Brainstem Catecholaminergic Neurons Modulate both Respiratory and Cardiovascular Function

Catecholamine neurons (CA) located in the brainstem project widely in the forebrain, hindbrain and spinal cord to many regions involved in the control of respiratory and cardiovascular function. For example, A6 noradrenergic neurons provide a tonic excitatory stimulus that maintains breathing frequency while A5 neurons provide an inhibitory influence on both cardiovascular and respiratory function to slow breathing frequency and heart rate. Mice with genetic defects that include CA neurons have abnormal respiration and blood pressure. For example, mice heterozygous for Phox2b with CA neuron defects have sleep-disordered breathing, and DBH knockout mice with absent CA cells centrally and peripherally have hypotension. Our hypothesis is that widespread brainstem CA neuron lesions in adult rats would significantly affect cardiorespiratory functions including breathing, chemoreception, blood pressure and heart rate. We produced the widespread brainstem CA neuron lesion by injecting anti-dopamine-β-hydroxylase-saporin (DBH-SAP) via the 4^th ventricle. The lesioned group had a 64–84% loss of A5, A6 and A7 tyrosine hydroxylase immunoreactive (ir) neurons along with 56–64% loss of C1 and C2 phenyl ethanolamine-N methyltransferase (PNMT)-ir neurons over 2–3 weeks. The significant respiratory changes included: (1) a decreased breathing frequency during air and 7% CO₂ breathing in both wakefulness and non-REM (NREM) sleep; (2) a reduced ventilatory response to 7% CO₂ in wakefulness (−28%) and in NREM sleep (−26%); and (3) increased variability of breathing in REM sleep but not in wakefulness or NREM sleep. Significant cardiovascular changes at two weeks included: (1) an increased MAP by 11.7 mmHg in the room air resting condition; (2) an unaffected cardiovascular response to hypercapnia; and (3) a smaller decrease of MAP in response to hypoxia.Conclusions: Central CA neurons have a net excitatory effect on breathing and chemoreception but a net inhibitory effect on blood pressure.