Abstract
Repetitive hypoxia is a key feature of obstructive sleep apnoea (OSA), a condition characterized by intermittent airways obstruction. Patients with OSA present with persistent increases in sympathetic activity and commonly develop hypertension. The objectives of this study were to determine if the persistent increases in sympathetic nerve activity, known to be induced by acute intermittent hypoxia (AIH), are mediated through activation of the pituitary adenylate cyclase activating polypeptide (PACAP) signaling system. Here, we show that the excitatory neuropeptide PACAP, acting in the spinal cord, is important for generating the sympathetic response seen following AIH. Using PACAP receptor knockout mice, and pharmacological agents in Sprague Dawley rats, we measured blood pressure, heart rate, pH, PaCO2, and splanchnic sympathetic nerve activity, under anaesthesia, to demonstrate that the sympathetic response to AIH is mediated via the PAC1 receptor, in a cAMP-dependent manner. We also report that both intermittent microinjection of glutamate into the rostroventrolateral medulla (RVLM) and intermittent infusion of a sub-threshold dose of PACAP into the subarachnoid space can mimic the sympathetic response to AIH. All the sympathetic responses are independent of blood pressure, pH or PaCO2 changes. Our results show that in AIH, PACAP signaling in the spinal cord helps drive persistent increases in sympathetic nerve activity. This mechanism may be a precursor to the development of hypertension in conditions of chronic intermittent hypoxia, such as OSA.
Highlights
Obstructive sleep apnoea (OSA) is characterized by collapse of the upper airway, resulting in frequent intermittent episodes of hypoxemia and hypercapnia
pituitary adenylate cyclase activating polypeptide (PACAP) Acting at PAC1 Receptors at the Level of the Spinal Cord Is Necessary for the Sympathetic Response to acute intermittent hypoxia (AIH)
To determine the physiological relevance of PACAP signaling during AIH, a sub-threshold dose (3 nmol) of PACAP (Farnham et al, 2011) 10 min prior to AIH was administered intrathecally
Summary
Obstructive sleep apnoea (OSA) is characterized by collapse of the upper airway, resulting in frequent intermittent episodes of hypoxemia and hypercapnia. While sympathoexcitation may be critical for survival in diseases characterized by high risk of acute crisis such as sudden infant death syndrome (SIDS), marked sympathoexcitation is a key feature of hypertension which, in turn, causes target organ damage, atherosclerosis, renal failure, heart failure and stroke. Common to both OSA and hypertension, elevated SNA is evident before the development of hypertension. The mechanism of this persistent sympathoexcitation is not understood
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