Abstract
6-Nitrodopamine (6-ND) is released from rat isolated atria being 100 times more potent than noradrenaline and adrenaline, and 10,000 times more potent than dopamine as a positive chronotropic agent. The present study aimed to investigate the interactions of 6-ND with the classical catecholamines, phosphodiesterase (PDE)-3 and PDE4, and the protein kinase A in rat isolated atria. Atrial incubation with 1 pM of dopamine, noradrenaline, or adrenaline had no effect on atrial frequency. Similar results were observed when the atria were incubated with 0.01 pM of 6-ND. However, co-incubation of 6-ND (0.01 pM) with dopamine, noradrenaline, or adrenaline (1 pM each) resulted in significant increases in atrial rate, which persisted over 30 min after washout of the agonists. The increased atrial frequency induced by co-incubation of 6-ND with the catecholamines was significantly reduced by the voltage-gated sodium channel blocker tetrodotoxin (1 µM, 30 min), indicating that the positive chronotropic effect of 6-ND is due in part to activation of nerve terminals. Pre-treatment of the animals with reserpine had no effect on the positive chronotropic effect induced by dopamine, noradrenaline, or adrenaline; however, reserpine markedly reduced the 6-ND (1 pM)-induced positive chronotropic effect. Incubation of the rat isolated atria with the protein kinase A inhibitor H-89 (1 µM, 30 min) abolished the increased atrial frequency induced by dopamine, noradrenaline, and adrenaline, but only attenuated the increases induced by 6-ND. 6-ND induces catecholamine release from adrenergic terminals and increases atrial frequency independently of PKA activation.
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References
Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S (2006) Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 50(8):941–952. https://doi.org/10.1016/j.neuropharm.2006.01.005
Bacq A, Balasse L, Biala G, Guiard B, Gardier AM, Schinkel A, Louis F, Vialou V, Martres MP, Chevarin C, Hamon M, Giros B, Gautron S (2012) Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Mol Psychiatry 17(9):926–939. https://doi.org/10.1038/mp.2011.87
Bien HJ (1953) Zur pharmakologie des reserpin eines neuen Alkaloids aus Rauwolfia serpentina Benth [Pharmacology of reserpin, a new alkaloid from Rauwolfia serpentina Benth]. Experientia 15;9(3):107–110. Undetermined Language. https://doi.org/10.1007/BF02178342
Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58(3):488–520. https://doi.org/10.1124/pr.58.3.5
Brasch H (1993) Field stimulation-induced noradrenaline release from guinea-pig atria is modulated by pre-junctional a2-adrenoceptors and protein kinase C. Basic Res Cardiol 88:545–556
Britto-Júnior J, Lima AT, Santos-Xavier J, Gonzalez P, Monica FZ, Campos R, Souza V, Schenka AA, Antunes E and De Nucci G (2023) Relaxation of marmoset (Callithrix spp.) thoracic aorta and pulmonary artery rings by endothelium-derived 6-nitrodopamine. Braz J Med Biol Res, in press
Britto-Júnior J, Coelho-Silva WC, Murari GF, Serpellone Nash CE, Mónica FZ, Antunes E, De Nucci G (2021) 6-Nitrodopamine is released by human umbilical cord vessels and modulates vascular reactivity. Life Sci 1(276):119425. https://doi.org/10.1016/j.lfs.2021.119425
Britto-Júnior J, de Oliveira MG, Dos Reis GC, Campos R, Moraes MO, Moraes MEA, Mónica FZ, Antunes E, De Nucci G (2022) 6-NitroDopamine is an endogenous modulator of rat heart chronotropism. Life Sci 10(307):120879. https://doi.org/10.1016/j.lfs.2022.120879 Epub ahead of print
Campos R, Pinheiro DHA, Britto-Júnior J, de Castro HA, Mendes GD, Moraes MO, Moraes MEA, Lopes-Martins RÁB, Antunes NJ, De Nucci G (2021) Quantification of 6-nitrodopamine in Krebs-Henseleit’s solution by LC-MS/MS for the assessment of its basal release from Chelonoidis carbonaria aortae in vitro. J Chromatogr B Anal Technol Biomed Life Sci 22(1173):122668. https://doi.org/10.1016/j.jchromb.2021.122668
Chijiwa T, Mishima A, Hagiwara M, Sano M, Hayashi K, Inoue T, Naito K, Toshioka T, Hidaka H (1990) Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J Biol Chem 25;265(9):5267–5272
Christ T, Galindo-Tovar A, Thoms M, Ravens U, Kaumann AJ (2009) Phosphodiesterases3- and 4-controlled compartments, activated by β1- and β2-adrenoceptors, differ for L-type Ca2+ current and inotropy in rat heart. Br J Pharmacol 156:62–83
Dolce B, Christ T, Grammatika Pavlidou N, Yildirim Y, Reichenspurner H, Eschenhagen T, Nikolaev VO, Kaumann AJ, Molina CE (2021) Impact of phosphodiesterases PDE3 and PDE4 on 5-hydroxytryptamine receptor4-mediated increase of cAMP in human atrial fibrillation. Naunyn Schmiedeberg's Arch Pharmacol 394(2):291–298. https://doi.org/10.1007/s00210-020-01968-1
Edmondson DE, Binda C (2018) Monoamine Oxidases. Subcell Biochem 87:117–139. https://doi.org/10.1007/978-981-10-7757-9_5
Engel K, Zhou M, Wang J (2004) Identification and characterization of a novel monoamine transporter in the human brain. J Biol Chem 279:50042–50049. https://doi.org/10.1074/jbc.M407913200
Engelhart DC, Granados JC, Shi D, Saier MH Jr, Baker ME Jr, Abagyan R, Nigam SK (2020) Systems biology analysis reveals eight SLC22 transporter subgroups, including OATs, OCTs, and OCTNs. Int J Mol Sci 5;21(5):1791. https://doi.org/10.3390/ijms21051791
Erickson JD, Eiden LE, Hoffman BJ (1992) Expression cloning of a reserpine-sensitive vesicular monoamine transporter. Proc Natl Acad Sci USA 15;89(22):10993–10997. https://doi.org/10.1073/pnas.89.22.10993
Fischmeister R, Castro LRV, Abi-Gerges A, Rochais F, Jurevicius J, Leroy J, Vandecasteele G (2006) Compartmentation of cyclic nucleotide signalling in the heart. The role of cyclic nucleotide phosphodiesterases. Circ Res 99:816–828
Flohé L (1974) Catechol-O-methyltransferase. Int Pharmacopsychiatry 9(1):52–60. https://doi.org/10.1159/000468115
Fu Q, Chen X, Xiang YK (2013) Compartmentalization of β-adrenergic signals in cardiomyocytes. Trends Cardiovasc Med 23(7):250–256. https://doi.org/10.1016/j.tcm.2013.02.001
Galindo-Tovar A, Kaumann AJ (2008) Phosphodiesterase-4 blunts inotropism and arrhythmias but not sinoatrial tachycardia of (-)-adrenaline mediated through mouse cardiac beta(1)-adrenoceptors. Br J Pharmacol 153(4):710–720. https://doi.org/10.1038/sj.bjp.0707631
Gasser PJ (2021) Organic cation transporters in brain catecholamine homeostasis. Handb Exp Pharmacol 266:187–197. https://doi.org/10.1007/164_2021_470
Gründemann D, Harlfinger S, Golz S, Geerts A, Lazar A, Berkels R, Jung N, Rubbert A, Schömig E (2005) Discovery of the ergothioneine transporter. Proc Natl Acad Sci USA 5;102(14):5256–5261. https://doi.org/10.1073/pnas.0408624102
Habuchi Y, Tanaka H, Nishio M, Yamamoto T, Komori T, Morikawa J, Yoshimura M (1997) Dopamine stimulation of cardiac beta-adrenoceptors: the involvement of sympathetic amine transporters and the effect of SKF38393. Br J Pharmacol 122(8):1669–1678. https://doi.org/10.1038/sj.bjp.0701574
Hirning LD, Fox AP, McCleskey EW, Olivera BM, Thayer SA, Miller RJ, Tsien RW (1988) Dominant role of N-type Ca2+ channels in evoked release of norepinephrine from sympathetic neurons. Science. 239(4835):57–61. https://doi.org/10.1126/science.2447647
Honerjäger P (1989) Pharmacology of positive inotropic phosphodiesterase III inhibitors. Eur Heart J 10(Suppl C):25–31. https://doi.org/10.1093/eurheartj/10.suppl_c.25
Huotari M, Passlin M, Nordberg HL, Forsberg M, Kotisaari S, Tuomisto L, Shintani F, Tanaka KF, Reenilä I, Laitinen K, Männistö PT (2001) Effect of intracerebral 6-nitronoradrenaline, an endogenous catechol-O-methyltransferase (COMT) inhibitor, on striatal dopamine metabolism in anaesthetised rats. J Neurosci Methods 15;109(1):47–52. https://doi.org/10.1016/s0165-0270(01)00400-9
Katano Y, Endoh M (1992) Effects of a cardiotonic quinolinone derivative Y-20487 on the positive inotropic action and cyclic AMP-accumulation in rat ventricular myocardium: comparison with rolipram, Ro 20–1724, milrinone, and isobutylmethylxanthine. Cardiovasc Pharmacol 20:715–722
Katsel PL, Tagliente TM, Schwarz TE, Craddock-Royal BD, Patel ND, Maayani S (2003) Molecular and biochemical evidence for the presence of type III adenylyl cyclase in human platelets. Platelets 14(1):21–33. https://doi.org/10.1080/0953710021000062905
Kaumann AJ, Galindo-Tovar A, Escudero E, Vargas ML (2009) Phosphodiesterases do not limit β1-adrenoceptor-mediated sinoatrial tachycardia: evidence with PDE3 and PDE4 in rabbits and PDE1-5 in rats. Naunyn-Schmied Arch Pharmacol 380:421–430
Kerfant BG, Zhao D, Lorenzen-Schmidt I, Wilson LS, Cai S, Chen SR, Maurice DH, Backx PH (2007) PI3Kgamma is required for PDE4, not PDE3, activity in subcellular microdomains containing the sarcoplasmic reticular calcium ATPase in cardiomyocytes. Circ Res 17;101(4):400–408. https://doi.org/10.1161/CIRCRESAHA.107.156422
Li X, Rose G, Chiari A, Pan HL, Tobin JR, Eisenach JC (2000) 6-NO(2)-norepinephrine increases norepinephrine release and inhibits norepinephrine uptake in rat spinal synaptosomes. J Pharmacol Exp Ther 292(3):895–899
Lima AT, Dos Santos EX, Britto-Júnior J, de Souza VB, Schenka AA, Campos R, Moraes MO, Moraes MEA, Antunes E, De Nucci G (2022) Release of 6-nitrodopamine modulates vascular reactivity of Pantherophis guttatus aortic rings. Comp Biochem Physiol C Toxicol Pharmacol 262:109471. https://doi.org/10.1016/j.cbpc.2022.109471
Liu GQ, Algeri S, Garattini S (1982) D-L-tetrahydropalmatine as monoamine depletor. Arch Int Pharmacodyn Ther 258(1):39–50
Andersen ML (2016) Guia brasileiro de produção, manutenção ou utilização de animais em atividade de ensino ou pesquisa cientifica, Conselho nacional de controle de experimentação animal. Ministério da Ciência, Tecnologia e Inovação, Brasília
Magaribuchi T, Kurahashi K, Akimoto Y, Fujiwara M (1988) Extraneuronal accumulation of isoproterenol in atria and ventricle of perfused rat heart. Life Sci 42(7):753–757. https://doi.org/10.1016/0024-3205(88)90647-9
Maier J, Niello M, Rudin D, Daws LC, Sitte HH (2021) The interaction of organic cation transporters 1-3 and PMAT with psychoactive substances. Handb Exp Pharmacol 66:199–214. https://doi.org/10.1007/164_2021_469
Manzoor S, Hoda N (2020) A comprehensive review of monoamine oxidase inhibitors as Anti-Alzheimer’s disease agents: a review. Eur J Med Chem 15(206):112787. https://doi.org/10.1016/j.ejmech.2020.112787
Michel MC, Murphy TJ, Motulsky HJ (2020) New author guidelines for displaying data and reporting data analysis and statistical methods in experimental biology. Mol Pharmacol 97(1):49–60. https://doi.org/10.1124/mol.119.118927
Motulsky HJ (2014) Common misconceptions about data analysis and statistics. Naunyn Schmiedeberg’s Arch Pharmacol 387(11):1017–1023. https://doi.org/10.1007/s00210-014-1037-6
Murnaghan MF (1968) Restoration of the chronotropic effect of tyramine on rat atria after reserpine. Br J Pharmacol 34(1):88–98. https://doi.org/10.1111/j.1476-5381.1968.tb07953.x
Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, Garner P, Holgate ST, Howells DW, Karp NA, Lazic SE, Lidster K, MacCallum CJ, Macleod M et al (2020) The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol 14;18(7):e3000410. https://doi.org/10.1371/journal.pbio.3000410
Nash CES, Antunes NJ, Coelho-Silva WC, Campos R, De Nucci G (2022) Quantification of cyclic AMP and cyclic GMP levels in Krebs-Henseleit solution by LC-MS/MS: application in washed platelet aggregation samples. J Chromatogr B Anal Technol Biomed Life Sci 15(1211):123472. https://doi.org/10.1016/j.jchromb.2022.123472
Riado SR, Zanesco A, Barker LA, De Luca IM, Antunes E, De Nucci G (1999) Long-term nitric oxide inhibition and chronotropic responses in rat isolated right atria. Hypertension. 34(4 Pt 2):802–807. https://doi.org/10.1161/01.hyp.34.4.802
Sorriento D, Santulli G, Del Giudice C, Anastasio A, Trimarco B, Iaccarino G (2012) Endothelial cells are able to synthesize and release catecholamines both in vitro and in vivo. Hypertension. 60(1):129–136. https://doi.org/10.1161/HYPERTENSIONAHA.111.189605
Shintani F, Kinoshita T, Kanba S, Ishikawa T, Suzuki E, Sasakawa N, Kato R, Asai M, Nakaki T (1996) Bioactive 6-nitronorepinephrine identified in mammalian brain. J Biol Chem 7;271(23):13561–13565. https://doi.org/10.1074/jbc.271.23.13561
Staveren WC, Markerink-van Ittersum M, Steinbusch HW, de Vente J (2001) The effects of phosphodiesterase inhibition on cyclic GMP and cyclic AMP accumulation in the hippocampus of the rat. Brain Res 12;888(2):275–286. https://doi.org/10.1016/s0006-8993(00)03081-x
Torres GE, Gainetdinov RR, Caron MG (2003) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4(1):13–25. https://doi.org/10.1038/nrn1008
Vandecasteele G, Bedioune I (2021) Investigating cardiac β-adrenergic nuclear signaling with FRET-based biosensors. Ann Endocrinol (Paris) 82(3-4):198–200. https://doi.org/10.1016/j.ando.2020.04.001
Vega T, De Pascual R, Bulbena O, García AG (1995) Effects of omega-toxins on noradrenergic neurotransmission in beating guinea pig atria. Eur J Pharmacol 4;276(3):231–238. https://doi.org/10.1016/0014-2999(95)00032-g
Vinogradova TM, Lyashkov AE, Zhu W, Ruknudin AM, Sirenko S, Yang D, Deo S, Barlow M, Johnson S, Caffrey JL, Zhou Y-Y, Xiao R-P, Cheng H, Stern MD, Maltsev VA, Lakatta EG (2006) High basal protein kinase A-dependent phosphorylation drives rhythmic internal Ca2+ store oscillations and spontaneous beating of cardiac pacemaker cells. Circ Res 98:505–514
Acknowledgements
JBJ thanks FAPESP for the post-doctoral fellowship (2021/14414-8). ATL and VF thank FAPESP for PhD fellowship (2021/13593-6, 2022/07737-8). EA and FM thank FAPESP (2017/15175-1). GDN thanks FAPESP (2019/16805-4) and CNPq (303839/2019-8).
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JBJ thanks FAPESP for the post-doctoral fellowship (2021/14414-8). ATL thanks FAPESP for PhD fellowship (2021/13593-6). VF thanks FAPESP for PhD fellowship (2022/07737-8). EA and FM thank FAPESP (2017/15175-1). GDN thanks FAPESP (2019/16805-4) and CNPq (303839/2019-8).
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Conceptualization: JBJ, GDN. Data curation: JBJ, GDN. Formal analysis: GDN Funding acquisition: EA, GDN. Investigation: JBJ, ATL, VF, GDN. Methodology: JBJ, ATL, VF, EA, FZM, GDN. Project administration: GDN. Supervision: FZM, EA. Visualization: EA, GDN. Writing—original draft: JBJ, FZM, EA, GDN. The authors declare that all data were generated in-house and that no paper mill was used.
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Britto-Júnior, J., Lima, A.T., Fuguhara, V. et al. Investigation on the positive chronotropic action of 6-nitrodopamine in the rat isolated atria. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1279–1290 (2023). https://doi.org/10.1007/s00210-023-02394-9
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DOI: https://doi.org/10.1007/s00210-023-02394-9