1. Chronically hypoxic rats kept in 10% (v/v) O2 for 3--6 weeks, were compared with littermate control rats. Pulmonary vascular resistance, measured from the slope of the pressure-flow relationship in isolated lungs perfused with blood of normal packed cell volume was higher in chronically hypoxic than control rats even during normoxia. 2. Chronically hypoxic rats weighed less than control rats but their pulmonary vascular volume, measured with labelled albumin was similar to control rats. This, together with evidence that the number of precapillary vessels is not reduced, does not suggest a large reduction in the vascular bed in chronic hypoxia. 3. A greater vasodilator action of isoprenaline and adenosine in chronically hypoxic than control lungs suggested a higher normoxic vascular tone. This higher tone was not the sole cause of increased resistance in chronically hypoxic lungs, since maximal vasodilatation did not reduce resistance to control levels. The chief cause was probably encroachment of new muscle on the vascular lumen of small vessels. 4. Pulmonary arterial compliance was reduced in chronically hypoxic lungs. 5. Reactivity of vessels to ventilation hypoxia, over a wide range of oxygen tension, to angiotensin II (ANG II) and to adenosine 5'-triphosphate (ATP) was significantly greater in chronically hypoxic than control lungs, but thresholds to these stimuli were not reduced.

1. The effect of blockade of nitric oxide synthesis in pulmonary endothelium by two L-arginine analogues was tested in isolated blood-perfused lungs of normal rats and rats exposed chronically to 10% O2. 2. In both groups of rats the analogues (N-monomethyl-L-arginine (L-NMMA) and N-nitro-L-arginine methyl ester (L-NAME)) enhanced hypoxic vasoconstriction. In normal rats, with rare exceptions, these analogues had little or no effect on pulmonary artery pressure (Ppa) at constant blood flow during normoxia. However, chronically hypoxic rats have pulmonary hypertension and in these rats the analogues always raised Ppa; the rise in Ppa after L-NMMA but not L-NAME could be partially reversed by L-arginine. L-NAME was more potent than L-NMMA. 3. To see whether the difference between rat groups was due to the high Ppa in chronically hypoxic rats, in control rats we raised Ppa passively by lung inflation to values higher than found in chronically hypoxic rats. L-NAME did not alter the effects of lung inflation on Ppa. 4. Ppa was also raised passively by plotting pressure-flow lines up to high flow rates; the lines were changed minimally by both analogues in control rats but in chronically hypoxic rats the lines were raised to higher pressures and steepened substantially. 5. In control rats, during vasoconstriction caused by hypoxia, endothelin 1 and almitrine, L-NAME caused further rises in pressure. We conclude that a stimulus for nitric oxide release in control rats is the narrowing of vessels caused by vasoconstriction rather than passive increases in intravascular pressure. 6. In chronically hypoxic rats arterioles are narrowed by growth of new muscle and there is some muscle tone even in normoxia. Thus narrowing of the vascular lumen is the stimulus common to both groups of rats which leads to nitric oxide synthesis and attenuation of Ppa by a negative feedback process. Narrowing is associated with a large increase in shear stress due to two factors; the pressure drop along a vessel segment is increased and the surface area of the lining of the affected segment is decreased. 7. Atrial natriuretic peptide caused dose-dependent pulmonary vasodilation in both rat groups but had a greater effect in chronically hypoxic rats. The action persisted and was enhanced after blockade of NO synthesis.

.Rats and mice were kept in a decompression chamber at 52 kPa (390 mmHg) for 1-4 weeks and their hearts and lungs were compared with littermate control animals. In both species growth was retarded in the hypoxic environment.2. In both species small peripheral lung vessels became thickened, developing two elastic laminae with a muscular coat between. A method was developed for assessing these changes in large numbers of animals. The number of thick-walled vessels was still high after 4 weeks' recovery in a normal environment. Pulmonary vascular resistance, measured by a perfusion method, increased in animals kept in the decompression chamber.3. Mouse lungs became heavier than controls; the increase was not due to a greater fluid content. Rat lungs were heavy in relation to body weight but not heavier than controls; there may have been slight thickening of alveolar walls. Chest areas, measured from radiographs, were large relative to body weight in hypoxic rats. 4. The relationship between right and left ventricular weight and body weight was studied in normal rats and mice. The left ventricle grew about four times more quickly than the right. Changes in ventricular weights during exposure in the decompression chamber and subsequent recovery in a normal environment were related to these normal growth curves. 5. In both species the right ventricle grew abnormally fast in the decompression chamber. It was absolutely heavier than that of controls and relative to body weight was extremely heavy. After 4 weeks' recovery the relationship between right ventricular weight and body weight was nearly normal; this was achieved by retarded growth or actual loss of weight.6. In mice the left ventricle grew normally in the decompression chamber and was heavy in relation to body weight. In rats its growth was retarded in the chamber and was normal in relation to body weight.

6. The results confirm the hypothesis that hypoxia is an important factor regulating local blood flow in relation to local ventilation.