Hypoxia stimulates ventilation, but when it is sustained, a decrease in the response is often seen. The mechanism of this depression or "roll off" is unclear. In this study we attempted to localize the responsible mechanism at one of three possible sites: the carotid bodies, the central nervous system (CNS), or the ventilatory apparatus. The ventilatory response to sustained hypoxia (PETO2, 40-50 Torr) was tested in 5 awake and 14 anesthetized adult cats. The roll off was found in both anesthetized and awake cats. Isocapnic hypoxia initially increased ventilation as well as phrenic and carotid sinus nerve activity in anesthetized cats (288 +/- 31, 269 +/- 31, 273 +/- 29% of control value, respectively). During the roll off, ventilation and phrenic nerve activity decreased similarly (to 230 +/- 26 and 222 +/- 28%, respectively after the roll off), but in contrast carotid sinus nerve activity remained unchanged (270 +/- 26%). Thus the ventilatory roll off was reflected in phrenic but not in carotid sinus nerve activity. We conclude that the cat represents a useful animal model of the roll off phenomenon and that the mechanism responsible for the secondary decrease in ventilation lays within the CNS.

SUMMARY1. Cardiomegaly has been produced in rats by sideropenic anaemia, by isoprenaline or thyroxine or by the application of both drugs, by artificial increase in resistance to blood flow and by long-term adaptation to hvpoxia and physical stress. The ratio of the growth of muscle to the growth of collagen in the heart has been studied.2. All possible variations in the ratio occurred depending on the type of stimulus used for inducing cardiomegaly and on the dynamics of the development of cardiomegaly. In cardiomegaly induced by sideropenia and by thyroxine the growth of muscle was not accompanied by the growth of collagen. Exposure to hypoxia or isoprenaline administration increased only the growth of collagen in the hypertrophic heart. in all other forms of cardiomegaly muscle and collagen formation were stimulated to the same extent.3. It is concluded that when certain organs hypertrophy during adult life several factors may determine the relative rapidity of growth of the muscular or parenchymal and the collagenous stromal components of the tissue.

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Mechanisms of ventilatory acclimatization to chronic hypoxia remain unclear. To determine whether the sensitivity of peripheral chemoreceptors to hypoxia increases during acclimatization, we measured ventilatory and carotid sinus nerve responses to isocapnic hypoxia in seven cats exposed to simulated altitude of 15,000 ft (barometric pressure = 440 Torr) for 48 h. A control group (n = 7) was selected for hypoxic ventilatory responses matched to the preacclimatized measurements of the experimental group. Exposure to 48 h of hypobaric hypoxia produced acclimatization manifested as decrease in end-tidal PCO2 (PETCO2) in normoxia (34.5 +/- 0.9 Torr before, 28.9 +/- 1.2 after the exposure) as well as in hypoxia (28.1 +/- 1.9 Torr before, 21.8 +/- 1.9 after). Acclimatization produced an increase in hypoxic ventilatory response, measured as the shape parameter A (24.9 +/- 2.6 before, 35.2 +/- 5.6 after; P less than 0.05), whereas values in controls remained unchanged (25.7 +/- 3.2 and 23.1 +/- 2.7; NS). Hypoxic exposure was associated with an increase in the carotid body response to hypoxia, similarly measured as the shape parameter A (24.2 +/- 4.7 in control, 44.5 +/- 8.2 in acclimatized cats). We also found an increased dependency of ventilation on carotid body function (PETCO2 increased after unilateral section of carotid sinus nerve in acclimatized but not in control animals). These results suggest that acclimatization is associated with increased hypoxic ventilatory response accompanied by enhanced peripheral chemoreceptor responsiveness, which may contribute to the attendant rise in ventilation.

Exposure to hypoxia, leading to hypoxic pulmonary hypertension (HPH), is associated with activation of alveolar macrophages (AM). However, it remains unclear how AM participate in this process. There are studies which imply that the AM product monocyte chemoattractant protein-1 (MCP-1) plays an important role. Thus we tested: 1. if the selective elimination of AM attenuates HPH in rats, 2. the correlation of MCP-1 plasmatic concentrations with the presence and absence of AM during exposure to hypoxia, 3. the direct influence of hypoxia on MCP-1 production in isolated AM. We found that experimental depletion of AM attenuated the chronic hypoxia-induced increase in mean pulmonary arterial pressure, but did not affect the serum MCP-1 concentrations. Furthermore, the MCP-1 production by AM in vitro was unaffected by hypoxia. Thus we conclude that AM play a significant role in the mechanism of HPH, but MCP-1 release from these cells is most likely not involved in this process. The increase of MCP-1 accompanying the development of HPH probably originates from other sources than AM.