Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans

Abstract

An important determinant of [H(+)] in the environment of the central chemoreceptors is cerebral blood flow. Accordingly we hypothesized that a reduction of brain perfusion or a reduced cerebrovascular reactivity to CO(2) would lead to hyperventilation and an increased ventilatory responsiveness to CO(2). We used oral indomethacin to reduce the cerebrovascular reactivity to CO(2) and tested the steady-state hypercapnic ventilatory response to CO(2) in nine normal awake human subjects under normoxia and hyperoxia (50% O(2)). Ninety minutes after indomethacin ingestion, cerebral blood flow velocity (CBFV) in the middle cerebral artery decreased to 77 +/- 5% of the initial value and the average slope of CBFV response to hypercapnia was reduced to 31% of control in normoxia (1.92 versus 0.59 cm(-1) s(-1) mmHg(-1), P < 0.05) and 37% of control in hyperoxia (1.58 versus 0.59 cm(-1) s(-1) mmHg(-1), P < 0.05). Concomitantly, indomethacin administration also caused 40-60% increases in the slope of the mean ventilatory response to CO(2) in both normoxia (1.27 +/- 0.31 versus 1.76 +/- 0.37 l min(-1) mmHg(-1), P < 0.05) and hyperoxia (1.08 +/- 0.22 versus 1.79 +/- 0.37 l min(-1) mmHg(-1), P < 0.05). These correlative findings are consistent with the conclusion that cerebrovascular responsiveness to CO(2) is an important determinant of eupnoeic ventilation and of hypercapnic ventilatory responsiveness in humans, primarily via its effects at the level of the central chemoreceptors.

Figures

Figure 1. Time course of resting CBFV of MCA, heart rate and mean blood pressure

A 100 mg oral dose of indomethacin (•) or sham study (○) at time 0. Cerebral flow velocity was represented as the percentage of the baseline value. Between the first 90 min and the last 35 min, the HCVR interventions were performed. +P < 0.05 compared to baseline; *P < 0.05 compared to sham value at the same time point.

Figure 2. Effect of indomethacin on the CBFV responses to PET,CO2 during normoxia (left panel) and hyperoxia (right panel)

The upper panel shows individual slopes. The low panel shows group data. Under both normoxic and hypercapnic conditions, indomethacin (•) attenuated the CBFV response compared to the sham study (□). There was no difference in the slopes between normoxia and hyperoxia either with or without indomethacin. *P < 0.05 compared to sham.

Figure 3. Effect of indomethacin on the ventilatory response to CO2

A, individual slopes; B, group data. Indomethacin (•) increased VE/PET,CO2 compared to the sham study (□). There was no difference between normoxia and hyperoxia in terms of VE/PET,CO2. *P < 0.05 compared to sham.

Figure 4. CBFV response to a reduction in PET,CO2 during the transition from hypercapnia to room air

CBFV response to a reduction in PET,CO2 (from 55.6 ± 1.0 to 41.5 ± 1.0 mmHg in the control trials; 54.6 ± 0.5 to 37.6 ± 0.9 mmHg in the indo trials) during the transition from hypercapnia to room air (n = 8). One subject's data are missing because he lost his CBFV signal immediately after the end of 6% CO2 inhalation. The other eight subjects consistently showed a reduction in CBFV response to CO2 withdrawal by indomethacin administration compared to the sham study.

Figure 5. Ventilatory response to PET,CO2 (□ control; ○ indo) and to jugular venous PCO2 (▪ control; • indo)

Jugular venous PCO2 was estimated using the formula PJV,CO2 = PET,CO2 + 10.6 − (y − 100) × 0.07, which was derived from the work of Fencl (1969, . The slope of the ΔVE/ΔPET,CO2 response was increased significantly via indomethacin (also see Fig. 2); however, the slope of the ΔVE/ΔPJV,CO2 was unchanged via indomethacin (P = 0.26).