Evidence from high-altitude acclimatization for an integrated cerebrovascular and ventilatory hypercapnic response but different responses to hypoxia

Ventilation and cerebral blood flow (CBF) are both sensitive to hypoxia and hypercapnia. To compare chemosensitivity in these two systems, we made simultaneous measurements of ventilatory and cerebrovascular responses to hypoxia and hypercapnia in 35 normal human subjects before and after acclimatization to hypoxia. Ventilation and CBF were measured during stepwise changes in isocapnic hypoxia and iso-oxic hypercapnia. We used MRI to quantify actual cerebral perfusion. Measurements were repeated after 2 days of acclimatization to hypoxia at 3,800 m altitude (partial pressure of inspired O2 = 90 Torr) to compare plasticity in the chemosensitivity of these two systems. Potential effects of hypoxic and hypercapnic responses on acute mountain sickness (AMS) were assessed also. The pattern of CBF and ventilatory responses to hypercapnia were almost identical. CO2 responses were augmented to a similar degree in both systems by concomitant acute hypoxia or acclimatization to sustained hypoxia. Conversely, the pattern of CBF and ventilatory responses to hypoxia were markedly different. Ventilation showed the well-known increase with acute hypoxia and a progressive decline in absolute value over 25 min of sustained hypoxia. With acclimatization to hypoxia for 2 days, the absolute values of ventilation and O2 sensitivity increased. By contrast, O2 sensitivity of CBF or its absolute value did not change during sustained hypoxia for up to 2 days. The results suggest a common or integrated control mechanism for CBF and ventilation by CO2 but different mechanisms of O2 sensitivity and plasticity between the systems. Ventilatory and cerebrovascular responses were the same for all subjects irrespective of AMS symptoms. NEW & NOTEWORTHY Ventilatory and cerebrovascular hypercapnic response patterns show similar plasticity in CO2 sensitivity following hypoxic acclimatization, suggesting an integrated control mechanism. Conversely, ventilatory and cerebrovascular hypoxic responses differ. Ventilation initially increases but adapts with prolonged hypoxia (hypoxic ventilatory decline), and ventilatory sensitivity increases following acclimatization. In contrast, cerebral blood flow hypoxic sensitivity remains constant over a range of hypoxic stimuli, with no cerebrovascular acclimatization to sustained hypoxia, suggesting different mechanisms for O2 sensitivity in the two systems.

Volatile Anaesthetic Depression of the Carotid Body Chemoreflex-Mediated Ventilatory Response to Hypoxia: Directions for Future Research

In assessing whether volatile anaesthetics directly depress the carotid body response to hypoxia it is necessary to combine in meta-analysis studies of when it is “functionally isolated” (e.g., recordings are made from its afferent nerve). Key articles were retrieved (full papers in English) and subjected to quantitative analysis to yield an aggregate estimate of effect. Results from articles that did not use such methodology were assessed separately from this quantitative approach, to see what could be learned also from a nonquantitative overview. Just 7 articles met the inclusion criteria for hypoxia and just 6 articles for hypercapnia. Within these articles, the anaesthetic (mean dose 0.75, standard deviation (SD) 0.40 minimum alveolar concentration, MAC) statistically significantly depressed carotid body hypoxic response by 24% (P=0.041), but a similar dose (mean 0.81 (0.42) MAC) did not affect the hypercapnic response. The articles not included in the quantitative analysis (31 articles), assessed qualitatively, also indicated that anaesthetics depress carotid body function. This conclusion helps direct future research on the anaesthetic effects on putative cellular/molecular processes that underlie the transduction of hypoxia in the carotid body.

Breath-to-breath hypercapnic response in neonatal rats: temperature dependency of the chemoreflexes and potential implications for breathing stability

The breathing of newborns is destabilized by warm temperatures. We hypothesized that in unanesthetized, intact newborn rats, body temperature (TB) influences the peripheral chemoreflex response (PCR response) to hypercapnia. To test this, we delivered square-wave challenges of 8% CO2 in air to postnatal day 4–5 (P4–P5) rats held at a TB of 30°C (Cold group, n = 11), 33°C (Cool group, n = 10), and 35°C thermoneutral zone group [thermoneutral zone (TNZ) group, n = 11], while measuring ventilation (V̇e) directly with a pneumotach and mask. Cool animals were challenged with 8% CO2 balanced in either air or hyperoxia ( n = 10) to identify the PCR response. Breath-to-breath analysis was performed on 30 room air breaths and every breath of the 1-min CO2 challenge. As expected, warmer TB was associated with an unstable breathing pattern in room air: TNZ animals had a coefficient of variation in V̇e (V̇e CV%) that was double that of animals held at cooler TB ( P < 0.001). Hyperoxia markedly suppressed the hypercapnic ventilatory response over the first 10 breaths (or ∼4 s), suggesting that this domain is dominated by the PCR response. The PCR response ( P = 0.03) and total response ( P = 0.04) were significantly greater in TNZ animals compared with hypothermic animals. The total response had a significant, negative relationship with V̇co2 ( R2 = 0.53; P < 0.001). Breathing stability was positively related to the total response ( R2 = 0.36; P < 0.001) and to a lesser extent, the PCR response ( R2 = 0.19; P = 0.01) and was negatively related to V̇co2 ( R2 = 0.34; P < 0.001). ANCOVA confirmed a significant effect of TB alone on breathing stability ( P < 0.01), with no independent effects of V̇co2 ( P = 0.41), the PCR response ( P = 0.82), or the total V̇e response ( P = 0.08). Our data suggest that in early postnatal life, the chemoreflex responses to CO2 are highly influenced by TB, and while related to breathing stability, are not predictors of stability after accounting for the independent effect of TB.

Cerebral Haemodynamic Response or Excitability is not Affected by Sildenafil

Sildenafil (Viagra®), a cyclic guanosine monophosphate-degrading phosphodiesterase 5 inhibitor, induces headache and migraine. Such headache induction may be caused by an increased neuronal excitability, as no concurrent effect on cerebral arteries is found. In 13 healthy females (23±3 years, 70.3±6.6 kg), the effect of sildenafil on a visual (reversing checkerboard) and a hypercapnic (6% CO2 inhalation) response was evaluated using functional magnetic resonance imaging (fMRI, 3 T MR scanner). On separate occasions, visual-evoked potential (VEP) measurements (latency (P100) and maximal amplitude) were performed. The measurements were applied at baseline and at both 1 and 2 h after ingestion of 100mg of sildenafil. Blood pressure, heart rate and side effects, including headache, were obtained. Headache was induced in all but one subject on both study days. Sildenafil did not affect VEP amplitude or latency (P100). The fMRI response to visual stimulation or hypercapnia was unchanged by sildenafil. In conclusion, sildenafil induces mild headache without potentiating a neuronal or local cerebrovascular visual response or a global cerebrovascular hypercapnic response. The implication is that sildenafil-induced headache does not include a general lowering of threshold for a neuronal or cerebrovascular response, and that sildenafil does not modulate the hypercapnic response in healthy subjects.