Animal studies and clinical pediatric practice have shown that acute alkalosis attenuates hypoxic pulmonary vasoconstriction (HPV). However, increased intracellular pH appears to enhance pulmonary vasoreactivity. We therefore hypothesized that prolonged alkalosis augments HPV. This study compares the effects of acute and prolonged alkalosis on HPV in isolated perfused lungs of 1-month-old lambs (n = 5) and the hypoxic responses of 300- to 500-microns diameter segments of pulmonary arteries (n = 7) from mature cats at control pH and after 30 min of alkalosis. In isolated lamb lungs, normocarbic (5% CO2) hypoxia (4% O2) increased the total pressure gradient (delta PT) by 6.0 +/- 2.7 (SEM) mm Hg (p < or = 0.05). Acute hypocarbia (3% CO2) increased the perfusate pH to approximately 7.52 and significantly decreased the hypoxic delta PT to normocarbic, normoxic (28% O2) levels. Subsequent exposure to normoxia (while maintaining alkalosis) further decreased delta PT. However, re-exposure to hypoxia after 60 min of normoxic alkalosis significantly increased delta PT by 11.6 +/- 1.6 mm Hg (p < or = 0.05) to a level similar to that seen during normocarbic hypoxia. The increased hypoxic reactivity (i.e., change in pressure between normoxia and hypoxia) during prolonged alkalosis was due to enhanced HPV of the small vessels within the middle segment of the pulmonary circuit, as defined by an inflow-outflow occlusion technique (p < or = 0.05). The occlusion data also suggested that most of this increase occurred in small arteries. Moreover, the hypoxic response of isolated small arteries from the cat was increased almost threefold (p < or = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)