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.

Carotid body-mediated ventilatory increases in response to acute hypoxia are attenuated in animals reared in an hypoxic environment. Normally, 02-sensitive K+ channels in neurosecretory type I carotid body cells are intimately involved in excitation of the intact organ by hypoxia. We have therefore studied K+ channels and their sensitivity to acute hypoxia The ventilatory responses to acute hypoxia of animals and humans change dramatically from fetal to adult life: in fetal animals, exposure to hypoxia is inhibitory to breathing movements (1), whereas in the adult, hypoxia causes a sustained increase in ventilation (2). Neonatal animals produce an intermediate biphasic response, with ventilation increasing and then falling again during sustained hypoxia (3). This transient increase, along with the sustained increase seen in adults, is a result of stimulation of peripheral chemoreceptors, primarily the carotid body (4, 5). Ventilatory responses to acute hypoxia of neonatal animals born and raised in hypoxic environments are blunted or absent (6), and a similar lack of ventilatory response to hypoxia has also been noted in adult animals exposed to hypoxia chronically (7) and in high-altitude residents (8). It is conceivable that common mechanisms underlie the lack of ventilatory response to hypoxia of chronically hypoxic neonatal animals and high-altitude residents.The carotid bodies of chronically hypoxic animals or humans show dramatic morphological changes following prolonged hypoxia: most notably, type I carotid body cellsThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. undergo hyperplasia and hypertrophy (9, 10). Type I cells are widely accepted as the chemosensory element of the carotid body, and various stimuli including hypoxia stimulate Ca2+-dependent release of neurotransmitters from these cells in a manner that correlates with increased discharge of afferent chemosensory fibers (5, 11). In recent years, several groups have used patchclamp techniques to investigate ion channels in type I cells, and there are several reports describing 02-sensitive K+ channels in these cells (12)(13)(14)(15)(16). These findings have given rise to a proposed mechanism for hypoxic chemotransduction in which inhibition of K+ channels by hypoxia leads to depolarization and increased excitability of type I cells sufficient to activate voltage-gated Ca2+ channels. This leads to Ca2+ influx and triggering of neurosecretion, an essential step in the chemotransductive pathway (5). Here we have compared ionic channels and their modulation by acute hypoxia in type I cells isolated from neonatal rats born and raised in normoxia and hypoxia in order to investigate whether the lack of chemoreceptor-mediated increases in ventilation seen in animals reared under chronically hypoxic conditions can be attributed to altered electrophysiological properties of type I cells. ...

The mammalian respiratory tract contains innervated groups of endocrine cells which are believed to respond to hypoxia. We have demonstrated the involvement of a specific regulatory peptide produced by the cells, calcitonin gene-related peptide (CGRP), in this response. Cells immunoreactive for CGRP or for protein gene product 9.5 (PGP 9.5), a general marker of nerves and endocrine cells, were quantified in sections of lungs from hypoxic (21 days, 10 per cent O2) and normoxic rats. An immunostaining method employing supra-optimal dilutions of primary antiserum was used. This detects variations in antigen concentration which may be masked if the routine, optimal dilution is used. The number of CGRP-immunoreactive endocrine cells was significantly (P less than 0.001) greater in the lungs of hypoxic rats (76.9 +/- 10.1 cells/cm2, mean +/- SEM) compared with controls (19.7 +/- 2.4). However, the numbers of PGP 9.5-immunoreactive cells were the same in both groups (81.3 +/- 12.2, hypoxic; 79.5 +/- 9.8 control), suggesting that the total number of endocrine cells did not change. It is concluded therefore that the apparent increase in CGRP-immunoreactive endocrine cells in hypoxic rat lungs is due to increased intracellular levels of the peptide. Since CGRP is a vasodilator, this could have important implications in the vasoconstrictor response to hypoxia.