SUMMARY1. Squid giant axons were impaled with electrodes to measure pNai, pHi, Em, and were injected with either aequorin or arsenazo III to measure [Ca] [Ca]. is 3 mM.4. The introduction of 2 mM-CN into the sea water bathing the axon does not affect the response to depolarization nor does the destruction of most of the ATP in the axon following the injection of apyrase.5. If axons are microinjected with phenol red rather than arsenazo, the entry of Ca produces an acidification in the peripheral parts ofthe axoplasm. Other experiments measuring [Ca]i show that Ca entry is strongly inhibited by a decrease in pHi.6. Making sea water alkaline with pH buffers scarcely affects the Ca entry induced by depolarization; making axoplasm alkaline by adding NH4+ to sea water greatly enhances Ca entry by Na/Ca exchange and also enhances the ability of axoplasmic buffers to absorb Ca.

Whole blood O2 equilibrium curves (OEC) were measured in 46 Peruvians native to high altitude (4,540 m) and in 25 sea-level controls. A method was employed that records the entire OEC from 0 to 150 Torr with constant pH and PCO2. The data were analyzed by fitting the Adair equation describing the successive oxygenation of hemoglobin. At pH 7.4 the PO2 at which hemoglobin is half-saturated with O2 (P50) was significantly higher in the high-altitude population (31.2 +/- 1.9 Torr) than in controls (29.2 +/- 1.8 Torr, P less than 0.001). The acid-base status of the high-altitude subjects, however, was that of compensated respiratory alkalosis (plasma pH 7.439 +/- 0.065), and when the P50's were corrected to the subjects' plasma pH the values (30.1 +/- 2.2 Torr) could no longer be distinguished from the controls. We conclude that, on the average, increased P50 resulting from increased red cell 2,3-diphosphyoglycerate concentration at high altitude is offset by compensated respiratory alkalosis with the net result that the position of the OEC more closely approaches that of sea-level humans than has hitherto been thought. Considerable variation exists in P50, both at sea level and high altitude. This variation might have important consequences for acclimatization and survival under adverse environmental conditions.

Chronic mountain sickness (CMS) or Monge's disease is a clinical entity observed among residents at attitude characterized by polycythaemia increased above the physiological level due to altitude adaptation. From correlation studies of haematocrit with ventilation rate of healthy and diseased native high altitude residents (4, 540 m) it was found that CMS is a clinical manifestation of aging. The higher the altitude the sooner the symptoms of excessive polycythaemia will become evident.

Squid axons were injected with arsenazo III and treated with sea water containing compounds usually classified as general anesthetics, (pentanol-decanol and a variety of hydrocarbons and their derivatives). Such treatment led to an increase in absorbance by arsenazo III at wavelengths sensitive to [Ca]i. The effect was independent of the presence or absence of Ca++ in sea water and it was not modified by substances that release Ca from internal stores. The effect was easily reversible. In axons injected with phenol red or impaled with a glass electrode sensitive to H+, a similar treatment led to an alkalinization that was also readily reversible. Both Ca release and the change to an alkaline pH had identical time courses. The dose required for action by all of the chemical agents studied could be predicted from a knowledge of their fractional saturation in sea water, i.e. from their thermodynamic activity. For compounds with 8-10 carbon atoms, Ca-release effects can occur at concentration less than those necessary to block either conduction or Na/Ca exchange. A special chemical agent was octylamine, which induced a marked rise in pHi and in addition its nonionic form produced the typical Ca release associated with general anesthetics.

Squid giant axons injected with either aequorin or arsenazo III and bathed in 3 mM Ca (Na) seawater were transferred to 3 mM Ca (K) seawater and the response of the aequorin light or the change in the absorbance of arsenazo III was followed . These experimental conditions were chosen because they measure the change in the rate of Na/Ca exchange in introducing Ca into the axon upon depolarization ; [Cal. is too low to effect a channel-based system of Ca entry. This procedure was applied to axons treated with a variety of compounds that have been implicated as inhibitors of Na/Ca exchange. The result obtained was that the substances tested could be placed in three groups . (a) Substances that were without effect on Ca entry effected by Na/Ca exchange were : D600 at 10-100 FM, nitrendipine at 1-5 uM, Ba2+ and Mg" at concentrations of 10-50 mM, lidocaine at 0.1-10 mM, cyanide at 2 mM, adriamycin at a concentration of 3,M, chloradenosine at 35 ,AM, 2,4-diaminopyridine at 1 mM, Cs' at 45-90 mM, and tetrodotoxin at 10'. (b) Substances that had a significant inhibitory effect on Na/Ca exchange were : Mn2+ , Cd2+ , and Las" at 1-50 mM, and quinidine at 50 pM . (c) There were also blocking agents and biochemical inhibitors whose action appeared to be the inhibition of nonmitochondrial Ca buffering in axoplasm rather than an inhibition of Na/Ca exchange . These were the general anesthetic 1-octanol at 0.1 mM and 1 mM orthovanadate plus apyrase.