Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO(2)

Abstract

We assessed the contribution of carotid body chemoreceptors to the ventilatory response to specific CNS hypercapnia in eight unanaesthetized, awake dogs. We denervated one carotid body (CB) and used extracorporeal blood perfusion of the reversibly isolated remaining CB to maintain normal CB blood gases (normoxic, normocapnic perfusate), to inhibit (hyperoxic, hypocapnic perfusate) or to stimulate (hypoxic, normocapnic perfusate) the CB chemoreflex, while the systemic circulation, and therefore the CNS and central chemoreceptors, were exposed consecutively to four progressive levels of systemic arterial hypercapnia via increased fractional inspired CO(2) for 7 min at each level. Neither unilateral CB denervation nor CB perfusion, per se, affected breathing. Relative to CB control conditions (normoxic, normocapnic perfusion), we found that CB chemoreflex inhibition decreased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 19% of control values (range 0-38%; n = 6), whereas CB chemoreflex stimulation increased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 223% of control values (range 204-235%; n = 4). We conclude that the gain of the CNS CO(2)/H(+) chemoreceptors in dogs is critically dependent on CB afferent activity and that CNS-CB interaction results in hyperadditive ventilatory responses to central hypercapnia.

Figure 1. Schematic diagram showing the essential features of the isolated carotid body perfusion technique in the unanaesthetized dog (not to scale)

The aortic arch is just visible at the bottom of the diagram. The left carotid body is denervated, but blood supply to the CNS is left intact. On the right side the carotid body is left intact, but all branch arteries in the carotid sinus region are ligated except the lingual. Vascular casts of the carotid sinus region with these ligations (or occlusions in the case of the lingual artery) showed that the carotid sinus region was isolated (Smith et al. 1995). A perfusion catheter is placed in the (ligated) external carotid with its tip placed just caudal to the carotid sinus. Ligations are made distal to any vessels supplying the carotid body. An occluder is placed around the lingual artery such that it can be inflated to isolate the region during perfusion; between perfusions the occluder is deflated, allowing flow through the region to maintain patency. Thus, during perfusion, flow through the isolated carotid sinus region is retrograde at a pressure slightly (∼10 mmHg) higher than systemic; the flow rate is <100 ml min⁻¹ (usually 40–60 ml min⁻¹), and excess perfused blood enters and mixes with the systemic circulation at the brachiocephalic artery, where we measured the flow rate as approximately 500 ml min⁻¹ (see Methods). Some of this admixture may reach the CNS via the right vertebral artery (see ‘Limitations of our preparation’ in Discussion for details). Abbreviations: BA, brachiocephalic artery; CB, carotid body; CBX, carotid body denervation; CCA, common carotid artery; and VA, vertebral artery. (This figure is a modification of a figure published by Smith et al. (1995).)

Figure 2. Polygraph records of the effect of CB inhibition and stimulation on eupnoeic air-breathing ventilation and the ventilatory response to central hypercapnia

Representative segments of polygraph records of trials of control (normal endogenous CB perfusion) and extracorporeal CB perfusion with normal (A and C), inhibitory (B) and stimulatory perfusate blood gases (D) at the isolated CB. A and B are from dog no. 3; C and D from dog no. 8. Dogs breathed air (segments 1 and 2) followed by step increases in inspired (and therefore arterial) (segments 3–6). Each segment represents 1 min of recorded data. Abbreviations: EMG_di, moving-time-averaged electromyogram of the costal diaphragm; , arterial ; , end-tidal ; and V_T, tidal volume.

Figure 5. Mean ventilatory responses to specific central hypercapnia with a background of normal, inhibitory and stimulatory CB perfusion

Mean values of the minute ventilation (A), tidal volume (B), breathing frequency (C) and mean electrical activity of the costal diaphragm electromyogram (D) response slopes to step increases in arterial (and therefore central) with a background of extracorporeal carotid body (CB) perfusion with normal (n= 8), inhibitory (n= 6) and stimulatory (n= 4) blood gases. All eight animals are represented in the normal CB central CO₂ response mean line. Given the differing number of animals in each group, the mean percentage change in slope relative to CB normal was calculated using only the data for the animals that were represented in the CB inhibition (n= 6) or CB stimulation (n= 4) groups. See main text for details.

Figure 4. Individual animal ventilatory responses to central hypercapnia with a background of normal (filled squares), inhibitory (open squares) and stimulatory (shaded triangles) CB perfusion

Response slopes of minute ventilation, breathing frequency, tidal volume and EMG_di to steady-state increases in arterial with a background of extracorporeal CB perfusion with normal, inhibitory and stimulatory perfusate blood gases are shown for each animal in Table 2.

Figure 3. A representative example (dog no. 1) of the ventilatory response to central hypercapnia with a background of normal, inhibitory and stimulatory CB perfusion

Minute ventilation (A), tidal volume (B), breathing frequency (C) and mean electrical activity of the costal diaphragm electromyogram (D) response slopes to step increases in arterial (and therefore central) with a background of extracorporeal carotid body (CB) perfusion with normal (filled squares), inhibitory (open squares) and stimulatory perfusate blood gases (shaded triangles).