PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo

Abstract

Farnham MMJ, Li Q, Goodchild AK, Pilowsky PM. PACAP is expressed in sympathoexcitatory bulbospinal C1 neurons of the brain stem and increases sympathetic nerve activity in vivo. Am J Physiol Regul Integr Comp Physiol 294: R1304-R1311, 2008. First published February 13, 2008 doi:10.1152/ajpregu.00753.2007.-Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide present in the rat brain stem. The extent of its localization within catecholaminergic groups and bulbospinal sympathoexcitatory neurons is not established. Using immunohistochemistry and in situ hybridization, we determined the extent of any colocalization with catecholaminergic and/or bulbospinal projections from the brain stem was determined. PACAP mRNA was found in tyrosine hydroxylaseimmunoreactive (TH-ir) neurons in the C1-C3 cell groups. In the rostral ventrolateral medulla (RVLM), PACAP mRNA was found in 84% of the TH-ir neurons and 82% of bulbospinal TH-ir neurons. The functional significance of these PACAP mRNA positive bulbospinal neurons was tested by intrathecal administration of PACAP-38 in anaesthetized rats. Splanchnic sympathetic nerve activity doubled (110%) and heart rate rose significantly (19%), although blood pressure was unaffected. In addition, as previously reported, PACAP was found in the A1 cell group but not in the A5 cell group or in the locus coeruleus. The RVLM is the primary site responsible for the tonic and reflex control of blood pressure through the activity of bulbospinal presympathetic neurons, the majority of which contain TH. The results indicate 1) that pontomedullary neurons containing both TH and PACAP that project to the intermediolateral cell column originate from C1-C3 and not A5, and 2) intrathecal PACAP-38 causes a prolonged, sympathoexcitatory effect.

Catestatin has an unexpected effect on the intrathecal actions of PACAP dramatically reducing blood pressure

“…Both peptides are present in nerve terminals that surround SPN, and both peptides exert potent cardiovascular effects elsewhere in the brain but have no effect on blood pressure or reflexes on their own in the spinal cord (9,12,13). A key difference, however, is that catestatin delivered intrathecally does not affect MAP, HR, sSNA, or adaptive reflexes (12).…”

“…Catestatin is contained within 88% of C1 RVLM neurons, and PACAP-38 is expressed in 85% of bulbospinal C1 RVLM neurons, indicating extensive colocalization of these neurotransmitters in this nucleus (9, 13). The separate effects of these peptides have been studied following injection into the intrathecal space and into the RVLM, (9,12,49,50), but the physiological significance of this extensive colocalization is unclear.Catestatin and PACAP are both vasodilator peptides in the periphery (11,54). Intrathecal PACAP increases splanchnic sympathetic nerve activity (sSNA) and heart rate (HR) but does not affect mean arterial blood pressure (MAP) (9).…”

“…Catestatin is contained within 88% of C1 RVLM neurons, and PACAP-38 is expressed in 85% of bulbospinal C1 RVLM neurons, indicating extensive colocalization of these neurotransmitters in this nucleus (9, 13). The separate effects of these peptides have been studied following injection into the intrathecal space and into the RVLM, (9,12,49,50), but the physiological significance of this extensive colocalization is unclear.…”

“…Two vesicular peptides of interest in the current study are catestatin (human chromogranin A 352-372 ), a vasoactive chromogranin A (CgA) cleavage product (32), and pituitary adenylate cyclase-activating polypeptide (PACAP) (39). Catestatin is contained within 88% of C1 RVLM neurons, and PACAP-38 is expressed in 85% of bulbospinal C1 RVLM neurons, indicating extensive colocalization of these neurotransmitters in this nucleus (9,13). The separate effects of these peptides have been studied following injection into the intrathecal space and into the RVLM, (9,12,49,50), but the physiological significance of this extensive colocalization is unclear.…”

“…Intrathecal PACAP increases splanchnic sympathetic nerve activity (sSNA) and heart rate (HR) but does not affect mean arterial blood pressure (MAP) (9). Intrathecal catestatin on its own has no effect on MAP, sSNA, or HR; however, it is pressor and sympathoexcitatory in the RVLM and significantly enhances the sympathetic baroreflex, although it blunts the hypoxic chemoreflex and somatosympathetic reflexes (13).…”