Hydroxyoxazolidines as alpha-aminoacetaldehye equivalents: novel inhibitors of calpain.

The synthesis of [1-[(5-hydroxy-4-(phenylmethyl)-3-oxazolidinyl)carbonyl]-2-ethylpropy lcarbamic acid phenylmethyl ester (2; MDL 104,903), a potent inhibitor of calpain, is described. Synthesis of related compounds, which offer insights into the mechanism of action for 2, are also described, as is an O-acetyl prodrug derivative of 2.

Changes to metabolite concentration in fetal sheep subjected to prolonged hypobaric hypoxia.

The effect of hypobaric hypoxaemia on the concentration of metabolic substrates in the ovine fetus and pregnant ewe with implanted vascular catheters, was investigated. At 120 to 141 days of gestation sheep were subjected to hypobaria (mean fetal carotid PO2 12.7 +/- 0.7 torr; n = 9) or normobaria (mean fetal carotid PO2 22.7 +/- 0.7 torr; n = 11; P less than 0.001). At 141 days gestation mean fetal weight was 3.46 +/- 0.72 kg in the hypobaric group compared to 4.15 +/- 0.51 in the normobaric group (P less than 0.05). Concentrations of glucose in maternal and fetal plasma and fructose in fetal plasma were similar in hypobaric and normobaric fetuses. The concentration of lactate in fetal plasma rose from 1.68 +/- 1.34 to 8.79 +/- 5.8 mmol/l (P less than 0.001) within 24 h of onset of hypoxia, but fell to 3.36 +/- 1.13 mmol/l by day 3 of treatment, though still significantly above the concentration of lactate in the control fetuses (1.47 +/- 0.47; P less than 0.001). There was no significant effect of hypoxia on the concentration of lactate or alanine in maternal plasma. Alanine concentration in the plasma of fetuses subjected to hypoxia significantly increased within 24 h of exposure (0.28 +/- 0.10 vs 0.58 +/- 0.39 mmol/l; P less than 0.01) and remained elevated for the duration of the study. There was no significant effect of gestational age on the concentration of metabolic substrates in either the control or experimental groups. Hypoxia is associated with a sustained rise in the concentration of plasma lactate and alanine in the fetus.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of prolonged hypobaric hypoxia on growth of fetal sheep.

The effect of prolonged hypobaric hypoxia on fetal sheep was studied. Pregnant ewes were subjected to an atmospheric pressure of 429 torr from 30 days to 135 days gestation (long-term study). Average fetal weight for the hypoxaemic group (3.35 +/- 0.53 kg; n = 4; mean +/- SD) was significantly lower than for the controls (4.23 +/- 0.29 kg; n = 7; P less than 0.05). A short-term study was undertaken with fetuses (n = 8) which were catheterized at 110 days gestation and whose dams were subjected to hypobaric hypoxia from 120 to 141 days gestation. The mean carotid PO2 of fetuses in the hypoxic group was 12.7 +/- 0.7 torr compared to 22.7 +/- 0.7 torr for the control group (n = 9; P less than 0.001) throughout the period of treatment. Fetal arterial oxygen content fell from 6.5 +/- 1.7 to 4.9 +/- 0.4 ml/dl (P less than 0.05), but rose to control values after 7 days due to an increase in fetal haemoglobin concentration (9.6 +/- 1.1 to 13.0 +/- 1.9 g/dl, P less than 0.001) and packed cell volume (33 +/- 3 to 45 +/- 4%, P less than 0.001). In the hypoxaemic fetuses, pH fell initially from 7.34 +/- 0.02 to 7.28 +/- 0.03 (P less than 0.05) and then recovered to 7.32 +/- 0.03 within 24 h. Mean fetal weight of the short-term hypoxic group was 3.46 +/- 0.72 kg compared to 4.15 +/- 0.51 for the control group (P less than 0.05). Both long- and short-term hypoxia produced a similar reduction in fetal body weight. The adrenal glands were significantly heavier in the hypoxic fetuses than in controls. Placental weight was not effected by hypoxia, but exposure from 30 days gestation reduced the average size of cotyledons (P less than 0.05). It is concluded that the fetal sheep increases its ability to acquire and transport oxygen in response to chronic hypoxia, but this compensation is not sufficient to prevent growth retardation or changes to the pattern of tissue growth.

Effect of hypoxia on the initiation of secondary wool follicles in the fetus.

The development of secondary wool follicles in single fetal sheep subjected to hypobaric hypoxaemia was studied. One group of pregnant ewes were exposed to 57.1 kPa from 30 to 135 days gestation. Fetal weights (mean +/- s.d.) for the hypoxaemic group (3.35 +/- 0.53 kg; n = 4) were significantly lower than for the controls (4.19 +/- 0.31 kg; n = 3, P less than 0.05). At 110 days gestation, a second group had arterial and venous catheters surgically implanted into the ewe and fetus and skin samples were taken from the fetus. At 120 days gestation (10 days after surgery) these animals were subjected to hypoxia for 20 days, at a level to maintain fetal carotid pO2 between 1.47 and 1.87 kPa (mean carotid pO2 for the control fetuses was 2.84 +/- 0.28 kPa). Fetal weight at 140 days was not significantly different in the hypoxaemic and control groups. Morphometric analysis revealed that the secondary to primary follicle ratio (S:P) was less in both groups of hypoxaemic fetuses than in their respective controls. Although hypoxia for 20 days did not significantly alter fetal weight, it produced a low S:P ratio similar to the longer-term hypoxaemic animals. It is concluded that hypoxia has a marked effect in reducing the initiation of secondary follicles in the last third of gestation.

Pulse-wave propagation in the arterial system of the diamond python Morelia spilotes.

Pulse-wave velocity (PWV) and pulse-wave amplification (PWA) were measured over a proximal [51 +/- 3 (SE) cm] and distal segment (60 +/- 6 cm) of the common descending aorta of 10 anesthetized diamond python snakes (Morelia spilotes). For proximal and distal segments, PWV values were 551 +/- 66 and 921 +/- 116 cm/s and PWA were 0.91 +/- 0.05 and 0.91 +/- 0.06, respectively. PWV for proximal and distal segments were significantly different (P less than 0.02), but PWA were not. PWA for separate harmonics of heart frequency showed no significant increase above unity. Increase of PWV between distal and proximal aorta indicates a reduction in arterial distensibility, a phenomenon that in other species is associated with amplification of the pressure pulse; this was not observed in snakes. Using a simple elastic tube model 56 cm in length and 3 mm in diameter it was found that the amplification produced by the measured PWV changes is offset by attenuation due to viscous damping. Thus similarity of pulse-wave contour throughout the snake's aorta is attributable to the opposing effects of elastic nonuniformity and viscous damping.

Systemic arterial hemodynamics in the diamond python Morelia spilotes.

Studies of pulsatile systemic arterial hemodynamics were conducted in 10 diamond python snakes to test the hypothesis that body shape--through spatial dispersion of peripheral reflecting sites--is an important determinant of impedance patterns and of pulse wave contour. Findings support the hypothesis. Flow patterns in the aortic roots were similar to those in humans, sheep, dogs, rabbits, and guinea pigs, but in contrast to larger animals, little change in flow contour was seen in other arteries. Pressure wave contour was similar in all systemic arteries from which records were taken with no secondary diastolic wave under any circumstances. Impedance patterns at different sites showed none of the fluctuations that in other animals are attributable to discrete wave reflection. Discrete proximal wave reflection at the confluence of aortic arches was minimal. Data are explicable on the basis of widely distributed peripheral reflecting sites--a consequence of the snake's long and tapered body.

Separation of slow reacting substance of anaphylaxis (SRS-A) from human lung into four biologically active fractions.

Slow reacting substance of anaphylaxis (SRS-A) was released from human lung passively sensitized with ragweed antibody and challenged with specific antigen E. After purification by ethanol extraction, incubation with alkali (0.1 M NaOH for 30 min at 37 degrees C) and chromatography on silicic acid and DEAE-cellulose, human SRS-A was separated into four biologically active fractions (Fractions I to IV). Arylsulfatase (Type H-1) in 0.1 M sodium acetate buffer, pH 4.5, destroyed the biologic activity of only Fraction I. All four fractions, like SO4=, inhibited the arylsulfatase activity at pH 4.5 but not at pH 6.0 when p-nitrocatechol sulfate was used as substrate. These results suggest that SRS-A contain a sulfur group and that human STS-A, like the prostaglandins, may be a family of compounds. The instability of the purified SRS-A to storage remains a major barrier to their further purification and chemical identification.

Interaction of leukocytes and endotoxin with the plasmin and kinin systems.

Leukocytes can generate a substance that, when added to some partially purified human kininogen, is capable of forming kinins. The addition of endotoxin or polystyrene latex particles to the incubated leukocytes doubled the amount of kinin generated. Certain preparations of kininogen, however, failed to allow kinin formation by the leukocytes. No evidence could be found that an activator of prekallikrein or a kallikrein was present in the granulocyte preparations. However, the addition of highly purified plasminogen to inactive kininogen preparations restored their ability to generate kinins in the presence of leukocytes. All the kininogen preparations that allowed kinin formation when incubated with leukocytes contained plasminogen. These data suggest that a plasminogen activator is present on the leukocyte surface. This activator activates plasminogen to form plasmin which in turn acts on kininogen to release a kinin and thus provides a mechanism for the formation of kinins in inflammatory exudates and during endotoxemia.

Gas transport and blood acid-base balance in diving sea snakes.

The values of hemoglobin concentration, Hb-O2 affinity and buffering capacity of the blood of six sea snake species considerably overlap values from terrestrial squamates. Decreased blood pH had little effect on the P50 but increased the n-value of Hb-O2 equilibrium curves. The O2 saturation of blood in the dorsal aorta varied between about 30 and 70% during voluntary diving in Acalyptophis peronii and Lapemis hardwickii. Voluntary dives ended when the lung PP02 was about 50 mm Hg and the arterial PO2 about 30 mm Hg indicating that roughly half of the O2 reserves had been used. In conjunction with relatively stable blood lactate concentration and pH, this indicates that voluntary dives occurred largely aerobically. In contrast, forced dives resulted in depletion of O2 reserves and large changes in blood acid-base balance. Long recovery periods following forced dives are inconsistent with field observations and thus suggest that extensive anaerobic metabolism does not normally occur in sea snakes. Bradycardia was not evident during forced dives. Large differences in PO2 between the lung and dorsal aorta indicated considerable right to left shunting either in the heart or in the lung. Venous blood represented over 50% of the systemic flow when there was considerable O2 in the lung. Therefore blood PO2 may remain relatively low despite elevated lung PO2 resulting from diving. In view of substantial capability for extra-pulmonary gas exchange, high shunting reduces the possibility of losing O2 through the skin and also may help prevent decompression sickness following deep dives.