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

This study focuses on presympathetic neurons of the rostral ventrolateral medulla (RVLM) that regulate sympathetic vasomotor tone. Many neurotransmitters are colocalized in RVLM neurons and are released under specific conditions to modulate efferent homeostatic responses. Of particular interest here are two peptides colocalized in catecholaminergic RVLM neurons: catestatin and pituitary adenylate cyclase-activating polypeptide (PACAP). Chromogranin A-derived catestatin is a potent endogenous noncompetitive nicotinic and adrenoreceptor antagonist. Catestatin impairs adenylate cyclase and phospholipase C action: mechanisms engaged by PACAP. Although PACAP and catestatin are likely coreleased, the possible effects of this are unknown. We aimed to determine whether catestatin affects the normal sympathoexcitatory but isotensive responses to intrathecal PACAP. Urethane-anesthetized, vagotomized, ventilated Sprague-Dawley rats (n = 22) were given an intrathecal injection of catestatin at different times prior to intrathecal administration of PACAP-38. Arterial pressure, splanchnic sympathetic nerve activity, heart rate, and reflex responses to baroreceptor and chemoreceptor activation were recorded. The key findings of this study are that pretreatment with catestatin time dependently enhances the PACAP-38 effect on mean arterial pressure and enhances sympathetic barosensitivity and chemosensitivity. The time-scale of the effect of catestatin on the response to PACAP-38 strongly suggests that catestatin is either causing changes in gene expression to exert its effects, or modifying intracellular mechanisms normally engaged by PAC(1) receptors. The ability of catestatin pretreatment to enhance barosensitivity and chemosensitivity after PACAP-38 injection supports the hypothesis that catestatin manipulates the intracellular environment within sympathetic neurons in a way that increases responses to PACAP.

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

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 cyclase-activating 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.

Intrathecal PACAP-38 causes prolonged widespread sympathoexcitation via a spinally mediated mechanism and increases in basal metabolic rate in anesthetized rat.

The rostral ventrolateral medulla differentially regulates sympathetic output to different vascular beds, possibly through the release of various neurotransmitters and peptides that may include pituitary adenylate cyclase-activating polypeptide (PACAP). An intrathecal administration of PACAP increases splanchnic sympathetic nerve activity and heart rate, but not mean arterial blood pressure. The mechanism behind this response is unknown but may be due to a differential control of sympathetic outflows. In this study we sought 1) to investigate whether intrathecal PACAP differentially affects sympathetic outflow, 2) to determine whether the intrathecal responses to PACAP are solely due to a spinally mediated mechanism, and 3) to determine whether intrathecal PACAP affects metabolic function. Experiments using urethane-anesthetized, vagotomized, ventilated, and paralyzed adult male Sprague-Dawley rats were conducted in this study. Intrathecal injections of PACAP-38 were given, and mean arterial pressure, heart rate, the activity of regional sympathetic nerves, end-tidal CO(2), and core temperature were recorded. The novel findings of this study are that 1) intrathecal PACAP-38 causes a prolonged widespread sympathoexcitation in multiple sympathetic beds, 2) this widespread sympathoexcitation is mediated within the spinal cord itself since spinal transection does not abrogate the response, and 3) that intrathecal PACAP-38 increases basal metabolic rate. Therefore, we conclude that intrathecal PACAP acts in the spinal cord to cause a prolonged widespread sympathoexcitation and that PACAP also causes an increase in basal metabolic rate that includes an increase in brown adipose tissue thermogenesis in our rat preparation.

Activation of PAC(1) and VPAC receptor subtypes elicits differential physiological responses from sympathetic preganglionic neurons in the anaesthetized rat.

BACKGROUND AND PURPOSE: Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide with central and peripheral cardiovascular actions. Intrathecal PACAP increases splanchnic sympathetic nerve activity and heart rate, but not mean arterial pressure (MAP). We hypothesize that the three PACAP receptors (PAC(1) , VPAC(1) and VPAC(2) ) have different actions in central cardiovascular control, and that their summed effect results in the lack of MAP response observed following intrathecal PACAP injection. EXPERIMENTAL APPROACH: The effects of the PACAP receptors on baseline cardiovascular parameters were investigated using selective agonists and antagonists administered into the intrathecal space of urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats. KEY RESULTS: Selective activation of the PACAP receptors had different effects on MAP. When activated by maxadilan, PAC(1) receptors increased MAP. The VPAC receptors decreased MAP when both were activated with vasoactive intestinal polypeptide or when only VPAC(1) receptors were activated. The PAC(1) and VPAC(2) receptor antagonist PACAP(6-38) had no cardiovascular effects, suggesting that PACAP is not tonically released. CONCLUSIONS AND IMPLICATIONS: PACAP neurotransmission was not responsible for the moment-to-moment tonic regulation of central cardiovascular control mechanisms. Nevertheless, PACAP release within the spinal cord may have pleiotropic effects on sympathetic outflow depending on the postsynaptic receptor type. PAC(1) and VPAC receptor subtypes produced opposing changes in blood pressure when activated by intrathecal PACAP-38 in the anaesthetized Sprague-Dawley rat, resulting in no net change in MAP.