Dynamic response of the peripheral chemoreflex loop to changes in end-tidal O2.

We studied the peripheral ventilatory response dynamics to changes in end-tidal O2 tension (PETO2) in 13 cats anesthetized with alpha-chloralose-urethan. The arterial O2 tension in the medulla oblongata was kept constant using the technique of artificial perfusion of the brain stem. At constant end-tidal CO2 tension, 72 ventilatory on-responses due to stepwise changes in PETO2 from hyperoxia (45-55 kPa) to hypoxia (4.7-9.0 kPa) and 62 ventilatory off-responses due to changes from hypoxia to hyperoxia were assessed. We fitted two exponential functions with the same time delay to the breath-by-breath ventilation and found a fast and a slow component in 85% of the ventilatory on-responses and in 76% of the off-responses. The time constant of the fast component of the ventilatory on-response was 1.6 +/- 1.5 (SD) s, and that of the off-response was 2.4 +/- 1.3 s; the gain of the on-response was smaller than that of the off-response (P = 0.020). For the slow component, the time constant of the on-response (72.6 +/- 36.4 s) was larger (P = 0.028) than that of the off-response (43.7 +/- 28.3 s), whereas the gain of the on-response exceeded that of the off-response (P = 0.031). We conclude that the ventilatory response of the peripheral chemoreflex loop to stepwise changes in PETO2 contains a fast and a slow component.     

Dynamics of the ventilatory response to central hypoxia in cats

The dynamics of the effect of central hypoxia on ventilation were investigated by the technique of artificial perfusion of the brain stem in alpha-chloralose-urethan-anesthetized cats. A two-channel roller pump and a four-way valve allowed switching the gas exchanger into and out of the extracorporeal circuit which controlled the brain stem perfusion. When isocapnic hypoxia (arterial PO2 range 18-59 Torr) was limited to the brain stem, a decline in ventilation was consistently found. In 12 cats 47 steps into and 48 steps out of central hypoxia were made. The ventilatory response was fitted using least squares with a model that consisted of a latency followed by a single-exponential function. The latencies for the steps into and out of hypoxia were not significantly different (P = 0.14) and were 32.3 +/- 4.0 and 25.1 +/- 3.6 (SE) s, respectively. The time constant for the steps into hypoxia (149.7 +/- 8.5 s) was significantly longer (P = 0.0002) than for the steps out of hypoxia (105.5 +/- 10.1 s). The time constants for the increase and decrease in ventilation after step changes in the central arterial PCO2 found in a previous study (J. Appl. Physiol. 66: 2168-2172, 1989) were not significantly different (P greater than 0.2) from the corresponding time constants in this study (for 7 cats common to both studies). Theories of the mechanisms behind hypoxic ventilatory decline need to account for the long latency, the similarity between the time constants for the ventilatory response to O2 and CO2, and the differences between the time constants for increasing and decreasing ventilation.     

Effect of Nomega -nitro-L-arginine on ventilatory response to hypercapnia in anesthetized cats

Teppema, Luc, Aad Berkenbosch, and Cees Olievier Effectof N-nitro-L-arginine onventilatory response to hypercapnia in anesthetized cats.J. Appl. Physiol. 82(1): 292-297, 1997.The effect of intravenous administration of 40 mg/kgN-nitro-L-arginine(L-NNA), an inhibitor of thesynthesis of nitric oxide (NO), on the ventilatory response toCO₂ was studied in anesthetizedcats. The ventilatory response toCO₂ was assessed during normoxiaby applying square-wave changes in end-tidalPCO₂ of ~1 kPa. EachCO₂ response was separated into afast peripheral and slow central component characterized by aCO₂ sensitivity (S_pand S_c, respectively), time constant, time delay, and anoffset (apneic threshold). L-NNAreduced S_p,S_c, and the apneic threshold significantly by ~30%. However, the ratioS_p/S_cwas not changed. It is argued that the reduction inS_p andS_c,S_p/S_cremaining constant, may be due to a potent inhibitory action ofL-NNA on the brain stemrespiratory-integrating centers and on the neuromechanical link betweenthese centers and respiratory movements. It is concluded that NO playsan important role in the control of breathing.

     

Dynamics of ventilatory response to step changes in PCO2 of blood perfusing the brain stem

The technique of artificial brain stem perfusion was used to assess the ventilatory response to step changes in PCO2 of the blood perfusing the brain stem of the cat. A two-channel roller pump and a four-way valve allow switching the gas exchanger into and out of the extracorporeal circuit, which controlled the perfusion to the brain stem. Seven alpha-chloralose-urethan-anesthetized cats were studied, and 25 steps of increasing and 23 steps of decreasing PCO2 were analyzed. A model consisting of a single-exponential function with time delay best described the ventilatory response. The time delays 11.7 +/- 8.1 and 6.4 +/- 6.8 (SD) s (obtained from mean values per cat) for the step into and out of hypercapnia, respectively, were not significantly different (P = 0.10) and were of the order of the transit time of the tubing from valve to brain stem. The steady-state CO2 sensitivities obtained from the on- and off-responses were also not significantly different (P = 0.10). The time constants 87 +/- 25 and 150 +/- 51 s, respectively, were significantly different (P = 0.0002). We conclude that the central chemoreflex is adequately modeled by a single component with a different time constant for on- and off-responses.     

Comparison of chemoreflex gains obtained with two different methods in cats

This study investigates the correspondence between results of the ventilatory response to CO2 obtained using the technique of dynamic end-tidal CO2 forcing (DEF) and results obtained using the technique of artificial brain stem perfusion (ABP). The DEF technique separates the dynamic ventilatory response into a slow and fast component with gains g1 and g2 as well as the extrapolated CO2 tension at zero ventilation (Bk). The ABP technique results in steady-state central (Sc) and peripheral (Sp) chemoreflex gains and extrapolated CO2 tension at zero ventilation (B). Experiments were performed on 14 alpha-chloralose-urethan anesthetized cats. A wide range of relative peripheral chemosensitivities was obtained by subjecting eight cats to normoxic and three cats to hypoxic CO2 challenges and three cats to both conditions. Statistical analysis of the experimental data showed that the vectors (g1, g2, Bk) and (Sc, Sp, B) for each cat did not differ significantly (P = 0.56). This was also the case for the vectors [g2/(g1 + g2), Bk] and [Sp/(Sc + Sp), B] (P = 0.21). We conclude that in the DEF experiments the slow ventilatory response to isoxic changes in end-tidal CO2 can be equated with the central chemoreflex loop and the faster ventilatory response to the peripheral chemoreflex loop. The agreement between the two techniques is good.     

Almitrine bismesylate and the central and peripheral ventilatory response to CO2

Effects of almitrine bismesylate on the peripheral and central chemoreflex to a CO2 challenge during normoxia were studied in nine alpha-chloralose-urethan anesthetized cats. With the dynamic end-tidal CO2 forcing technique the ventilatory response after a square-wave change in end-tidal PCO2 (PETCO2) was partitioned into a central and a peripheral part using a two-compartment model. With almitrine administered intravenously (0.6 mg/kg followed by a maintenance dose of 0.4 mg.kg-1 X h-1) the CO2 sensitivity of the peripheral chemoreflex increased on the average from 0.315 to 0.564 l.min-1 X kPa-1 (P less than 0.001, 6 cats, 73 runs), whereas the CO2 sensitivity of the central chemoreflex remained the same (P = 0.87). The extrapolated PETCO2 at zero ventilation (apneic threshold) of the (total) steady-state response curve decreased on the average from 3.50 to 2.36 kPa (P less than 0.001). With the artificial brain stem perfusion technique it was confirmed that almitrine did not affect ventilation by administering it to the blood perfusing the brain stem. We conclude that almitrine bismesylate during normoxia enhances the CO2 sensitivity of the peripheral chemoreflex loop and decreases the apneic threshold due to an action located outside the brain stem.     

Involvement of Endoplasmic Reticulum Stress in Inflammatory Bowel Disease: A Different Implication for Colonic and Ileal Disease?

Background

Endoplasmic reticulum (ER) stress has been suggested to play a role in inflammatory bowel disease (IBD). The three branches (ATF6, IRE1 and PERK) of the unfolded protein response (UPR) have different roles and are not necessarily activated simultaneously.

Methodology/Principal Findings

Expression of UPR-related genes was investigated in colonic and ileal biopsies of 23 controls, 15 ulcerative colitis (UC) and 54 Crohn''s disease (CD) patients. This expression was confirmed at protein level in colonic and ileal samples of five controls, UC and CD patients. HSPA5, PDIA4 and XBP1s were significantly increased in colonic IBD at mRNA and/or protein levels, indicating activation of the ATF6 and IRE1 branch. Colonic IBD was associated with increased phosphorylation of EIF2A suggesting the activation of the PERK branch, but subsequent induction of GADD34 was not observed. In ileal CD, no differential expression of the UPR-related genes was observed, but our data suggested a higher basal activation of the UPR in the ileal mucosa of controls. This was confirmed by the increased expression of 16 UPR-related genes as 12 of them were significantly more expressed in ileal controls compared to colonic controls. Tunicamycin stimulation of colonic and ileal samples of healthy individuals revealed that although the ileal mucosa is exhibiting this higher basal UPR activation, it is still responsive to ER stress, even more than colonic mucosa.

Conclusions/Significance

Activation of the three UPR-related arms is seen in colonic IBD-associated inflammation. However, despite EIF2A activation, inflamed colonic tissue did not increase GADD34 expression, which is usually involved in re-establishment of ER homeostasis. This study also implies the presence of a constitutive UPR activation in healthy ileal mucosa, with no further activation during inflammation. Therefore, engagement of the UPR differs between colon and ileum and this could be a factor in the development of ileal or colonic disease.