Ventilatory chemoresponsiveness, narcolepsy–cataplexy and human leukocyte antigen DQB1*0602 status

Abstract

We hypothesised that hypocretin (orexin) plays a role in the determination of ventilatory chemosensitivity. 130 patients with narcolepsy-cataplexy (mean¡SD age 20¡10 yrs, 69% male) and 117 controls (22¡6.9 yrs, 62% male) were recruited and tested for human leukocyte antigen (HLA)-DQB1*0602 status, hyperoxia hypercapnic (change in minute ventilation (DV9E)/carbon dioxide tension (DPCO 2 ) L?min KEYWORDS: Chemoresponsiveness, human leukocyte antigen DQB1, hypercapnia, hypoxia, narcolepsy H ypoxic and hypercapnic sensing are processed through neuromuscular circuits resulting in an increase or decrease of tidal volume, respiratory frequency and minute ventilation (V9E). Such chemosensory reflexes operate to influence sleep apnoea, chronic obstructive pulmonary disease (COPD), heart failure, and acute adaptation to high altitude [1]. A variation in chemosensitivity across various inbred rodent strains and familial clustering of ventilatory traits in humans provides a strong rationale for gene and protein isolation efforts to unravel molecular mechanisms for these traits operating in health and disease [2].Hypocretin (orexin) is a hypothalamic neurotransmitter, which, when given intracerebroventricularly in mice, promotes both wakefulness and ventilation [3,4]. Both hypocretin knockout and hypocretin neuron-ablated mice show attenuation of respiratory excitation during fightor-flight responses [5]. Particular to chemoresponsiveness, hypocretin/orexin knockout mice have attenuated hypercapnic ventilatory responses [6]; supplementation of hypocretin-1 or -2 partially restores an attenuated response to hypercapnia, while administration of hypocretin receptor-1 antagonist will reduce hypercapnic responsiveness in wild type mice [7]. Post-hypoxic long-term facilitation, a physiological feature that is presumed to reduce sleep apnoea, is absent in hypocretin/orexin knockout mice [8].The human model of hypocretin deficiency is narcolepsy with cataplexy [9,10]. This disorder is also associated with the gene marker, human leukocyte antigen (HLA)-DQB1*0602 [11]. This disease is also considered to be associated with a higher expression of sleep-disordered breathing [12,13]. Our primary hypothesis was that an impaired chemoresponsiveness would be present

Respiratory regulation in narcolepsy

“…In contrast to findings suggested by animal gene knock out model, we found no group differences in regard to hypercapnic responsiveness, but rather found significant differences in hypoxic responsiveness. Reduced hypoxic responsiveness in narcolepsycataplexy patients was unrelated to BMI, age, and sex [19].…”

“…We will also report chemoresponsiveness in patients with narcolepsycataplexy, a human model of orexin deficiency, which indicates an unexpected finding that the mechanism for differences between patients and controls in hypoxic responsiveness could relate to HLA marker status rather than orexin deficiency [19].…”

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

“…Observations of ventilatory responses to these conditions in orexin peptide knockouts and after central administration of orexin peptides has been mixed; some studies have found an involvement of orexin in mediating increased ventilatory responses to hypercapnia (Deng et al, 2007;Nakamura et al, 2007;Dias et al, 2009Dias et al, , 2010Nattie and Li, 2010), decreased pulmonary activity to hypoxia (Deng et al, 2007;Nakamura et al, 2007), or no detectable response to either condition (Zhang et al, 2005). Conversely, a study of patients with narcolepsy-cataplexy detected attenuated responses to hypoxia but not hypercapnia (Han et al, 2010), which is exactly opposite that found in rodent models. Clearly, more work needs to be done to confirm a role for orexin in mediating ventilatory responses to changing blood gas levels as opposed to controlling sleep/ wake cycles to maintain energy homeostasis.…”

Atropine microdialysis within or near the pre-Bötzinger Complex increases breathing frequency more during wakefulness than during NREM sleep

“…For example, it is well known that the neuropeptide orexin contributes to arousal state (26) and that orexinergic neurons are more active in the awake state than during sleep (54). These neurons have widespread projections to the brain stem, including respiratory-related nuclei (43,58), and there is evidence that orexin contributes to chemosensitivity, particularly more in the awake state compared with NREM sleep (17).…”