Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat

Abstract

Farnham MM, Inglott MA, Pilowsky PM. Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol 300: H214 -H222, 2011. First published October 15, 2010 doi:10.1152/ajpheart.00662.2010.-The rostral ventrolateral medulla contains presympathetic neurons that project monosynaptically to sympathetic preganglionic neurons (SPN) in the spinal cord and are essential for the tonic and reflex control of the cardiovascular system. SPN directly innervate the adrenal medulla and, via postganglionic axons, affect the heart, kidneys, and blood vessels to alter sympathetic outflow and hence blood pressure. Over 80% of bulbospinal, catecholaminergic (C1) neurons contain pituitary adenylate cyclaseactivating polypeptide (PACAP) mRNA. Activation of PACAP receptors with intrathecal infusion of PACAP-38 causes a robust, prolonged elevation in sympathetic tone. Given that a common feature of most forms of hypertension is elevated sympathetic tone, this study aimed to determine in the spontaneously hypertensive rat (SHR) and the Wistar Kyoto rat (normotensive control) 1) the proportion of C1 neurons containing PACAP mRNA and 2) responsiveness to intrathecal PACAP-38. We further investigated whether intrathecal infusion of the PACAP antagonist, PACAP(6 -38), reduces the hypertension in the SHR. The principal findings are that 1) the proportion of PACAP mRNA-containing C1 neurons is not different between normotensive and hypertensive rats, 2) intrathecal PACAP-38 causes a strain-dependent, sustained sympathoexcitation and tachycardia with variable effects on mean arterial pressure in normotensive and hypertensive rats, and 3) PACAP(6 -38) effectively attenuated the effects of intrathecal PACAP-38, but had no effect alone, on any baseline variables. This finding indicates that PACAP-38 is not tonically released in the spinal cord of rats. A role for PACAP in hypertension in conscious rats remains to be determined. sympathetic activity; spinal cord; pituitary adenylate cyclase-activating polypeptide THE ROSTRAL VENTROLATERAL MEDULLA (RVLM) is crucial for the tonic and reflex control of the cardiovascular system (see Refs. 15 and 43 for reviews). RVLM presympathetic neurons are commonly defined as being inhibited following baroreceptor activation and having a spinal axon (2, 28, 29). Neurochemically, 60 -80% of presympathetic neurons are C1 neurons (29,42,48,49), having all of the enzymes required for adrenaline synthesis. Presympathetic RVLM neurons project monosynaptically to sympathetic preganglionic neurons (SPN) in the intermediolateral (IML) cell column of the spinal cord (34,38). SPN, in turn, regulate the activity of the heart, kidneys, blood vessels, and adrenal chromaffin cells, thereby determining sympathetic outflow and ultimately blood pressure.Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory 38-amino-acid peptide originally identified in ovine hypothalamus (32) that also exists as a...

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

“…The procedures were performed as described previously (Abbott and Pilowsky, 2009;Farnham et al, 2011;Inglott et al, 2011;Shahid et al, 2011). The left phrenic nerve and the left greater splanchnic sympathetic nerve at a site proximal to the coeliac ganglion were isolated and dissected.…”

“…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).…”

Characterizations of a synthetic pituitary adenylate cyclase-activating polypeptide analog displaying potent neuroprotective activity and reduced in vivo cardiovascular side effects in a Parkinson's disease model

“…However, VPAC2 stimulation produces particular actions such as vasodilation, tachycardia and water retention (Farnham et al, 2011;Tsutsumi et al, 2002;Warren et al, 1992), and those effects would limit its use as a neuroprotective drug. Therefore, a PACAP derivative with an improved metabolic stability and the capacity to activate the PAC1 (anti-apoptotic) receptor, or simultaneously the PAC1 and VPAC1 (anti-inflammatory) receptors, without stimulating VPAC2, would be of great interest.…”

“…Thus, modulation of TNF-α should be an neuroprotective effects linked to a decrease of neuronal apoptosis and a reduction of inflammation. However, besides its neuroprotective effects, it has also been reported that PACAP, through VPAC2 receptor activation, can generate adverse effects such as hypotension, water retention, and tachycardia (Deguil et al, 2010;Farnham et al, 2011;Inglott et al, 2012;Mirfendereski et al, 1997;Tsutsumi et al, 2002;Warren et al, 1992). Also, it has been shown that a VPAC2 agonist exerts deleterious effects in a stroke model (Darsalia et al, 2013).…”

“…In fact, PACAP is prompted to rapid degradation by dipeptidyl peptidase IV (DPP IV), an enzyme that converts PACAP38 into PACAP(3-38) and then PACAP(5-38), two fragments that behave as antagonists. Another limitation is that it also exerts peripheral actions (Farnham et al, 2011;Warren et al, 1992). Particularly, using pharmacological tools and transgenic animals, it was demonstrated that three distinct G protein-coupled receptors i.e.…”