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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.

We determined the effects of changing ventilatory stimuli on the hypocapnia-induced apneic and hypopneic thresholds in sleeping dogs. End-tidal carbon dioxide pressure (PET(CO2)) was gradually reduced during non-rapid eye movement sleep by increasing tidal volume with pressure support mechanical ventilation, causing a reduction in diaphragm electromyogram amplitude until apnea/periodic breathing occurred. We used the reduction in PET(CO2) below spontaneous breathing required to produce apnea (DeltaPET(CO2)) as an index of the susceptibility to apnea. DeltaPET(CO2) was -5 mm Hg in control animals and changed in proportion to background ventilatory drive, increasing with metabolic acidosis (-6.7 mm Hg) and nonhypoxic peripheral chemoreceptor stimulation (almitrine; -5.9 mm Hg) and decreasing with metabolic alkalosis (-3.7 mm Hg). Hypoxia was the exception; DeltaPET(CO2) narrowed (-4.1 mm Hg) despite the accompanying hyperventilation. Thus, hyperventilation and hypocapnia, per se, widened the DeltaPET(CO2) thereby protecting against apnea and hypopnea, whereas reduced ventilatory drive and hypoventilation narrowed the DeltaPET(CO2) and increased the susceptibility to apnea. Hypoxia sensitized the ventilatory responsiveness to CO2 below eupnea and narrowed the DeltaPET(CO2); this effect of hypoxia was not attributable to an imbalance between peripheral and central chemoreceptor stimulation, per se. We conclude that the DeltaPET(CO2) and the ventilatory sensitivity to CO2 between eupnea and the apneic threshold are changeable in the face of variations in the magnitude, direction, and/or type of ventilatory stimulus, thereby altering the susceptibility for apnea, hypopnea, and periodic breathing in sleep.

Sleep unmasks a highly sensitive hypocapnia-induced apnoeic threshold, whereby apnoea is initiated by small transient reductions in arterial CO 2 pressure (P aCO 2 ) below eupnoea and respiratory rhythm is not restored until P aCO 2 has risen significantly above eupnoeic levels. We propose that the 'CO 2 reserve' (i.e. the difference in P aCO 2 between eupnoea and the apnoeic threshold (AT)), when combined with 'plant gain' (or the ventilatory increase required for a given reduction in P aCO 2 ) and 'controller gain' (ventilatory responsiveness to CO 2 above eupnoea) are the key determinants of breathing instability in sleep. The CO 2 reserve varies inversely with both plant gain and the slope of the ventilatory response to reduced CO 2 below eupnoea; it is highly labile in non-random eye movement (NREM) sleep. With many types of increases or decreases in background ventilatory drive and P aCO 2 , the slope of the ventilatory response to reduced P aCO 2 below eupnoea remains unchanged from control. Thus, the CO 2 reserve varies inversely with plant gain, i.e. it is widened with hyperventilation and narrowed with hypoventilation, regardless of the stimulus and whether it acts primarily at the peripheral or central chemoreceptors. However, there are notable exceptions, such as hypoxia, heart failure, or increased pulmonary vascular pressures, which all increase the slope of the CO 2 response below eupnoea and narrow the CO 2 reserve despite an accompanying hyperventilation and reduced plant gain. Finally, we review growing evidence that chemoreceptor-induced instability in respiratory motor output during sleep contributes significantly to the major clinical problem of cyclical obstructive sleep apnoea.

Abstract-Previous work has shown sensitization of carotid chemoreceptor (CC) responsiveness during exercise as well as in chronic heart failure (CHF). Accordingly, we hypothesized that the CCs contribute to the sympathetic restraint of skeletal muscle blood flow during exercise and CHF. We examined the effect of transient CC inhibition on total (Con T ) and hindlimb (Con L ) conductance, and blood pressure at rest and during exercise (2.5 miles per hour, 5% grade) in chronically instrumented dogs. Via a carotid arterial catheter, CCs were inhibited using dopamine (5 to 10 g/kg) or hyperoxic lactated Ringer's solution. Although vasodilation did not occur with CC inhibition in resting healthy dogs, CC inhibition during exercise caused an immediate vasodilatory response (increase in Con T and Con L and decrease in blood pressure). When comparing the peak Con L response from CC inhibition versus ␣-adrenergic blockade (phentolamine), we found that the CCs accounted for approximately one-third of the total sympathetic restraint during exercise. CHF was then induced by chronic rapid cardiac pacing and characterized by impaired cardiac function, enhanced chemosensitivity, and greater sympathetic restraint at rest and during exercise. In contrast to healthy dogs, CC inhibition in resting CHF dogs produced vasodilation, whereas a similar vasodilatory response was observed during exercise in CHF as compared with healthy dogs. The vasodilation following CC inhibition during exercise and in CHF was abolished with ␣-adrenergic blockade and was absent in healthy exercising animals after carotid body denervation. These results establish an important role for the CCs in cardiovascular control in the healthy animal during exercise and in the CHF animal both at rest and during exercise. Key Words: chemosensitivity Ⅲ sympathetic nervous activity Ⅲ exercise Ⅲ chronic heart failure Ⅲ blood flow D uring exercise, sympathetic vasoconstrictor activity increases, resulting in vasoconstriction in the gut and kidneys and will compete with local vasodilatory influences to constrain locomotor limb blood flow during exercise 1,2 to maintain blood pressure. 3 It is generally assumed that the increased sympathetic nervous activity (SNA) during exercise is caused by feedforward mechanisms such as central command and feedback from muscle metaboreceptors, muscle mechanoreceptors, and/or a resetting of systemic baroreceptors. 3 We propose that the tonic sensory input from the carotid chemoreceptors (CCs) might also be an important source of exercise-induced sympathetic vasoconstrictor activity.The CCs are traditionally thought to be the major oxygen sensors in the body, and their stimulation is assumed to cause a reflex-mediated increase in ventilation. However, CC stimulation also elicits significant increases in sympathetic vasoconstrictor outflow. 4,5 Importantly, the CCs are sensitive to a variety of stimuli in addition to oxygen, including, metabolic acidosis, 6 norepinephrine, 7 potassium, 8 glucose, 9 and angiotensin II, 10 all of which c...