Pietro Scotto

Body Temperature, Autonomic Responses, and Acute Mountain Sickness

A few studies have reported increased body temperature (T(o)) associated with acute mountain sickness (AMS), but these usually include exercise, varying environmental conditions over days, and pulmonary edema. We wished to determine whether T(o) would increase with AMS during early exposure to simulated altitude at rest. Ninety-four exposures of 51 men and women to reduced P(B) (423 mmHg = 16,000 ft = 4850 m) were carried out for 8 to 12 h. AMS was evaluated by LL and AMS-C scores near end of exposure, and T(o) was measured by oral digital thermometer before altitude and after 1 (A1), 6 (A6), and last (A12) h at simulated altitude. Other measurements included ventilation, O(2) consumption and autonomic indicators of plasma catecholamines, HR, and HR variability. Average T(o) increased by 0.5 degrees F from A1 to A12 in all subjects (p < 0.001). Comparison between 16 subjects with lowest AMS scores (mean LL = 1.0, range = 0 to 2.5) and 16 other subjects with highest AMS scores (mean LL = 7.4, range = 5 to 11) demonstrated a transient decline in T(o) from A1 to A6 in AMS, in contrast to a rise in non-AMS (p = 0.001). Catecholamines, HR, and HR variability (increased low F/high F ratio) indicated significant elevation of sympathetic activity in AMS, where T(o) fell, but no change in metabolic rate. The apparently greater heat loss during early AMS suggests increased hypoxic vasodilation in spite of enhanced sympathetic drive. Greater hypoxic vasodilation and elevated HR in AMS in the absence of other changes suggest that augmentation of beta-adrenergic tone may be involved in early AMS pathophysiology.

Ventilation during simulated altitude, normobaric hypoxia and normoxic hypobaria

To investigate the possible effect of hypobaria on ventilation (VE) at high altitude, we exposed nine men to three conditions for 10 h in a chamber on separate occasions at least 1 week apart. These three conditions were: altitude (PB = 432, FIO2 = 0.207), normobaric hypoxia (PB = 614, FIO2 = 0.142) and normoxic hypobaria (PB = 434, FIO2 = 0.296). In addition, post-test measurements were made 2 h after returning to ambient conditions at normobaric normoxia (PB = 636, FIO2 = 0.204). In the first hour of exposure VE was increased similarly by altitude and normobaric hypoxia. The was 38% above post-test values and end-tidal CO2 (PET(CO2) was lower by 4 mmHg. After 3, 6 and 9 h, the average VE in normobaric hypoxia was 26% higher than at altitude (p < 0.01), resulting primarily from a decline in VE at altitude. The difference between altitude and normobaric hypoxia was greatest at 3 h (+ 39%). In spite of the higher VE during normobaric hypoxia, the PET(CO2) was higher than at altitude. Changes in VE and PET(CO2) in normoxic hypobaria were minimal relative to normobaric normoxia post-test measurements. One possible explanation for the lower VE at altitude is that CO2 elimination is relatively less at altitude because of a reduction in inspired gas density compared to normobaric hypoxia; this may reduce the work of breathing or alveolar deadspace. The greater VE during the first hour at altitude, relative to subsequent measurements, may be related to the appearance of microbubbles in the pulmonary circulation acting to transiently worsen matching. Results indicate that hypobaria per se effects ventilation under altitude conditions.

Ventilation is greater in women than men, but the increase during acute altitude hypoxia is the same

We wished to determine whether the previously reported lower arterial or alveolar P(CO2) in women than men, and in luteal (LUT) compared with follicular (FOL) menstrual cycle phase would persist during normal oral contraceptive use and during early altitude exposure. Ventilation and blood gases were measured at baseline (636 mmHg approximately 5400 ft, 1650 m) and during simulated altitude at 426 mmHg ( approximately 16000 ft, 4880 m), after 1 h (A1) and during the 12th h (A12), in 18 men (once) and in 19 women twice, during LUT and FOL and in 20 women twice while on placebo (PLA) or highest progestin dose (PIL) oral contraceptives. At baseline, Pa(CO2) was significantly higher in men than all women by 3.3 mmHg. When progesterone-progestin (PRO) was elevated in women, Pa(CO2) was significantly lower than in FOL and PLA, but the latter were still significantly lower than men. At altitude the P(CO2) differences between men and women and PRO levels persisted, with PA(CO2) falling by 3.6 and 7.3 mmHg at A1 and A12 in all, indicating an equivalent increase in alveolar ventilation. The mean arterial-end tidal P(CO2) difference was never >2 mmHg in the groups, indicating no VA/Q mismatch related to gender, PRO levels or altitude. All women had higher breathing frequency than men, resulting in greater deadspace ventilation. At altitude, the mean Pa(O2) was approximately 44 mmHg (Sa(O2) approximately 79%) for all, indicating equivalent oxygenation, but alveolar-arterial P(O2) differences were greater in women than men and higher when PRO was elevated. These results show that, relative to men, women have a compensated respiratory alkalosis, accentuated with elevated PRO. However, the ventilation response to acute altitude is the same in women and men.

Place navigation in rats guided by a vestibular and kinesthetic orienting gradient.

The role of the slope of terrain in orientation was examined in rats trained to find, among 4 equidistant feeders, the 1 located in the upper left quadrant of a 10% tilted arena (1-m radius). Rats started from the center in light and with randomly changing slope direction reached the correct goal in 90% of 1st choices after 29 sessions. The same rats maintained 83% correct choices when the experiment was conducted in darkness. On a horizontal arena, their performance became random. After training, successful navigation was also observed (71% correct 1st choices) when the rats were started from different points at about 30 cm from the wall. This finding suggests that the slope of terrain may be used to establish a cognitive map based primarily on kinesthetic and vestibular signals. The flexibility of such a map seems to be rather limited, however, because changing the goal position with respect to inclination requires prolonged retraining.

Validation of a two-compartment model of ventilation/perfusion distribution

Ventilation (V (A)) to perfusion (Q ) heterogeneity (V (A)/Q ) analyses by a two-compartment lung model (2C), utilizing routine gas exchange measurements and a computer solution to account for O(2) and CO(2) measurements, were compared with multiple inert gas elimination technique (MIGET) analyses and a multi-compartment (MC) model. The 2C and MC estimates of V (A)/Q mismatch were obtained in 10 healthy subjects, 43 patients having chronic obstructive pulmonary disease (COPD) and in 14 dog experiments where hemodynamics and acid-base status were manipulated with gas mixtures, fluid loading and tilt-table stressors. MIGET comparisons with 2C were made on 6 patients and 32 measurements in healthy subjects before and after exercise at normoxia and altitude hypoxia. Statistically significant correlations for logarithmic standard deviations of V (A)/Q distributions (SD(V (A)/Q )) were obtained for all 2C comparisons, with similar values between 2C and both other methods in the 1.1-1.5 range, compatible with mild to moderate COPD. 2C tended to overestimate MC and MIGET values at low and underestimate them at high SD(V (A)/Q ) values. SD(V (A)/Q ) weighted by Q agreed better with MC and MIGET estimates in the normal range, whereas SD(V (A)/Q ) weighted by V (A) was closer to MC at higher values because the V (A)-weighted SD(V (A)/Q ) is related to blood-to-gas PCO(2) differences that are elevated in disease, thereby allowing better discrimination. The 2C model accurately described functional V (A)/Q characteristics in 26 normal and bronchoconstricted dogs during non-steady state rebreathing and could be used to quantify the effect of reduced O(2) diffusing capacity in diseased lungs. These comparisons indicate that 2C adequately describes V (A)/Q mismatch and can be useful in clinical or experimental situations where other techniques are not feasible.

Acute effects of head-down tilt and hypoxia on modulators of fluid homeostasis

In an effort to understand the interaction between acute postural fluid shifts and hypoxia on hormonal regulation of fluid homeostasis, the authors measured the responses to head‐down tilt with and without acute exposure to normobaric hypoxia. Plasma atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP), plasma aldosterone (ALD), and plasma renin activity (PRA) were measured in six healthy male volunteers who were exposed to a head‐down tilt protocol during normoxia and hypoxia. The tilt protocol consisted of a 17° head‐up phase (30 minutes), a 28° head‐down phase (1 hour), and a 17° head‐up recovery period (2 hours, with the last hour normoxic in both experiments). Altitude equivalent to 14,828 ft was simulated by having the subjects breathe an inspired gas mixture with 13.9% oxygen. The results indicate that the postural fluid redistribution associated with a 60‐minute head‐down tilt induces the release of ANP and cGMP during both hypoxia and normoxia. Hypoxia increased cGMP, cAMP, ALD, and PRA throughout the protocol and significantly potentiated the increase in cGMP during head‐down tilt. Hypoxia had no overall effect on the release of ANP, but appeared to attenuate the increase with head‐down tilt. This study describes the acute effects of hypoxia on the endocrine response during fluid redistribution and suggests that the magnitude, but not the direction, of these changes with posture is affected by hypoxia.

Glucose deprivation promotes activation of mTOR signaling pathway and protein synthesis in rat skeletal muscle cells

Signaling through mammalian target of rapamycin (mTOR) has been shown to play a central role in the regulation of skeletal muscle growth induced by a wide range of stimuli either mechanical or metabolic, such as growth factors and amino acids. Here, we demonstrate that mTOR and its downstream target, the ribosomal S6 kinase (p70S6K), are activated in L6 myocytes by a short-term glucose deprivation. Such response is specific of skeletal muscle and is likely responsible for the increased rate of protein synthesis and expression of the muscle-specific proteins during recovery from glucose deprivation. Nitric oxide and phosphatidylinositol-3-kinase (PI3K) are upstream positive regulators of mTOR since their pharmacological inhibition prevents the activation of p70S6K in response to glucose deprivation. We therefore propose a model of response to a brief period of glucose deprivation that may occur in skeletal muscle cells during resistance exercise and that may lead to protein accretion when blood flow recovers and all nutrients are again available.

CL316,243, a β3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength

Studies in vitro have demonstrated that β3-adrenergic receptors (β3-ARs) regulate protein metabolism in skeletal muscle by promoting protein synthesis and inhibiting protein degradation. In this study, we evaluated whether activation of β3-ARs by the selective agonist CL316,243 modifies the functional and structural properties of skeletal muscles of healthy mice. Daily injections of CL316,243 for 15 days resulted in a significant improvement in muscle force production, assessed by grip strength and weight tests, and an increased myofiber cross-sectional area, indicative of muscle hypertrophy. In addition, atomic force microscopy revealed a significant effect of CL316,243 on the transversal stiffness of isolated muscle fibers. Interestingly, the expression level of mammalian target of rapamycin (mTOR) downstream targets and neuronal nitric oxide synthase (NOS) was also found to be enhanced in tibialis anterior and soleus muscles of CL316,243 treated mice, in accordance with previous data linking β3-ARs to mTOR and NOS signaling pathways. In conclusion, our data suggest that CL316,243 systemic administration might be a novel therapeutic strategy worthy of further investigations in conditions of muscle wasting and weakness associated with aging and muscular diseases.

Effects of gas density on experimentally obstructed ventilation during acute hypoxia.

When patients with obstructive lung disease breathe helium-oxygen mixtures, their arterial PCO2, is lowered towards normal, indicating more effective ventilation. However, there is a lack of detailed respiratory data from clinical cases, so that the mechanisms remain unclear. To study relevant variables during hypoxemia and obstruction in the absence of disease, we undertook experiments with healthy subjects breathing normoxic and hypoxic gas mixtures of differing densities (air, 13.7% O2 in N2 and 13.7% O2 in helium) through an experimental obstruction (resistive airway loading). This increased airway resistance was twice that reported from the ambient-pleural pressure differences in patients with moderately severe emphysema. Without imposed resistance the total ventilation (VE) increased 27% on both hypoxic mixtures. With normoxia, the obstruction increased tidal volume but decreased frequency so that VE and alveolar ventilation (VA) were essentially unchanged. With hypoxia, breathing pattern changed similarly, but now VE decreased while VA was maintained. Helium returned the breathing patterns toward normal. Obstruction lowered the rapid increase in VE from two or three breaths of N2, but the decrease from two or three breaths of O2 was unchanged. We detected an increase in metabolic rate with obstructed breathing that was reduced by the helium mixtures. The remarkable finding was that despite the obstruction being markedly uncomfortable because of the high resistance, we did not find any substantial disturbance in gas exchange, compared to hypoxia with no obstruction. Thus, the main mechanisms responsible for improved blood gases in patients breathing helium mixtures were outside the scope of our experiment and likely related to disease factors.