Abstract
The present study aimed to reveal the effects of urotensin II (UII) on sympathetic vasomotor tone in the rostral ventrolateral medulla (RVLM). UII (0.3, 3, and 30 nmol/L, 50 nL) was microinjected into the RVLM. Blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured to determine the sympathetic vasomotor tone. BP, HR, and RSNA were simultaneously recorded after drugs had been microinjected into the RVLM. Microinjection of UII (0.3, 3, and 30 nmol/L, 50 nL) into the RVLM significantly increased BP, HR, and RSNA. Pretreatment with BIM23127 (300 nmol/L, 50 nL), a potent antagonist of the UII receptor GPR14, abolished the effect of UII. Previous microinjection of PD98059 (25 μmol/L, 50 nL), an inhibitor of ERK, significantly suppressed the effects of UII. Preinjection of an inhibitor of the N-type Ca2+ channel, ω-conotoxin GVIA (50 nmol/L, 50 nL), inhibited the effects of UII. The present study demonstrated that microinjection of UII into the RVLM significantly increased sympathetic vasomotor tone, which was mediated by the GPR14/ERK/N-type Ca2+ channel pathway. UII may become a novel therapeutic target for autonomic nervous system regulation, especially in hypertension.
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References
Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature. 1999;401:282–6.
Svistunov AA, Tarasov VV, Shakhmardanova SA, Sologova SS, Bagaturiya ET, Chubarev VN, et al. Urotensin II: molecular mechanisms of biological activity. Curr Protein Pept Sci. 2018;19:924–34.
Nobata S, Donald JA, Balment RJ, Takei Y. Potent cardiovascular effects of homologous urotensin II (UII)-related peptide and UII in unanesthetized eels after peripheral and central injections. Am J Physiol Regul Integr Comp Physiol. 2011;300:R437–46.
Nothacker HP, Clark S. From heart to mind. The urotensin II system and its evolving neurophysiological role. FEBS J. 2005;272:5694–702.
Seyedabadi M, Goodchild AK, Pilowsky PM. Differential role of kinases in brain stem of hypertensive and normotensive rats. Hypertension. 2001;38:1087–92.
Hunt BD, Ng LL, Lambert DG. A rat brain atlas of urotensin-II receptor expression and a review of central urotensin-II effects. Naunyn Schmiedebergs Arch Pharm. 2010;382:1–31.
Ono T, Kawaguchi Y, Kudo M, Kushikata T, Hashiba E, Yoshida H, et al. Urotensin II evokes neurotransmitter release from rat cerebrocortical slices. Neurosci Lett. 2008;440:275–9.
Bruzzone F, Cervetto C, Mazzotta MC, Bianchini P, Ronzitti E, Leprince J, et al. Urotensin II receptor and acetylcholine release from mouse cervical spinal cord nerve terminals. Neuroscience. 2010;170:67–77.
Jégou S, Cartier D, Dubessy C, Gonzalez BJ, Chatenet D, Tostivint H, et al. Localization of the urotensin II receptor in the rat central nervous system. J Comp Neurol. 2006;495:21–36.
Lin Y, Tsuchihashi T, Matsumura K, Abe I, Iida M. Central cardiovascular action of urotensin II in conscious rats. J Hypertens. 2003;21:159–65.
Lin Y, Tsuchihashi T, Matsumura K, Fukuhara M, Ohya Y, Fujii K, Iida M. Central cardiovascular action of urotensin II in spontaneously hypertensive rats. Hypertens Res. 2003;26:839–45.
Wu YM, Xue HM, Xiao L, He RR. Urotensin II inhibits carotid sinus baroreflex in anesthetized male rats. Acta Pharm Sin. 2007;28:216–20.
Wu YM, Wang R, He RR. Urotensin II inhibits electrical activity of hippocampal CA1 neurons by potentiating the GABA(A) receptor-mediated Cl(-) current. Neurosci Bull. 2006;22:110–4.
Lu Y, Zou CJ, Huang DW, Tang CS. Cardiovascular effects of urotensin II in different brain areas. Peptides. 2002;23:1631–5.
Dampney RA, Polson JW, Potts PD, Hirooka Y, Horiuchi J. Functional organization of brain pathways subserving the baroreceptor reflex: studies in conscious animals using immediate early gene expression. Cell Mol Neurobiol. 2003;23:597–616.
Lu N, Yu HY, Wang R, Zhu YC. Central reactive oxygen species mediate cardiovascular effects of urotensin II in spontaneously hypertensive rats. Sheng Li Xue Bao. 2012;64:142–8.
Forty EJ, Ashton N. The urotensin system is up-regulated in the pre-hypertensive spontaneously hypertensive rat. PLoS One. 2013;8:e83317.
Duan XC, Guo R, Liu SY, Xiao L, Xue HM, Guo Q, Jin S, Wu YM. Gene transfer of cystathionine β-synthase into RVLM increases hydrogen sulfide-mediated suppression of sympathetic outflow via KATP channel in normotensive rats. Am J Physiol Heart Circ Physiol. 2015;308:H603–11.
Duan XC, Liu SY, Guo R, Xiao L, Xue HM, Guo Q, Jin S, Wu YM. Cystathionine-β-synthase gene transfer into rostral ventrolateral medulla exacerbates hypertension via nitric oxide in spontaneously hypertensive rats. Am J Hypertens. 2015;28:1106–13.
Paxinos G, Watson C (eds). The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press: Cambridge, MA, USA, 1998.
Gartlon J, Parker F, Harrison DC, Douglas SA, Ashmeade TE, Riley GJ, et al. Central effects of urotensin-II following ICV administration in rats. Psychopharmacol (Berl). 2001;155:426–33.
Lacerda JE, Campos RR, Araujo GC, Andreatta-Van Leyen S, Lopes OU, Guertzenstein PG. Cardiovascular responses to microinjections of GABA or anesthetics into the rostral ventrolateral medulla of conscious and anesthetized rats. Braz J Med Biol Res. 2003;36:1269–77.
Herold CL, Behm DJ, Buckley PT, Foley JJ, Wixted WE, Sarau HM, et al. The neuromedin B receptor antagonist, BIM-23127, is a potent antagonist at human and rat urotensin-II receptors. Br J Pharm. 2003;139:203–7.
Filipeanu CM, Brailoiu E, Le Dun S, Dun NJ. Urotensin-II regulates intracellular calcium in dissociated rat spinal cord neurons. J Neurochem. 2002;83:879–84.
Kim YA, Lee DG, Yi KY, Lee BH, Jung YS. Blockade of urotensin II receptor prevents vascular dysfunction. Biomol Ther (Seoul). 2016;24:523–8.
Kim MY, Ilyosbek S, Lee BH, Yi KY, Jung YS. A novel urotensin II receptor antagonist, KR-36676, prevents ABCA1 repression via ERK/IL-1β pathway. Eur J Pharm. 2017;803:174–8.
Kim TH, Lee DG, Kim YA, Lee BH, Yi KY, Jung YS. A novel urotensin II receptor antagonist, KR-36996 inhibits smooth muscle proliferation through ERK/ROS pathway. Biomol Ther (Seoul). 2017;25:308–14.
Zhang J, Abdel-Rahman AA. Mitogen-activated protein kinase phosphorylation in the rostral ventrolateral medulla plays a key role in imidazoline (i1)-receptor-mediated hypotension. J Pharm Exp Ther. 2005;314:945–52.
Lin Y, Matsumura K, Tsuchihashi T, Fukuhara M, Fujii K, Iida M. Role of ERK and Rho kinase pathways in central pressor action of urotensin II. J Hypertens. 2004;22:983–8.
Wilk-Blaszczak MA, Stein B, Xu S, Barbosa MS, Cobb MH, Belardetti F. The mitogen-activated protein kinase p38-2 is necessary for the inhibition of N-type calcium current by bradykinin. J Neurosci. 1998;18:112–8.
Martin SW, Butcher AJ, Berrow NS, et al. Phosphorylation sites on calcium channel alpha1 and beta subunits regulate ERK-dependent modulation of neuronal N-type calcium channels. Cell Calcium. 2006;39:275–92.
Funding
This work was supported by the Program for the National Natural Science Foundation of China (31671185, 81770499, 31871154, 91849120).
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Cao, Yk., Guo, Q., Ma, Hj. et al. Microinjection of urotensin II into the rostral ventrolateral medulla increases sympathetic vasomotor tone via the GPR14/ERK pathway in rats. Hypertens Res 43, 765–771 (2020). https://doi.org/10.1038/s41440-020-0460-y
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DOI: https://doi.org/10.1038/s41440-020-0460-y