Cerebral blood flow was determined by an N
2
O method in 7 normal men at sea level and after 6 to 12 hr and 3 to 5 days at 3810 m altitude. An infrared N
2
O analyzer was used both to measure end-tidal PN
2
O so that it could be kept constant for 15 min and to determine blood N
2
O, for which a simple gas extraction method was devised. In addition, acute changes in cerebral blood flow were estimated from cerebral A-V O
2
differences. Control cerebral blood flow was 43 ml per 100 g per min; it increased 24% at 6 to 12 hours and 13% at 3 to 5 days at altitude. After 3 to 5 days, pH of cerebrospinal fluid was normal (7.31) in four subjects while arterial blood pH was alkaline (7.47); arterial blood Pco
2
had fallen from 41 to 30 mm Hg. Acute correction of hypoxia restored cerebral blood flow to control while mean Pco
2
was still 31 mm Hg. Addition of O
2
and CO
2
to inspired air raised cerebral blood flow 34% above control at Pao
2
= 170, Paco
2
= 35 mm Hg. Values obtained by extrapolation suggest that if arterial Pco
2
was raised to control (41 mm Hg), cerebral blood flow would have been 60% above control. Cerebral blood flow thus appears to return to normal at the prevailing Paco
2
, probably because the pH of cerebrospinal fluid and of the extracellular fluid of cerebral vascular smooth muscle is kept normal by active transport across the ‘blood-brain’ barrier. It is postulated that an ion-impermeable barrier separates the blood stream from extracellular fluid of the smooth muscle of cerebral arterioles.
After 1 h of exposure to 0.5 atm of pressure, the electron microscopy of intra-acinar arterioles of the young female adult rat showed edema and subendothelial blebs. Pulmonary hypertension developed rapidly with an increase in hemoglobin, hematocrit, and right ventricular weight. By 24 h, there was a threefold increase in the number of fibroblasts within the arteriolar wall, followed during the next 2 days by transformation of the fibroblast through a transitional cell form to a smooth muscle cell. By 1 wk, the neomuscularization was essentially complete. There was further minor thickening and increase in density of the wall over the next 9 mo. On return to 1 atm after prolonged hypoxia, within 4 wk, the smooth muscle of neomuscularized arterioles dedifferentiated but did not disappear. There was a concurrent rapid fall in the pulmonary arterial pressure, hemoglobin, hematocrit, and right ventricular weight. Veins, capillaries, and arteries remained normal. Parallel studies in the male rat during 14 days of hypoxia demonstrated the same phenomena except slightly accelerated over the female. The rapid sequential changes in the arteriole, beginning with subendothelial blebs and wall edema, followed by fibroblast recruitment and transformation into smooth muscle through a transitional cell form, suggest a cascade. The anatomic and physiological responses to hypoxia are not sex related.
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