Skip to main content

Advertisement

SpringerLink
Log in

Dopamine D4 receptor subtype activation reduces the rat cardiac parasympathetic discharge

  • Integrative physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The dopaminergic system influences the heart rhythm by inhibiting the rat cardiac sympathetic and parasympathetic neurotransmissions through activation of D2-like receptors (encompassing the D2, D3, and D4 subtypes). Whereas D2 receptor subtype activation results in cardiac sympatho-inhibition, the dopamine receptor subtypes involved in rat cardiac vago-inhibition remain unknown. Hence, this study investigated the specific functional role of the D2-like receptor subtypes (D2, D3, and/or D4) inhibiting the rat heart cholinergic drive. For this purpose, male Wistar rats were pithed and prepared for cardiac vagal stimulation. Bradycardic responses were obtained by electrical stimulation of vagal fibres (3, 6, 9 Hz; n = 100) or i.v. acetylcholine (ACh; 1, 5, 10 μg/kg; n = 15). Expression of D2, D3, and D4 receptors was studied in left and right atrium samples by PCR (n = 4). Intravenous injections of quinpirole (D2-like agonist; 1–30 μg/kg), but not of SFK-38393 (D1-like agonist; 1–30 μg/kg), dose-dependently inhibited the vagally induced bradycardia. The vago-inhibition induced by quinpirole (which failed to affect the bradycardia to i.v. ACh) was unchanged after i.v. injections of the antagonists L-741,626 (D2; 100 μg/kg) or SB-277011-A (D3; 100 μg/kg), but it was abolished by L-745,870 (D4; 100 μg/kg). mRNA levels of D2, D3, and D4 receptor subtype were detected in the left and right rat atria. Our results suggest that the quinpirole-induced vagolytic effect involves prejunctional D4 receptor subtypes, located in the left and right atria. This provides new evidence on the relevance of D4 receptor modulating the heart parasympathetic control.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Altamirano-Espinoza AH, González-Hernández A, Manrique-Maldonado G, Marichal-Cancino BA, Ruiz-Salinas I, Villalón CM (2013) The role of dopamine D2, but not D3 or D4, receptor subtypes, in quinpirole-induced inhibition of the cardioaccelerator sympathetic outflow in pithed rats. Br J Pharmacol 170:1102–1111. https://doi.org/10.1111/bph.12358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Azdad K, Piet R, Poulain DA, Oliet SHR (2003) Dopamine D4 receptor-mediated presynaptic inhibition of GABAergic transmission in the rat supraoptic nucleus. J Neurophysiol 90:559–565. https://doi.org/10.1152/jn.00226.2003

    Article  CAS  PubMed  Google Scholar 

  3. Banday AA, Lokhandwala MF (2008) Dopamine receptors and hypertension. Curr Hypertens Rep 10:268–275. https://doi.org/10.1007/s11906-008-0051-9

    Article  CAS  PubMed  Google Scholar 

  4. Beaulieu J-M, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63:182–217. https://doi.org/10.1124/pr.110.002642

    Article  CAS  PubMed  Google Scholar 

  5. Bettoni M, Zimmermann M (2002) Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation 105:2753–2759. https://doi.org/10.1161/01.cir.0000018443.44005.d8

    Article  PubMed  Google Scholar 

  6. Boehm S, Kubista H (2002) Fine tuning of sympathetic transmitter release via ionotropic and metabotropic presynaptic receptors. Pharmacol Rev 54:43–99. https://doi.org/10.1124/pr.54.1.43

    Article  CAS  PubMed  Google Scholar 

  7. Bonaventura J, Quiroz C, Cai NS, Rubinstein M, Tanda G, Ferré S (2017) Key role of the dopamine D4 receptor in the modulation of corticostriatal glutamatergic neurotransmission. Sci Adv 3:e1601631. https://doi.org/10.1126/sciadv.1601631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bowery BJ, Razzaque Z, Emms F, Patel S, Freedman S, Bristow L, Kulagowski J, Seabrook GR (1996) Antagonism of the effects of (+)-PD 128907 on midbrain dopamine neurones in rat brain slices by a selective D2 receptor antagonist L-741,626. Br J Pharmacol 119:1491–1497. https://doi.org/10.1111/j.1476-5381.1996.tb16063.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bunzow JR, Van Tol HH, Grandy DK, Albert P, Salon J, Christie M, Machida CA, Neve KA, Civelli O (1988) Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 336:783–787. https://doi.org/10.1038/336783a0

    Article  CAS  PubMed  Google Scholar 

  10. Chang JS, Yoo CS, Yi SH, Hong KH, Oh HS, Hwang JY, Kim S-G, Ahn YM, Kim YS (2009) Differential pattern of heart rate variability in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 33:991–995. https://doi.org/10.1016/j.pnpbp.2009.05.004

    Article  PubMed  Google Scholar 

  11. Coumel P (1996) Autonomic influences in atrial tachyarrhythmias. J Cardiovasc Electrophysiol 7:999–1007. https://doi.org/10.1111/j.1540-8167.1996.tb00474.x

    Article  CAS  PubMed  Google Scholar 

  12. De Jong APH, Verhage M (2009) Presynaptic signal transduction pathways that modulate synaptic transmission. Curr Opin Neurobiol 19:245–253. https://doi.org/10.1016/j.conb.2009.06.005

    Article  CAS  PubMed  Google Scholar 

  13. Dopamine Receptors Scientific Review (Strange PG & Neve K). Tocris Bioscience Page, from https://www.tocris.com/literature/scientific-reviews/dopamine-receptors. Accessed 24 February 2020.

  14. Dyavanapalli J, Byrne P, Mendelowitz D (2013) Activation of D2-like dopamine receptors inhibits GABA and glycinergic neurotransmission to pre-motor cardiac vagal neurons in the nucleus ambiguus. Neuroscience 247:213–226. https://doi.org/10.1016/j.neuroscience.2013.05.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. García M, Morán A, Martín ML, Ortiz de Urbina AV, San Román L (2007) Diabetes-induced changes in 5-hydroxytryptamine modulation of vagally-induced bradycardia in rat heart. Clin Exp Pharmacol Physiol 34:1199–1206. https://doi.org/10.1111/j.1440-1681.2007.04688.x

    Article  CAS  PubMed  Google Scholar 

  16. García-Pedraza JÁ, García M, Martín ML, Eleno N, Morán A (2017) Chronic sarpogrelate treatment reveals 5-HT7 receptor in the serotonergic inhibition of the rat vagal bradycardia. J Cardiovasc Pharmacol 69:13–22. https://doi.org/10.1097/FJC.0000000000000433

    Article  CAS  PubMed  Google Scholar 

  17. Gordan R, Gwathmey JK, Xie L-H (2015) Autonomic and endocrine control of cardiovascular function. World J Cardiol 7:204–214. https://doi.org/10.4330/wjc.v7.i4.204

    Article  PubMed  PubMed Central  Google Scholar 

  18. Holmes A, Lachowicz JE, Sibley DR (2004) Phenotypic analysis of dopamine receptor knockout mice; recent insights into the functional specificity of dopamine receptor subtypes. Neuropharmacology 47:1117–1134. https://doi.org/10.1016/j.neuropharm.2004.07.034

    Article  CAS  PubMed  Google Scholar 

  19. Hyde TM, Knable MB, Murray AM (1996) Distribution of dopamine D1-D4 receptor subtypes in human dorsal vagal complex. Synapse 24:224–232. https://doi.org/10.1002/(SICI)1098-2396(199611)24:3<224::AID-SYN4>3.0.CO;2-G

    Article  CAS  PubMed  Google Scholar 

  20. Jose PA, Eisner GM, Felder RA (2003) Regulation of blood pressure by dopamine receptors. Nephron Physiology 95:19–27. https://doi.org/10.1159/000073676

    Article  CAS  Google Scholar 

  21. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. J Pharmacol Pharmacother 1:94–99. https://doi.org/10.1371/journal.pbio.1000412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. López C, Gómez-Roso M, García-Pedraza JÁ, Martín ML, Morán A, García-Domingo M (2019) Fluoxetine oral treatment discloses 5-HT1D receptor as vagoinhibitor of the cardiac cholinergic neurotransmission in rat. Can J Physiol Pharmacol 97:90–98. https://doi.org/10.1139/cjpp-2018-0390

    Article  CAS  PubMed  Google Scholar 

  23. Manrique-Maldonado G, Altamirano-Espinoza AH, Rivera-Mancilla E, Hernández-Abreu O, Villalón CM (2019) Activation of dopamine D3 receptor subtypes inhibits the neurogenic systemic vasodilation induced by stimulation of the perivascular CGRPergic discharge. ACS Chem Neurosci 10:3751–3757. https://doi.org/10.1021/acschemneuro.9b00277

    Article  CAS  PubMed  Google Scholar 

  24. Manrique-Maldonado G, González-Hernández A, Marichal-Cancino BA, Villamil-Hernández MT, del Mercado OA, Centurión D, Villalón CM (2011) The dopamine receptors mediating inhibition of the sympathetic vasopressor outflow in pithed rats: pharmacological correlation with the D(2)-like type. Basic Clin Pharmacol Toxicol 109:506–512. https://doi.org/10.1111/j.1742-7843.2011.00762.x

    Article  CAS  PubMed  Google Scholar 

  25. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78:189–225. https://doi.org/10.1152/physrev.1998.78.1.189

    Article  CAS  PubMed  Google Scholar 

  26. Neve KA, Seamans JK, Trantham-Davidson H (2004) Dopamine receptor signaling. J Recept Signal Transduct Res 24:165–205. https://doi.org/10.1081/rrs-200029981

    Article  CAS  PubMed  Google Scholar 

  27. O’Malley KL, Harmon S, Tang L, Todd RD (1992) The rat dopamine D4 receptor: sequence, gene structure, and demonstration of expression in the cardiovascular system. New Biol 4:137–146

    PubMed  Google Scholar 

  28. Ogawa M, Zhou S, Tan AY, Song J, Gholmieh G, Fishbein MC, Luo H, Siegel RJ, Karagueuzian HS, Chen LS, Lin S-F, Chen P-S (2007) Left stellate ganglion and vagal nerve activity and cardiac arrhythmias in ambulatory dogs with pacing-induced congestive heart failure. J Am Coll Cardiol 50:335–343. https://doi.org/10.1016/j.jacc.2007.03.045

    Article  PubMed  Google Scholar 

  29. Patel S, Freedman S, Chapman KL, Emms F, Fletcher AE, Knowles M, Marwood R, Mcallister G, Myers J, Curtis N, Kulagowski JJ, Leeson PD, Ridgill M, Graham M, Matheson S, Rathbone D, Watt AP, Bristow LJ, Rupniak NM, Baskin E, Lynch JJ, Ragan CI (1997) Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor. J Pharmacol Exp Ther 283:636–647

    CAS  PubMed  Google Scholar 

  30. Paton JFR, Boscan P, Pickering AE, Nalivaiko E (2005) The yin and yang of cardiac autonomic control: vago-sympathetic interactions revisited. Brain Res Rev 49:555–565. https://doi.org/10.1016/j.brainresrev.2005.02.005

    Article  CAS  PubMed  Google Scholar 

  31. Peupelmann J, Boettger MK, Ruhland C, Berger S, Ramachandraiah CT, Yeragani VK, Bär K-J (2009) Cardio-respiratory coupling indicates suppression of vagal activity in acute schizophrenia. Schizophr Res 112:153–157. https://doi.org/10.1016/j.schres.2009.03.042

    Article  PubMed  Google Scholar 

  32. Piechaczyk M, Blanchard JM, Marty L, Dani C, Panabieres F, El Sabouty S, Fort P, Jeanteur P (1984) Post-transcriptional regulation of glyceraldehyde-3-phosphate-dehydrogenase gene expression in rat tissues. Nucleic Acids Res 12:6951–6963. https://doi.org/10.1093/nar/12.18.6951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Price CJ, Pittman QJ (2001) Dopamine D4 receptor activation inhibits presynaptically glutamatergic neurotransmission in the rat supraoptic nucleus. J Neurophysiol 86:1149–1155. https://doi.org/10.1152/jn.2001.86.3.1149

    Article  CAS  PubMed  Google Scholar 

  34. Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY, Boyfield I, Branch CL, Cilia J, Coldwell MC, Hadley MS, Hunter AJ, Jeffrey P, Jewitt F, Johnson CN, Jones DN, Medhurst AD, Middlemiss DN, Nash DJ, Riley GJ, Routledge C, Stemp G, Thewlis KM, Trail B, Vong AK, Hagan JJ (2000) Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A. J Pharmacol Exp Ther 294:1154–1165

    CAS  PubMed  Google Scholar 

  35. Ricci A, Bronzetti E, Fedele F, Ferrante F, Zaccheo D, Amenta F (1998) Pharmacological characterization and autoradiographic localization of a putative dopamine D4 receptor in the heart. J Auton Pharmacol 18:115–121. https://doi.org/10.1046/j.1365-2680.1998.1820115.x

    Article  CAS  PubMed  Google Scholar 

  36. Roquebert J, Morán A, Demichel P, Sauvage MF (1991) Pharmacological characterization of dopamine receptors in parasympathetic innervation of rat heart. Eur J Pharmacol 200:59–63. https://doi.org/10.1016/0014-2999(91)90665-d

    Article  CAS  PubMed  Google Scholar 

  37. Roquebert J, Morán A, Sauvage MF, Demichel P (1992) Effects of quinpirole on autonomic nervous control of heart rate in rats. Fundam Clin Pharmacol 6:67–73. https://doi.org/10.1111/j.1472-8206.1992.tb00096.x

    Article  CAS  PubMed  Google Scholar 

  38. Ruiz-Salinas I, González-Hernández A, Manrique-Maldonado G, Marichal-Cancino BA, Altamirano-Espinoza AH, Villalón CM (2013) Predominant role of the dopamine D3 receptor subtype for mediating the quinpirole-induced inhibition of the vasopressor sympathetic outflow in pithed rats. Naunyn Schmiedebergs Arch Pharmacol 386:393–403. https://doi.org/10.1007/s00210-013-0841-8

    Article  CAS  PubMed  Google Scholar 

  39. Scigliano G, Ronchetti G, Girotti F (2008) Autonomic nervous system and risk factors for vascular disease. Effects of autonomic unbalance in schizophrenia and Parkinson’s disease. Neurol Sci 29:15–21. https://doi.org/10.1007/s10072-008-0853-1

    Article  PubMed  Google Scholar 

  40. Seeman P, Van Tol HH (1994) Dopamine receptor pharmacology. Trends Pharmacol Sci 15:264–270

    Article  CAS  Google Scholar 

  41. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146–151. https://doi.org/10.1038/347146a0

    Article  CAS  PubMed  Google Scholar 

  42. Tan AY, Zhou S, Ogawa M, Song J, Chu M, Li H, Fishbein MC, Lin S-F, Chen LS, Chen P-S (2008) Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines. Circulation 118:916–925. https://doi.org/10.1161/CIRCULATIONAHA.108.776203

    Article  PubMed  PubMed Central  Google Scholar 

  43. Thomas TC, Kruzich PJ, Joyce BM, Gash CR, Suchland K, Surgener SP, Rutherford EC, Grandy DK, Gerhardt GA, Glaser PEA (2007) Dopamine D4 receptor knockout mice exhibit neurochemical changes consistent with decreased dopamine release. J Neurosci Methods 166:306–314. https://doi.org/10.1016/j.jneumeth.2007.03.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wu B, Xu S, Dai R, Hong M, Wu H, Lin R (2019) Epicardial ganglionated plexi ablation increases the inducibility of ventricular tachyarrhythmias in a canine postmyocardial infarction model. J Cardiovasc Electrophysiol 30:741–746. https://doi.org/10.1111/jce.13912

    Article  PubMed  Google Scholar 

  45. Zeng C, Armando I, Luo Y, Eisner GM, Felder RA, Jose PA (2008) Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice. Am J Physiol Heart Circ Physiol 294:H551–H569. https://doi.org/10.1152/ajpheart.01036.2007

    Article  CAS  PubMed  Google Scholar 

  46. Zeng C, Sanada H, Watanabe H, Eisner GM, Felder RA, Jose PA (2004) Functional genomics of the dopaminergic system in hypertension. Physiol Genomics 19:233–246. https://doi.org/10.1152/physiolgenomics.00127.2004

    Article  CAS  PubMed  Google Scholar 

Download references

Availability of data and material

All material and data obtained and processed in this manuscript is available for further query to the authors in the Laboratory of Pharmacology of the University of Salamanca.

Funding

This work received financial support from the University of Salamanca (project KB7N/463AC01) and SEP-Cinvestav (grant no. 50, Mexico City).

Author information

Authors and Affiliations

  1. Laboratorio de Farmacología, Dep. de Fisiología y Farmacología, Facultad de Farmacia, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, 37007, Salamanca, Spain

    José Ángel García-Pedraza, Asunción Morán, María Luisa Martín & Mónica García-Domingo

  2. Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Dep. de Fisiología y Farmacología, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, 37007, Salamanca, Spain

    Claudia Ollauri-Ibáñez & Alicia Rodríguez-Barbero

  3. Departamento de Farmacobiología, Cinvestav-Coapa, Czda. Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, 14330, Mexico City, Mexico

    Carlos M. Villalón

Authors
  1. José Ángel García-Pedraza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asunción Morán
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. María Luisa Martín
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claudia Ollauri-Ibáñez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alicia Rodríguez-Barbero
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlos M. Villalón
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mónica García-Domingo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceived and designed experiments: AM, CMV, MGD. Performed experiments: AM, ARB, COI, JAGP, MGD. Analysed data: AM, CMV, JAGP, MGD, MLM. Wrote and revised the manuscript: AM, CMV, JAGP, MGD.

Corresponding author

Correspondence to Mónica García-Domingo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

This study was approved by the University of Salamanca Institutional Bioethics committee (permit number 006N°201400037737). Maintenance and manipulation protocols were performed following European guidelines (Directive 2010/63/EU) and Spanish legislation (R.D. 53/2013) for the use and care of animals in Biomedical Research, in full compliance with (i) the guide for the Care and Use of Laboratory Animals in USA and (ii) the ARRIVE guidelines for reporting experiments involving animals [21].

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

García-Pedraza, J.Á., Morán, A., Martín, M.L. et al. Dopamine D4 receptor subtype activation reduces the rat cardiac parasympathetic discharge. Pflugers Arch - Eur J Physiol 472, 1693–1703 (2020). https://doi.org/10.1007/s00424-020-02452-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-020-02452-8

Keywords

Search

Navigation