Catestatin in rat RVLM is sympathoexcitatory, increases barosensitivity, and attenuates chemosensitivity and the somatosympathetic reflex

Abstract

Gaede AH, Pilowsky PM. Catestatin in rat RVLM is sympathoexcitatory, increases barosensitivity, and attenuates chemosensitivity and the somatosympathetic reflex. Am J Physiol Regul Integr Comp Physiol 299: R1538 -R1545, 2010. First published October 6, 2010 doi:10.1152/ajpregu.00335.2010.-The fundamental role and corollary effects of neuropeptides that govern cardiorespiratory control in the brain stem are poorly understood. One such regulatory peptide, catestatin [Cts,], noncompetitively inhibits nicotinic-cholinergic-stimulated catecholamine release. Previously, we demonstrated the presence of chromogranin A mRNA in brain stem neurons that are important for the maintenance of arterial pressure. In the present study, using immunofluorescence histochemistry, we show that Cts immunoreactivity is colocalized with tyrosine hydroxylase in C1 neurons of the rostral ventrolateral medulla (RVLM, n ϭ 3). Furthermore, we investigated the effects of Cts on resting blood pressure, splanchnic sympathetic nerve activity, phrenic nerve activity, heart rate, and adaptive reflexes. Cts (1 mM in 50 nl or 100 M in 50 -100 nl) was microinjected into the RVLM in urethaneanesthetized, vagotomized, ventilated Sprague-Dawley rats (n ϭ 19). Cardiovascular responses to stimulation of carotid baroreceptors, peripheral chemoreceptors, and the sciatic nerve (somatosympathetic reflex) were analyzed. Cts (1 mM in 50 nl) increased resting arterial pressure (28 Ϯ 3 mmHg at 2 min postinjection), sympathetic nerve activity (15 Ϯ 3% at 2 min postinjection), and phrenic discharge amplitude (31 Ϯ 4% at 10 min postinjection). Cts increased sympathetic barosensitivity 40% (slope increased from Ϫ0.05 Ϯ 0.01 before Cts to Ϫ0.07 Ϯ 0.01 after Cts) and attenuated the somatosympathetic reflex [1st peak: 36% (from 132 Ϯ 32.1 to 84.0 Ϯ 17.0 V); 2nd peak: 44% (from 65.1 Ϯ 21.4 to 36.6 Ϯ 14.1 V)] and chemoreflex (blood pressure response to anoxia decreased 55%, sympathetic response decreased 46%). The results suggest that Cts activates sympathoexcitatory bulbospinal neurons in the RVLM and plays an important regulatory role in adaptive reflexes. baroreflex; hypoxic chemoreflex; Sprague-Dawley rat; chromogranin A THE CATECHOLAMINE release-inhibitory cleavage product of chromogranin A (CgA) was identified and named catestatin (Cts) in 1997 (23). Cts inhibits ACh-and nicotine-induced catecholamine secretion in cell culture (21, 23), and studies in humans suggest that it may play an important role in hypertension (38).Cts is unusual in its ability to function as an antagonist at neuronal nicotinic ACh receptors (nAChRs) and, possibly, other receptors, such as ␤-adrenoceptors and histamine H 1 receptors (8,14,25), as opposed to directly activating specific "Cts" receptors, as seen with other neurotransmitters and neuropeptides. Here we investigate the distribution of Cts in catecholamine-containing neurons of the brain stem and the physiological effects of Cts following microinjection into the rostral ventrolateral medulla (RVLM). The RVLM comprises a heterogeneo...

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

“…This indicates that intrathecal catestatin on its own is not involved in the reflex control of the cardiovascular system. Previously, we reported that microinjection of catestatin into the RVLM increased barosensitivity and attenuated chemosensitivity (13). Differences in injection method, site, and dose may explain this discrepancy.…”

“…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).…”

“…In the periphery, catestatin causes vasodilation (11) and has antimicrobial actions in the human epidermis, suggesting a role for catestatin in the cutaneous defense system (47). In the brain stem, it is sympathoexcitatory and enhances sympathetic barosensitivity (13).…”

“…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). Catestatin is cardioprotective and blunts the sympathoexcitatory response to spinal stimulation in the pithed rat (23,35,43).…”