-h-old newborn. By 7 days exposure to 4, 570 m, a significant element of fixed PH developed, which increased dr amatically between the 7- and 14-day exposure periods and appeared to correlate with a narrowed pulmonary artery lumen and increased medial and adventitial thickness. Fourteen-day CH exposed calves also demonst rated a decreased hypoxic pulmonary pressor response compared with bot h age-matched controls and animals exposed to hypoxia for lesser perio ds of time. We conclude that perinatal exposure to hypoxia, by arresti ng the normal postnatal fall in PAP and TPR, may lead to early and pro gressive fixed, vasodilator unresponsive PH and thus contribute to the often refractory nature of PH in otherwise normal neonates.