Timing, Sleep, and Respiration in Health and Disease - Progress in Molecular Biology and Translational Science - page 201

airway resistance and irritant sensitivity contributes to the nocturnal wors-
ening of symptoms in asthma patients.
Complementary to the master circadian oscillator in the SCN, secondary
oscillators exist in a variety of sites and are under the control of the
SCN. 86,115 Among these are peripheral oscillators in the respiratory system.
Circadian oscillations of mRNA for the clock genes Per1, Per2, Bmal1, and
Clock have been detected in the larynx, trachea, bronchus, and lung. 116
Lesion of the bilateral SCN abolishes the circadian respiratory rhythms
suggesting that peripheral oscillations are not sufficient to maintain rhyth-
micity without input from the SCN. Rhythmicity is also lost in arrhythmic
Cry1 / Cry2 / knockout mice, 116 suggesting that rhythmicity in this
peripheral oscillator cannot occur without a normally functioning master
oscillator. Vagotomy, but not sympathetectomy, also abolishes the circadian
respiratory rhythms, suggesting a vagally mediated role of the parasympa-
thetic nervous system, which is supported by the fact that the rhythms
can be attenuated by antimuscarinic agents. 116
As discussed above, hypercapnia is an important and potent modulator of
breathing. The sensitivity of the respiratory system to CO 2 varies in both a
circadian and state-dependent manner ( Fig. 8.2 B). Several studies in humans
have demonstrated that the respiratory system is least sensitive to stimulation
by hypercapnia in the early morning and most sensitive later in the day. One
study demonstrated a similar circadian pattern of sensitivity to hyp-
oxia. 117,118 In another study, the peak sensitivity to CO 2 occurred in the
mid-afternoon. 88 Circadian variation in sensitivity to stimulation by hypoxia
and hypercapnia is also seen in awake rats 91,119,120 and in ducks. 93
3.2. Influence of breathing on circadian rhythms
A wide variety of factors have been shown to modulate circadian timing
(i.e., reset the circadian clock). The most notable of these is light. This is easy
to appreciate, considering that the 24-h day most organisms are subject to is
dictated by the rotation of the earth relative to the sun and thus dictated by a
light-dark cycle. In addition to light, a number of other phase-shifting stim-
uli have been identified. Among these are the respiratory stimuli hypercapnia
and hypoxia. In human studies, acute hypoxia transiently phase-shifted PEF,
temperature, and grip strength, 121 while acute mild hypercapnia caused small
and transient phase shift of core body temperature rhythms. 122 Both of these
studies were confounded by environmental variables. For golden hamsters,
the time of maximal phase shifting of wheel-running activity for both