PACAP causes PAC₁/VPAC₂ receptor mediated hypertension and sympathoexcitation in normal and hypertensive rats

Abstract

Farnham MM, Lung MS, Tallapragada VJ, Pilowsky PM. PACAP causes PAC 1/VPAC2 receptor mediated hypertension and sympathoexcitation in normal and hypertensive rats. Am J Physiol Heart Circ Physiol 303: H910 -H917, 2012. First published August 10, 2012; doi:10.1152/ajpheart.00464.2012.-Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide that plays an important role in hypertension and stress responses. PACAP acts at three G protein-coupled receptors [PACAP type 1 receptor (PAC 1 ) and vasoactive intestinal peptide receptor types 1 and 2 (VPAC 1 and VPAC2)] and is localized to sites involved in cardiovascular control, most significantly the rostral ventrolateral medulla (RVLM). The RVLM is crucial for the tonic and reflex control of efferent sympathetic activity. Increases in sympathetic activity are observed in most types of hypertension and heart failure. PACAP delivered intrathecally also causes massive sympathoexcitation. We aimed to determine the presence and abundance of the three PACAP receptors in the RVLM, the role, in vivo, of PACAP in the RVLM on tonic and reflex cardiovascular control, and the contribution of PACAP to hypertension in the spontaneously hypertensive rat (SHR). Data were obtained using quantitative PCR and microinjection of PACAP and its antagonist, PACAP(6 -38), into the RVLM of anesthetized artificially ventilated normotensive rats or SHRs. All three receptors were present in the RVLM. PACAP microinjection into the RVLM caused sustained sympathoexcitation and tachycardia with a transient hypertension but did not affect homeostatic reflexes. The responses were partially mediated through PAC1/VPAC2 receptors since the effect of PACAP was attenuated (ϳ50%) by PACAP(6 -38). PACAP was not tonically active in the RVLM in this preparation because PACAP(6 -38) on its own had no inhibitory effect. PACAP has long-lasting cardiovascular effects, but altered PACAP signaling within the RVLM is not a cause of hypertension in the SHR. blood pressure; rostral ventrolateral medulla; sympathetic; neuropeptides; pituitary adenylate cyclase-activating polypeptide; vasoactive intestinal peptide receptor PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) exists in discrete regions of the brain stem and spinal cord involved in cardiovascular control, one of which is the rostral ventrolateral medulla (RVLM) (7,12,17,22,35,59). The RVLM is crucial for cardiovascular control (20,40,48,49) as it contains the neurons that determine resting mean arterial pressure (MAP) and responds to the activation of adaptive reflexes (11,21,37,38,51). Changes in autonomic function resulting from activation of the baroreceptor, somatosympathetic, and chemoreceptor reflexes are all principally mediated by increasing or decreasing the activity of RVLM neurons, which, in turn, project to and excite sympathetic preganglionic neurons in the thoracolumbar spinal cord (28,36,39,43,44,49,62).Peripheral administration of PACAP-38 (PACAP) dilates blood vessels, causing hypotension (42, 53). Centra...

Tonically Active cAMP-Dependent Signaling in the Ventrolateral Medulla Regulates Sympathetic and Cardiac Vagal Outflows

“…This is in keeping with our finding that the G as subunit mRNA is abundant in the RVLM (Parker et al, 2012) and consistent with a postsynaptic site of action, as suggested previously in neonatal RVLM brain slice preparations, in which 8-Br-cAMP and the adenylyl cyclase activator forskolin increased the firing rate of RVLM "pacemaker" neurons in the presence of tetrodotoxin (Sun and Guyenet, 1990). Activation of G as -linked receptors in the RVLM using pituitary adenylate cyclase-activating peptide evokes sympathoexcitation and pressor responses, although reflex functions were unaffected (Farnham et al, 2012). On cAMP Signaling in the Ventrolateral Medulla the other hand, cardiac vagal nerve activity is increased by systemic adenosine (da Silva et al, 2012) or by activation of b-adrenergic receptors, specifically b1, which reduces GABAergic and glycinergic (as well as glutamatergic) conductances at cardiac vagal preganglionic neurons (Bateman et al, 2012).…”

“…It is possible that blocking PKA may redistribute the active pool of cAMP to other effectors; however, at least in the RVLM, blocking either EPAC or HCN channels alone had little effect. There is little evidence supporting the idea of tonically active peptides in the RVLM Pilowsky et al, 2008;Farnham et al, 2012). Nevertheless the findings here suggest that a neurotransmitter acting via G aslinked receptor/s is active in the ventrolateral medulla.…”

Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy

“…Glutamate is a major excitatory neurotransmitter, and responsible for normal maintenance of reflex responses (Miyawaki et al, 1996;Pilowsky and Goodchild, 2002;Pilowsky et al, 2009), which also plays an important role in the development of seizure (Casillas-Espinosa et al, 2012;Powell et al, 2014a;Bhandare et al, 2016b). Heart-rate baroreflex sensitivity decreases with intracerebroventricular injection of PACAP in trout (Lancien et al, 2011), whereas in rats, PACAP agonist or antagonist microinjection into the RVLM produce no significant effect (Farnham et al, 2012). In spontaneously hypertensive rats, increased microglial activation, and pro-inflammatory cytokines in PVN causes autonomic (baroreflex) dysfunction (Masson et al, 2015).…”

“…During acute seizures, PACAP and microglia act on presympathetic rostral ventrolateral medulla (RVLM) neurons in the brainstem to promote proarrhythmogenic changes, but not sympathoexcitation . In many cardiovascular autonomic nuclei PACAP is pressor and sympathoexcitatory (Farnham et al, 2008;Farnham et al, 2011;Inglott et al, 2011) and changes baroreflex response in trout (Lancien et al, 2011) but not in rats (Farnham et al, 2012). PACAP expression is increased in central autonomic nuclei (paraventricular nucleus) after kainic acid (KA)-induced seizures in rats (Nomura et al, 2000).…”

Neurotransmitter-mediated anxiogenic action of PACAP-38 in rats

“…Furthermore, PACAP-38 causes hyperthermia in rats [16,17], counteracts reserpine-induced hypothermia [6], depresses the intake of food [18] and water intake [19], inhibits open-field activity [20]. PACAP plays an important role in hypertension and stress response [21].…”