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 developed in the neonate, pulmonary arterial pressures (PAP) and cardiac outputs (CO) were measured, and total pulmonary resistances (TPR) were calculated 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 normoxic (barometric pressure of 640 mmHg - 1,500 m) and hypoxic conditions with and without an infusion of the vasodilator acetylcholine (ACh). Studies were done at 4 h and at 2, 4, 8, and 15 days of life in both control and CH animals. The fixed component of PH was defined as that PAP or TPR above the control baseline value which remained in CH animals after an infusion ACh at 1,500 m. Small pulmonary arteries were also examined histologically in an attempt to correlate relative changes in the reversible and fixed elements of PH with alterations in vessel structure. Chronic exposure to 4,570 m altitude prevented the normal postnatal fall in PAP and TPR observed in control animals. Instead, PAP, TPR, and the structure of small pulmonary arteries initially remained 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 dramatically 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 demonstrated a decreased hypoxic pulmonary pressor response compared with both age-matched controls and animals exposed to hypoxia for lesser periods of time. We conclude that perinatal exposure to hypoxia, by arresting the normal postnatal fall in PAP and TPR, may lead to early and progressive fixed, vasodilator unresponsive PH and thus contribute to the often refractory nature of PH in otherwise normal neonates.