Pulmonary O2 uptake and leg blood flow kinetics during moderate exercise are slowed by hyperventilation-induced hypocapnic alkalosis

The effect of hyperventilation-induced hypocapnic alkalosis (Hypo) on the adjustment of pulmonary O2 uptake (V̇o2p) and leg femoral conduit artery (“bulk”) blood flow (LBF) during moderate-intensity exercise (Mod) was examined in eight young male adults. Subjects completed four to six repetitions of alternate-leg knee-extension exercise during normal breathing [Con; end-tidal partial pressure of CO2 (PetCO2) ∼40 mmHg] and sustained hyperventilation (Hypo; PetCO2 ∼20 mmHg). Increases in work rate were made instantaneously from baseline (3 W) to Mod (80% estimated lactate threshold). V̇o2p was measured breath by breath by mass spectrometry and volume turbine, and LBF (calculated from mean femoral artery blood velocity and femoral artery diameter) was measured simultaneously by Doppler ultrasound. Concentration changes of deoxy (Δ[HHb])-, oxy (Δ[O2Hb])-, and total hemoglobin-myoglobin (Δ[HbTot]) of the vastus lateralis muscle were measured continuously by near-infrared spectroscopy (NIRS). The kinetics of V̇o2p, LBF, and Δ[HHb] were modeled using a monoexponential equation by nonlinear regression. The time constants for the phase 2 V̇o2p (Hypo, 49 ± 26 s; Con, 28 ± 8 s) and LBF (Hypo, 46 ± 16 s; Con, 23 ± 6 s) were greater ( P < 0.05) in Hypo compared with Con. However, the mean response time for the overall Δ[HHb] response was not different between conditions (Hypo, 23 ± 5 s; Con, 24 ± 3 s), whereas the Δ[HHb] amplitude was greater ( P < 0.05) in Hypo (8.05 ± 7.47 a.u.) compared with Con (6.69 ± 6.31 a.u.). Combined, these results suggest that hyperventilation-induced hypocapnic alkalosis is associated with slower convective (i.e., slowed femoral artery and microvascular blood flow) and diffusive (i.e., greater fractional O2 extraction for a given ΔV̇o2p) O2 delivery, which may contribute to the hyperventilation-induced slowing of V̇o2p (and muscle O2 utilization) kinetics.

GFP-expressing locus ceruleus neurons from Prp57 transgenic mice exhibit CO2/H+ responses in primary cell culture

The locus ceruleus (LC) contains neurons that increase their firing rate (FR) in vitro when exposed to elevated CO2/H+ and have been proposed to influence the respiratory network to make compensatory adjustments in ventilation. Prp57 transgenic mice express green fluorescent protein (GFP) in the LC and were used to isolate, culture, and target LC neurons for electrophysiological recording. We hypothesized that GFP-LC neurons would exhibit CO2/H+ chemosensitivity under primary culture conditions, evidenced as a change in FR. This is the first study to quantify CO2/H+ responses in LC neuron FR in cell culture. Neurons were continuously bathed with solutions containing antagonists of glutamate and GABA receptors, and the acid-base status was changed from control (5% CO2; pH ∼7.4) to hypercapnic acidosis (9% CO2; pH ∼7.2) and hypocapnic alkalosis (3% CO2; pH ∼7.6). FR was quantified during perforated patch current clamp recordings. Approximately 86% of GFP-LC neurons were stimulated, and ∼14% were insensitive to changes in CO2/H+. The magnitude of the response of these neurons depended on the baseline FR, ranging from 155.9 ± 6% when FR started at 2.95 ± 0.49 Hz to 381 ± 55.6% when FR started at 1.32 ± 0.31 Hz. These results demonstrate that cultured LC neurons from Prp57 transgenic mice retain functional sensing molecules necessary for CO2/H+ responses. Prp57 transgenic mice will serve as a valuable model to delineate mechanisms involved in CO2/H+ responsiveness in catecholaminergic neurons.

The role of hyperventilation: hypocapnia in the pathomechanism of panic disorder

OBJECTIVE: The authors present a profile of panic disorder based on and generalized from the effects of acute and chronic hyperventilation that are characteristic of the respiratory panic disorder subtype. The review presented attempts to integrate three premises: hyperventilation is a physiological response to hypercapnia; hyperventilation can induce panic attacks; chronic hyperventilation is a protective mechanism against panic attacks. METHOD: A selective review of the literature was made using the Medline database. Reports of the interrelationships among panic disorder, hyperventilation, acidosis, and alkalosis, as well as catecholamine release and sensitivity, were selected. The findings were structured into an integrated model. DISCUSSION: The panic attacks experienced by individuals with panic disorder develop on the basis of metabolic acidosis, which is a compensatory response to chronic hyperventilation. The attacks are triggered by a sudden increase in (pCO2) when the latent (metabolic) acidosis manifests as hypercapnic acidosis. The acidotic condition induces catecholamine release. Sympathicotonia cannot arise during the hypercapnic phase, since low pH decreases catecholamine sensitivity. Catecholamines can provoke panic when hyperventilation causes the hypercapnia to switch to hypocapnic alkalosis (overcompensation) and catecholamine sensitivity begins to increase. CONCLUSION: Therapeutic approaches should address long-term regulation of the respiratory pattern and elimination of metabolic acidosis.

Effects of hypercapnia and hypocapnia on [Ca2+]i mobilization in human pulmonary artery endothelial cells

The hydrogen ion is an important factor in the alteration of vascular tone in pulmonary circulation. Endothelial cells modulate vascular tone by producing vasoactive substances such as prostacyclin (PGI2) through a process depending on intracellular Ca2+ concentration ([Ca2+]i). We studied the influence of CO2-related pH changes on [Ca2+]iand PGI2 production in human pulmonary artery endothelial cells (HPAECs). Hypercapnic acidosis appreciably increased [Ca2+]i from 112 ± 24 to 157 ± 38 nmol/l. Intracellular acidification at a normal extracellular pH increased [Ca2+]i comparable to that observed during hypercapnic acidosis. The hypercapnia-induced increase in [Ca2+]i was unchanged by the removal of Ca2+ from the extracellular medium or by the depletion of thapsigargin-sensitive intracellular Ca2+ stores. Hypercapnic acidosis may thus release Ca2+ from pH-sensitive but thapsigargin-insensitive intracellular Ca2+ stores. Hypocapnic alkalosis caused a fivefold increase in [Ca2+]i compared with hypercapnic acidosis. Intracellular alkalinization at a normal extracellular pH did not affect [Ca2+]i. The hypocapnia-evoked increase in [Ca2+]i was decreased from 242 ± 56 to 50 ± 32 nmol/l by the removal of extracellular Ca2+. The main mechanism affecting the hypocapnia-dependent [Ca2+]i increase was thought to be the augmented influx of extracellular Ca2+ mediated by extracellular alkalosis. Hypercapnic acidosis caused little change in PGI2 production, but hypocapnic alkalosis increased it markedly. In conclusion, both hypercapnic acidosis and hypocapnic alkalosis increase [Ca2+]i in HPAECs, but the mechanisms and pathophysiological significance of these increases may differ qualitatively.

Mediators of alkalosis-induced relaxation of piglet pulmonary veins

Pulmonary venous constriction leads to significant pulmonary hypertension and increased edema formation in several models using newborns. Although alkalosis is widely used in treating neonatal and pediatric pulmonary hypertension, its effects on pulmonary venous tone have not previously been directly measured. This study sought to determine whether alkalosis caused pulmonary venous relaxation and, if so, to identify the mediator(s) involved. Pulmonary venous rings (500-μm external diameter) were isolated from 1-wk-old piglets and precontracted with the thromboxane mimetic U-46619. Responses to hypocapnic alkalosis were then measured under control conditions after inhibition of endothelium-derived modulator activity or K+ channels. In control rings, alkalosis caused a 34.4 ± 4.8% decrease in the U-46619-induced contraction. This relaxation was significantly blunted in rings without functional endothelium and in rings treated with nitric oxide synthase or guanylate cyclase inhibitors. However, neither cyclooxygenase inhibition nor voltage-dependent, calcium-dependent, or ATP-dependent K+-channel inhibitors altered alkalosis-induced relaxation. These data suggest that alkalosis caused significant dilation of piglet pulmonary veins that was mediated by the nitric oxide-cGMP pathway.