Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anatomically compromised, collapsible airway, the sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons leads to collapse of the pharyngeal airway. In turn, the ability of the sleeping subject to compensate for this airway obstruction will determine the degree of cycling of these events. Several of the classic neurotransmitters and a growing list of neuromodulators have now been identified that contribute to neurochemical regulation of pharyngeal motor neuron activity and airway patency. Limited progress has been made in developing pharmacotherapies with acceptable specificity for the treatment of sleep-induced airway obstruction. We review three types of major long-term sequelae to severe OSA that have been assessed in humans through use of continuous positive airway pressure (CPAP) treatment and in animal models via long-term intermittent hypoxemia (IH): 1) cardiovascular. The evidence is strongest to support daytime systemic hypertension as a consequence of severe OSA, with less conclusive effects on pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias. The underlying mechanisms mediating hypertension include enhanced chemoreceptor sensitivity causing excessive daytime sympathetic vasoconstrictor activity, combined with overproduction of superoxide ion and inflammatory effects on resistance vessels. 2) Insulin sensitivity and homeostasis of glucose regulation are negatively impacted by both intermittent hypoxemia and sleep disruption, but whether these influences of OSA are sufficient, independent of obesity, to contribute significantly to the "metabolic syndrome" remains unsettled. 3) Neurocognitive effects include daytime sleepiness and impaired memory and concentration. These effects reflect hypoxic-induced "neural injury." We discuss future research into understanding the pathophysiology of sleep apnea as a basis for uncovering newer forms of treatment of both the ventilatory disorder and its multiple sequelae.

Our concern in these studies was with the cardiovascular consequences of reflexes from fatiguing inspiratory muscles in the human. We recently demonstrated that induction of inspiratory muscle fatigue in healthy subjects by means of voluntary hyperpnoea against resistance caused a gradual increase in muscle sympathetic nerve activity (MSNA) in the resting limb (St Croix et al. 2000). This finding, taken together with the finding of increased neural activity in type IV afferents from the diaphragm during fatiguing contractions of this muscle in the anaesthetized rat (Hill, 1. We recently showed that fatigue of the inspiratory muscles via voluntary efforts caused a time-dependent increase in limb muscle sympathetic nerve activity (MSNA) (St Croix et al. 2000). We now asked whether limb muscle vasoconstriction and reduction in limb blood flow also accompany inspiratory muscle fatigue.2. In six healthy human subjects at rest, we measured leg blood flow (« Q L ) in the femoral artery with Doppler ultrasound techniques and calculated limb vascular resistance (LVR) while subjects performed two types of fatiguing inspiratory work to the point of task failure (3-10 min). Subjects inspired primarily with their diaphragm through a resistor, generating (i) 60 % maximal inspiratory mouth pressure (P M ) and a prolonged duty cycle (T I /T TOT = 0.7); and (ii) 60 % maximal P M and a T I /T TOT of 0.4. The first type of exercise caused prolonged ischaemia of the diaphragm during each inspiration. The second type fatigued the diaphragm with briefer periods of ischaemia using a shorter duty cycle and a higher frequency of contraction. End-tidal P CO 2 was maintained by increasing the inspired CO 2 fraction (F I,CO 2 ) as needed. Both trials caused a 25-40 % reduction in diaphragm force production in response to bilateral phrenic nerve stimulation.3. « Q L and LVR were unchanged during the first minute of the fatigue trials in most subjects; however, « Q L subsequently decreased (_30 %) and LVR increased (50-60 %) relative to control in a time-dependent manner. This effect was present by 2 min in all subjects. During recovery, the observed changes dissipated quickly (< 30 s). Mean arterial pressure (MAP; +4-13 mmHg) and heart rate (+16-20 beats min _1 ) increased during fatiguing diaphragm contractions.4. When central inspiratory motor output was increased for 2 min without diaphragm fatigue by increasing either inspiratory force output (95 % of maximal inspiratory pressure (MIP)) or inspiratory flow rate (5 w eupnoea), « Q L , MAP and LVR were unchanged; although continuing the high force output trials for 3 min did cause a relatively small but significant increase in LVR and a reduction in « Q L .5. When the breathing pattern of the fatiguing trials was mimicked with no added resistance, LVR was reduced and « Q L increased significantly; these changes were attributed to the negative feedback effects on MSNA from augmented tidal volume.6. Voluntary increases in inspiratory effort, in the absence of diaphragm fatigue, had no effec...

The relative contributions of hypoxia and hypercapnia in causing persistent sympathoexcitation after exposure to the combined stimuli were assessed in nine healthy human subjects during wakefulness. Subjects were exposed to 20 min of isocapnic hypoxia (arterial O(2) saturation, 77-87%) and 20 min of normoxic hypercapnia (end-tidal P(CO)(2), +5.3-8.6 Torr above eupnea) in random order on 2 separate days. The intensities of the chemical stimuli were manipulated in such a way that the two exposures increased sympathetic burst frequency by the same amount (hypoxia: 167 +/- 29% of baseline; hypercapnia: 171 +/- 23% of baseline). Minute ventilation increased to the same extent during the first 5 min of the exposures (hypoxia: +4.4 +/- 1.5 l/min; hypercapnia: +5.8 +/- 1.7 l/min) but declined with continued exposure to hypoxia and increased progressively during exposure to hypercapnia. Sympathetic activity returned to baseline soon after cessation of the hypercapnic stimulus. In contrast, sympathetic activity remained above baseline after withdrawal of the hypoxic stimulus, even though blood gases had normalized and ventilation returned to baseline levels. Consequently, during the recovery period, sympathetic burst frequency was higher in the hypoxia vs. the hypercapnia trial (166 +/- 21 vs. 104 +/- 15% of baseline in the last 5 min of a 20-min recovery period). We conclude that both hypoxia and hypercapnia cause substantial increases in sympathetic outflow to skeletal muscle. Hypercapnia-evoked sympathetic activation is short-lived, whereas hypoxia-induced sympathetic activation outlasts the chemical stimulus.

We studied ventilatory and neurocirculatory responses to combined hypoxia (arterial O2 saturation 80%) and hypercapnia (end-tidal CO2 + 5 Torr) in awake humans. This asphyxic stimulus produced a substantial increase in minute ventilation (6.9 +/- 0.4 to 20.0 +/- 1.5 l/min) that promptly subsided on return to room air breathing. During asphyxia, muscle sympathetic nerve activity (intraneural microelectrodes) increased to 220 +/- 28% of the room air baseline. Approximately two-thirds of this sympathetic activation persisted after return to room air breathing for the duration of our measurements (20 min in 8 subjects, 1 h in 2 subjects). In contrast, neither ventilation nor sympathetic outflow changed during time control experiments. A 20-min exposure to hyperoxic hypercapnia also caused a sustained increase in sympathetic activity, but, unlike the aftereffect of asphyxia, this effect was short lived and coincident with continued hyperpnea. In summary, relatively brief periods of asphyxic stimulation cause substantial increases in sympathetic vasomotor outflow that outlast the chemical stimuli. These findings provide a potential explanation for the chronically elevated sympathetic nervous system activity that accompanies sleep apnea syndrome.

We tested the hypothesis that reflexes arising from working respiratory muscle can elicit increases in sympathetic vasoconstrictor outflow to limb skeletal muscle, in seven healthy human subjects at rest. We measured muscle sympathetic nerve activity (MSNA) with intraneural electrodes in the peroneal nerve while the subject inspired (primarily with the diaphragm) against resistance, with mouth pressure (PM) equal to 60 % of maximal, a prolonged duty cycle (TI/TTot) of 0.70, breathing frequency (fb) of 15 breaths min−1 and tidal volume (VT) equivalent to twice eupnoea. This protocol was known to reduce diaphragm blood flow and cause fatigue. MSNA was unchanged during the first 1–2 min but then increased over time, to 77 ± 51 % (s.d.) greater than control at exhaustion (mean time, 7 ± 3 min). Mean arterial blood pressure (+12 mmHg) and heart rate (+27 beats min−1) also increased. When the VT, fb and TI/TTot of these trials were mimicked with no added resistance, neither MSNA nor arterial blood pressure increased. MSNA and arterial blood pressure also did not change in response to two types of increased central respiratory motor output that did not produce fatigue: (a) high inspiratory flow rate and fb without added resistance; or (b) high inspiratory effort against resistance with PM of 95 % maximal, TI/TTot of 0.35 and fb of 12 breaths min−1. The heart rate increased by 5–16 beats min−1 during these trials. Thus, in the absence of any effect of increased central respiratory motor output per se on limb MSNA, we attributed the time‐dependent increase in MSNA during high resistance, prolonged duty cycle breathing to a reflex arising from a diaphragm that was accumulating metabolic end products in the face of high force output plus compromised blood flow.

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.

Arterial baroreflexes contribute importantly to blood pressure regulation through their influence on parasympathetic outflow to the sinus node and sympathetic outflow to the peripheral circulation. Baroreflex control of heart rate is known to be diminished in older individuals. Whether advancing age is associated with a parallel attenuation in baroreflex control of sympathetic outflow to the peripheral circulation has not been studied in humans. To provide such information, we made direct measurements of muscle sympathetic nerve activity (MSNA) in healthy males who ranged in age from 18 to 71 yr. The subjects were arbitrarily divided into three groups: younger (18-34 yr; n = 35), middle aged (35-50 yr; n = 15), and older (51-71 yr; n = 16). Although basal levels of MSNA were higher in older subjects than in younger and middle-aged subjects, the gains of baroreflex control of MSNA were the same in the older, middle-aged, and younger subjects (-4.6 +/- 0.6, -4.8 +/- 0.9, -5.1 +/- 0.5 U/mmHg, P greater than 0.10). In contrast, the gains of baroreflex control of cardiac intervals were attenuated in the older and middle-aged subjects compared with the younger subjects (9.8 +/- 1.2, 13.6 +/- 1.4, 21.7 +/- 1.3 ms/mmHg, P less than 0.05). Our data indicate that although the parasympathetic component of the arterial baroreflex becomes impaired with advancing age, the sympathetic component can be well maintained in healthy individuals even into the seventh decade.

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