Cardiovascular responses produced by resistin injected into paraventricular nucleus mediated by the glutamatergic and CRFergic transmissions within rostral ventrolateral medulla

Document Type : Original Article

Authors

1 Department of Physiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

2 Department of Physiology, School of Veterinary Medicine, Shiraz University

Abstract

Objective(s): Resistin, as a 12.5 kDa cysteine-rich polypeptide, is expressed in hypothalamus and regulates sympathetic nerve activity. It is associated with obesity, metabolic syndrome and cardiovascular diseases. In this study, we investigated the neural pathway of cardiovascular responses induced by injection of resistin into paraventricular nucleus (PVN) with rostral ventrolateral medulla (RVLM).
Materials and Methods: Adult male rats were anesthetized with urethane (1.4 g/kg intraperitoneally). Resistin (3 µg/1 µl/rat) was first injected into PVN, and the glutamatergic, corticotrophin-releasing factor (CRF)-ergic and angiotensinogenic transmission was inhibited by injecting of their antagonist in RVLM. Arterial pressure (AP) and heart rate (HR) were monitored before and after the injection.
Results: The results showed that resistin injection into PVN significantly increased AP and HR compared to control group and prior to its injection (P<0.05). Injection of AP5 ((2R)-amino-5-phosphonovaleric acid; (2R)-amino-5-phosphonopentanoate) (50 nM/rat), losartan (10 nM/rat) and astressin (50 nM/rat) into RVLM reduced cardiovascular responses produced by injected resistin into PVN. Injection of AP5+losartan or astressin+losartan or astressin+AP5 into RVLM could significantly reduce cardiovascular responses produced by resistin compared to before injection (P<0.05). Furthermore, the depressor responses generated by AP5+losartan injected into RVLM were significantly stronger than the depressor responses generated by AP5+astressin and/or astressin+losartan injected into RVLM (P<0.05).
Conclusion: It can be concluded that glutamatergic and CRFergic transmissions have crucial contribution to cardiovascular responses produced by resistin. The results provided new and potentially important insight regarding neural transmission when the plasma level of resistin increases; this reveals the role of resistin in cardiovascular responses such as metabolic syndrome and hypertension.

Keywords


1. McAllen R. Mediation of the fastigial pressor response and a somatosympathetic reflex by ventral medullary neurones in the cat. J Physiol. 1985;368:423-433.
2. Guyenet P. Role of the ventral medulla oblongata in blood pressure regulation. Cen Regu Auton Fun 1990:145-167.
3. Verberne AJ, OWENS NC. Cortical modulation of the cardiovascular system. Prog Neurobiol 1998;54:149-168.
4. Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci 2006;7:335-346.
5. Hill JW. PVN pathways controlling energy homeostasis. Ind J Endocrinol Metabol 2012;16: 627-636.
6. Benarroch EE. Paraventricular nucleus, stress response, and cardiovascular disease. Clin Auton Res 2005;15:254-263.
7. Dampney RA, Michelini LC, Li DP, Pan HL. Regulation of sympathetic vasomotor activity by the hypothalamic paraventricular nucleus in normotensive and hypertensive states. Am J Physiol Heart Circ Physiol 2018;1;315: 1200-1214
8. Shafton AD, Ryan A, Badoer E. Neurons in the hypothalamic paraventricular nucleus send collaterals to the spinal cord and to the rostral ventrolateral medulla in the rat. Brain Res 1998;801:239-243.
9. Tjen-A-Looi SC, Guo Z-L, Fu L-W, Longhurst JC. Paraventricular Nucleus Modulates Excitatory Cardiovascular Reflexes during Electroacupuncture. Sci Rep 2016;6:25910-25923.
10.    Xu B, Zheng H, Patel KP. Enhanced activation of RVLM-projecting PVN neurons in rats with chronic heart failure. Am J Physiol Heart Cir Physiol 2012;302: 1700-1711.
11.    Lee SK, Ryu PD, Lee SY. Differential distributions of neuropeptides in hypothalamic paraventricular nucleus neurons projecting to the rostral ventrolateral medulla in the rat. Neurosci Lett 2013;556:160-165.
12.    Bardgett ME, Sharpe AL, Toney GM. Activation of corticotropin-releasing factor receptors in the rostral ventrolateral medulla is required for glucose-induced sympathoexcitation. Am J Physiol Endocrinol Metabol 2014;307:944-953.
13.    Milner TA, Reis DJ, Pickel VM, Aicher SA, Giuliano R. Ultrastructural localization and afferent sources of corticotropin-releasing factor in the rat rostral ventrolateral medulla: implications for central cardiovascular regulation. J Comp Neurol 1993;333:151-167.
14.    Gabor A, Leenen FH. Central neuromodulatory pathways regulating sympathetic activity in hypertension. J Appl Physiol (1985) 2012;113:1294-1303.
15.    Ito S, Hiratsuka M, Komatsu K, Tsukamoto K, Kanmatsuse K, Sved AF. Ventrolateral medulla AT1 receptors support arterial pressure in Dahl salt-sensitive rats. Hypertension 2003;41:744-750.
16.    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307-312.
17.    Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Com 2001;285:561-564.
18.    Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, Plumpton C, et al. Resistin is expressed in human macrophages and directly regulated by PPARγ activators. Biochem Biophys Res Com 2003;300:472-476.
19.    Morash BA, Ur E, Wiesner G, Roy J, Wilkinson M. Pituitary resistin gene expression: effects of age, gender and obesity. Neuroendocrinol 2004;79:149-156.
20.    Tovar S, Nogueiras R, Tung LY, Castaneda TR, Vazquez MJ, Morris A, et al. Central administration of resistin promotes short-term satiety in rats. Euro J Endocrinol 2005;153:1-5.
21.    Vazquez MJ, Gonzalez CR, Varela L, Lage R, Tovar S, Sangiao-Alvarellos S, et al. Central resistin regulates hypothalamic and peripheral lipid metabolism in a nutritional-dependent fashion. Endocrinol 2008;149:4534-4543.
22.    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307-312.
23.    Viengchareun S, Zennaro MC, Pascual-Le Tallec L, Lombes M. Brown adipocytes are novel sites of expression and regulation of adiponectin and resistin. FEBS Lett 2002;532:345-350.
24.    Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Tumor necrosis factor α is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes. Biochem Biophys Res Com 2001;288:1027-1031.
25.    Ling C, Kindblom J, Wennbo H, Billig H. Increased resistin expression in the adipose tissue of male prolactin transgenic mice and in male mice with elevated androgen levels. FEBS Lett 2001;507:147-150.
26.    Morash BA, Ur E, Wiesner G, Roy J, Wilkinson M. Pituitary resistin gene expression: effects of age, gender and obesity. Neuroendocrinol 2004;79:149-156.
27.    Bhalla V, Kalogeropoulos A, Georgiopoulou V, Butler J. Serum resistin: physiology, pathophysiology and implications for heart failure. Biomark Med. 2010;4:445-452.
28.    Takeishi Y, Niizeki T, Arimoto T, Nozaki N, Hirono O, Nitobe J, et al. Serum resistin is associated with high risk in patients with congestive heart failure--a novel link between metabolic signals and heart failure. Circ J 2007;71:460-464.
29.    Norata GD, Ongari M, Garlaschelli K, Raselli S, Grigore L, Catapano AL. Plasma resistin levels correlate with determinants of the metabolic syndrome. Eur J Endocrinol 2007;156:279-84.
30.    Fisher JP, Young CN, Fadel PJ. Central sympathetic overactivity: maladies and mechanisms. Auton Neurosci 2009;148:5-15.
31.    Esler M, Rumantir M, Wiesner G, Kaye D, Hastings J, Lambert G. Sympathetic nervous system and insulin resistance: from obesity to diabetes. Am J Hypertension 2001;14:304-309.
32.    Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, et al. FIZZ1, a novel cysteine‐rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J 2000;19:4046-4055.
33.    Kosari S, Rathner JA, Chen F, Kosari S, Badoer E. Centrally administered resistin enhances sympathetic nerve activity to the hindlimb but attenuates the activity to brown adipose tissue. Endocrinol 2011;152:2626-2633.
34.    Berghoff M, Hochberg A, Schmid A, Schlegel J, Karrasch T, Kaps M, et al. Quantification and regulation of the adipokines resistin and progranulin in human cerebrospinal fluid. Euro J Clin Invest 2016;46:15-26.
35.    Kos K, Harte AL, da Silva NF, Tonchev A, Chaldakov G, James S, et al. Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus. J Clin Endocrinol Metabol 2007;92:1129-1136.
36.    Akbari A, Jelodar G. Central administration of resistin into the paraventricular nucleus (PVN) produces significant cardiovascular responses. Physiol Pharmacol 2017;21:216-224.
37.    Benomar Y, Gertler A, De Lacy P, Crepin D, Ould Hamouda H, Riffault L, et al. Central resistin overexposure induces insulin resistance through Toll-like receptor 4. Diabetes 2013;62:102-114.
38.    Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. Elsevier. 2005:39-48.
39.    Yang Z, Coote JH. Influence of the hypothalamic paraventricular nucleus on cardiovascular neurones in the rostral ventrolateral medulla of the rat. J Physiol 1998;513:521-530.
40.    Zhou W, Fu L-W, Tjen-A-Looi SC, Guo Z-l, Longhurst JC. Role of glutamate in a visceral sympathoexcitatory reflex in rostral ventrolateral medulla of cats. Am J Physiol Heart Circ Physiol2006;291: 1309-1318.
41.    Wang WZ, Gao L, Wang HJ, Zucker IH, Wang W. Tonic glutamatergic input in the rostral ventrolateral medulla is increased in rats with chronic heart failure. Hypertension 2009;53:370-4.
42.    Zhang Y, Li Y, Yu L, Zhou L. Association between serum resistin concentration and hypertension: A systematic review and meta-analysis. Oncotarget 2017;8:41529-41537.
43.    Habeeballah H, Alsuhaymi N, Stebbing MJ, Jenkins TA, Badoer E. Central administration of insulin and leptin together enhance renal sympathetic nerve activity and fos production in the arcuate nucleus. Front Physiol 2016;7:672-681.
44.    Van Kempen TA, Dodos M, Woods C, Marques-Lopes J, Justice NJ, Iadecola C, et al. Sex differences in NMDA GluN1 plasticity in rostral ventrolateral medulla neurons containing corticotropin-releasing factor type 1 receptor following slow-pressor angiotensin II hypertension. Neuroscience. 2015;307:83-97.
45.    Benarroch EE. Paraventricular nucleus, stress response, and cardiovascular disease. Clin Auton Res 2005;15:254-263.
46.    Hu L, Zhu DN, Yu Z, Wang JQ, Sun ZJ, Yao T. Expression of angiotensin II type 1 (AT(1)) receptor in the rostral ventrolateral medulla in rats. J Appl Physiol (1985) 2002;92:2153-161.
47.    Averill DB, Tsuchihashi T, Khosla MC, Ferrario CM. Losartan, nonpeptide angiotensin II-type 1 (AT1) receptor antagonist, attenuates pressor and sympathoexcitatory responses evoked by angiotensin II and L-glutamate in rostral ventrolateral medulla. Brain Res 1994;665:245-252.
48.    Tagawa T, Dampney RA. AT(1) receptors mediate excitatory inputs to rostral ventrolateral medulla pressor neurons from hypothalamus. Hypertension 1999;34:1301-1307.
49.    Gabor A, Leenen FHH. Central neuromodulatory pathways regulating sympathetic activity in hypertension. J Appl Physiol (Bethesda, Md : 1985) 2012;113:1294-1303.
50.    Tagawa T, Horiuchi J, Potts PD, Dampney RA. Sympathoinhibition after angiotensin receptor blockade in the rostral ventrolateral medulla is independent of glutamate and gamma-aminobutyric acid receptors. J Auton Nerv Syst 1999;77:21-30.