title: Vasopressin V1a receptors mediate the hypertensive effects of [Pyr1]apelin-13 in the rat rostral ventrolateral medulla.
abstract: Dysfunctions in CNS regulation of arterial blood pressure lead to an increase in sympathetic nerve activity that participates in the pathogenesis of hypertension. The apelin-apelin receptor system affects arterial blood pressure homeostasis; however, the central mechanisms underlying apelin-mediated changes in sympathetic nerve activity and blood pressure have not been clarified. We explored the mechanisms involved in the regulation of [Pyr1]apelin-13-mediated cardiovascular control within the rostral ventrolateral medulla (RVLM) using selective receptor antagonists. We show that [Pyr1]apelin-13 acts as a modulating neurotransmitter in the normotensive RVLM to affect vascular tone through interaction with the vasopressin V1a receptor but that [Pyr1]apelin-13-induced sympathoexcitation is independent of angiotensin II receptor type 1, oxytocin, ionotropic glutamate and GABAAreceptors. Our data confirm a role for the apelin peptide system in cardiovascular regulation at the level of the RVLM and highlight that this system is a possible potential therapeutic target for the treatment of hypertension.
  
  
  
  Apelin is a ubiquitous peptide that can elevate arterial blood pressure (ABP) yet understanding of the mechanisms involved remain incomplete. Bilateral microinjection of [Pyr1]apelin-13 into the rostral ventrolateral medulla (RVLM), a major source of sympathoexcitatory neurones, increases ABP and sympathetic nerve activity. We aimed to investigate the potential involvement of neurotransmitter systems through which the apelin pressor response may occur within the RVLM. Adult male Wistar rats were anaesthetized and ABP was monitored via a femoral arterial catheter. Bilateral RVLM microinjection of [Pyr1]apelin-13 significantly increased ABP (9 ± 1 mmHg) compared to saline (-1 ± 2mmHg; P < 0.001), which was blocked by pretreatment with the apelin receptor antagonist, F13A (0 ± 1 mmHg; P < 0.01). The rise in ABP was associated with an increase in the low frequency spectra of systolic BP (13.9 ± 4.3% total power; P < 0.001), indicative of sympathetic vasomotor activation. The [Pyr1]apelin-13-mediated pressor response and the increased low frequency spectra of systolic BP response were fully maintained despite RVLM pretreatment with the angiotensin II type 1 receptor antagonist losartan, the oxytocin receptor antagonist desGly-NH2, d(CH2)5[D-Tyr2,Thr4]OVT, the ionotropic glutamate receptor antagonist kynurenate or the GABAAantagonist bicuculline (P > 0.05). By contrast, the [Pyr1]apelin-13 induced pressor and sympathoexcitatory effects were abolished by pretreatment of the RVLM with the vasopressin V1a receptor antagonist, SR 49059 (-1 ± 1 mmHg; 1.1 ± 1.1% total power, respectively; P < 0.001). These findings suggest that the pressor action of [Pyr1]apelin-13 in the RVLM of normotensive rats is not mediated via angiotensin II type 1 receptor, oxytocin, ionotropic glutamate or GABAAreceptors but instead involves a close relationship with the neuropeptide modulator vasopressin.
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Griffiths
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lolait
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Harris
authors.affiliation: School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.
authors.forename: Julian F R
authors.initials: JFR
authors.lastname: Paton
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Anne-Marie
authors.identifier: 0000-0001-5255-8506
authors.initials: AM
authors.lastname: O'Carroll
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists / Q000494:pharmacology; D000075244:Apelin Receptors / Q000037:antagonists & inhibitors; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000378:metabolism*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D000075244:Apelin Receptors; D036341:Intercellular Signaling Peptides and Proteins; D017483:Receptors, Vasopressin; C586143:apelin 13, Pyr(1)-
keywords: APJ; apelin; blood pressure; rostral ventrolateral medulla; sympathetic nervous system; vasopressin