We have shown that angiotensin II (Ang II) and angiotensin-(1–7) [Ang-(1–7)] increased arterial blood pressure (BP) via glutamate release when microinjected into the rostral ventrolateral medulla (RVLM) in normotensive rats (control). In the present study, we tested the hypothesis that Ang II and Ang-(1–7) in the RVLM are differentially activated in stress-induced hypertension (SIH) by comparing the effects of microinjection of Ang II, Ang-(1–7), and their receptor antagonists on BP and amino acid release in SIH and control rats. We found that Ang II had greater pressor effect, and more excitatory (glutamate) and less inhibitory (taurine and γ-aminobutyric acid) amino acid release in SIH than in control animals. Losartan, a selective AT1 receptor (AT1R) antagonist, decreased mean BP in SIH but not in control rats. PD123319, a selective AT2 receptor (AT2R) antagonist, increased mean BP in control but not in SIH rats. However, Ang-(1–7) and its selective Mas receptor antagonist Ang779 evoked similar effects on BP and amino acid release in both SIH and control rats. Furthermore, we found that in the RVLM, AT1R, ACE protein expression (western blot) and ACE mRNA (real-time PCR) were significantly higher, whereas AT2R protein, ACE2 mRNA and protein expression were significantly lower in SIH than in control rats. Mas receptor expression was similar in the two groups. The results support our hypothesis and demonstrate that upregulation of Ang II by AT1R, not Ang-(1–7), system in the RVLM causes hypertension in SIH rats by increasing excitatory and suppressing inhibitory amino acid release.
References
[1]
Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM (2007) Renin-angiotensin system and cardiovascular risk. Lancet 369: 1208–1219.
[2]
Paul M, Poyan Mehr A, Kreutz R (2006) Physiology of local renin-angiotensin systems. Physiol Rev 86: 747–803.
[3]
Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, et al. (2000) A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275: 33238–33243.
[4]
Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, et al. (2000) A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. Circ Res 87(5): E1–9.
[5]
Vickers C, Hales P, Kaushik V, Dick L, Gavin J, et al. (2002) Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 277: 14838–14843.
[6]
Santos RA, Simoese Silva AC, Maric C, Silva DM, Machado RP, et al. (2003) angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci 100: 8258–8263.
[7]
Dobruch J, Paczwa P, Lon S (2003) Hypotensive function of the brain angiotensin-(1-7) in Sprague Dawley and renin transgenic rats. J Physiol Pharmacol 54: 371–381.
[8]
Phillips MI, Sumners C (1998) Angiotensin II in central nervous system physiology. Regul Pept 78: 1–11.
[9]
Chappell MC, Brosnihan KB, Diz DI, Ferrario CM (1989) Identification of angiotensin-(1–7) in rat brain. Evidence for differential processing of angiotensin peptides. J Biol Chem 264: 16518–16523.
[10]
Phillips MI, Oliveira EM (2008) Brain renin angiotensin in disease. J Mol Med 86: 715–722.
[11]
Dupont AG, Brouwers S (2010) Brain angiotensin peptides regulate sympathetic tone and blood pressure. J Hypertens 28: 1599–1610.
[12]
Kumagai H, Oshima N, Matsuura T, Iigaya K, Imai M, et al. (2012) Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure. Hypertens Res 35: 132–141.
[13]
Hu L, Zhu DN, Yu Z, Wang JQ, Sun ZJ, et al. (2002) Expression of angiotensin II type 1 (AT1) receptor in the rostral ventrolateral medulla in rats. J Appl Physiol 92: 2153–2161.
[14]
Wang J, Shen LL, Cao YX, Zhu DN (2003) Effects of electroacupuncture on pressor response to angiotensin-(1–7) by amino acid release in the rostral ventrolateral medulla. Acupuncture and Electro-Therapeutics Research, the International Journal 28: 25–34.
[15]
Wang J, Peng YJ, Zhu DN (2005) Amino acids mediate the hypotensive effect of angiotensin-(1–7) at the caudal ventrolateral medulla in rats. Regulatory Peptides 129: 1–7.
[16]
Stornetta RL, Sevigny CP, Schreihofer AM, Rosin DL, Guyenet PG (2002) Vesicular glutamate transporter DNPI/VGLUT2 is expressed by both C1 adrenergic and nonaminergic presympathetic vasomotor neurons of the rat medulla. J Comp Neurol 444: 207–220.
[17]
Xu Y, Zhang SZ, Wan Y, Yang G (2002) Expression of angiotensinogen mRNA in rat hypothalamus during stress. J Fourth Mil Med Univ 23: 596–598.
[18]
Yang G, Xi ZX, Wan Y, Wang H, Bi G (1993) Changes in circulating and tissue angiotensin II during acute and chronic stress. Biol Signals 2: 166–172.
[19]
Mayorov DN, Head GA (2003) AT1 receptors in the RVLM mediate pressor responses to emotional stress in rabbits. Hypertension 41: 1168–1173.
[20]
Xia CM, Shao CH, Xin L, Wang YR, Ding CN, et al. (2008) Effects of melatonin on blood pressure in stress-induced hypertension in rats. Clin Exp Pharmacol Physiol 35: 1258–1264.
[21]
Xiao F, Jiang MY, Du DS, Xia CM, Wang J, et al. (2013) Orexin A regulates cardiovascular responses in stress-induced hypertensive rats. Neuropharmacology 7: 16–24.
[22]
Gao L, Wang WZ, Wang W, Li HW, Sumners C, et al. (2008) Effects of angiotensin type 2 receptor overexpression in the rostral ventrolateral medulla on blood pressure and urine excretion in normal rats. Hypertension 51: 521–527.
[23]
Gwathmey TM, Pendergrass KD, Reid SD, Rose JC, Diz DI, et al. (2010) Angiotensin-(1–7)-ACE2 attenuates reactive oxygen species formation to angiotensin II within the cell nucleus. Hypertension 55: 166–171.
[24]
Sartório CL, Fraccarollo D, Galuppo P, Leutke M, Ertl G, et al. (2007) Mineralocorticoid receptor blockade improves vasomotor dysfunction and vascular oxidative stress early after myocardial infarction. Hypertension 50: 919–925.
[25]
AlGhatrif M, Kuo YF, Al Snih S, Raji MA, Ray LA, et al. (2011) Trends in hypertension prevalence, awareness, treatment and control in older Mexican Americans, 1993–2005. Ann. Epidemiol 21: 15–25.
[26]
McMullan S, Pilowsky PM (2012) Sympathetic premotor neurones project to and are influenced by neurones in the contralateral rostral ventrolateral medulla of the rat in vivo. Brain Res 23: 34–43.
[27]
Dampney RA (1997) Role of angiotensin II receptor subtypes in mediating the sympathoexcitatory effects of exogenous and endogenous angiotensin peptides in the rostral ventrolateral medulla of rabbits. Brain Res 772: 107–114.
[28]
Ito S, Hiratsuka M, Komatsu K, Tsukamoto K, Kanmatsuse K, et al. (2003) Ventrolateral medulla AT1Rs support arterial pressure in Dahl salt-sensitive rats. Hypertension 41: 744–750.
[29]
Nakagaki T, Hirooka Y, Ito K, Kishi T, Hoka S, et al. (2011) Role of angiotensin-(1–7) in rostral ventrolateral medulla in blood pressure regulation via sympathetic nerve activity in Wistar-Kyoto and spontaneous hypertensive rats. Clin Exp Hypertens. 33: 223–230.
[30]
Li P, Sun HJ, Cui BP, Zhou YB, Han Y (2013) Angiotensin-(1–7) in the rostral ventrolateral medulla modulates enhanced cardiac sympathetic afferent reflex and sympathetic activation in renovascular hypertensive rats. Hypertension 61: 820–827.
[31]
Ito S, Komatsu K, Tsukamoto K, Kanmatsuse K, Sved AF (2002) Ventrolateral medulla AT1Rs support blood pressure in hypertensive rats. Hypertension 40: 552–559.
[32]
Zhou LM, Shi Z, Gao J, Han Y, Yuan N, et al. (2010) Angiotensin-(1–7) and angiotension II in the rostral ventrolateral medulla modulate the cardiac sympathetic afferent reflex and sympathetic activity in rats. Pflugers Arch 459: 681–688.
[33]
Crackower MA, Sarao R, Oudit GY (2002) Angiotensin converting enzyme is an essential regulator of heart function. Nature 417: 822–828.
[34]
Feng Y, Yue X, Xia H, Bindom SM, Hickman PJ, et al. (2008) Angiotensin-converting enzyme2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation. Circ Res 102: 729–736.
[35]
Nunes FC, Braga VA (2011) Chronic angiotensin II infusion modulates angiotensin II type 1 receptor expression in the subfornical organ and the rostral ventrolateral medulla in hypertensive rats. J Renn Angiotensin Aldosterone Syst 12: 440–445.
[36]
Ferreira AJ, Shenoy V, Yamazato Y, Sriramula S, Francis J, et al. (2009) Evidence for angiotensin-converting enzyme2 as a therapeutic target for the prevention of pulmonary hypertension. Am J Respir Crit Care Med 179: 1048–1054.
[37]
Zhou W, Fu LW, Guo ZL, Longhurst JC (2007) Role of glutamate in the rostral ventrolateral medulla in acupuncture-related modulation of visceral reflex sympathoexcitation. Am J Physiol Heart Circ Physiol 292: H1868–1875.
[38]
Shinohara K, Hirooka Y, Kishi T, Sunagawa K (2012) Reduction of nitric oxide-mediated γ-Amino butyric acid release in rostral ventrolateral medulla is involved in superoxide-induced sympathoexcitation of hypertensive rats. Cir J 76: 2814–2821.
