Abstract
6-Nitrodopamine (6-ND) is an endogenous modulator of the contractility in the rat isolated epididymal vas deferens (RIEVD) and considered to be the main peripheral mediator of the emission process. Use of selective and unselective β-adrenergic receptor antagonists has been associated with ejaculatory failure. Here, the effects of selective β1- and β1/β2-adrenergic receptor antagonists on RIEVD contractions induced by 6-ND, dopamine, noradrenaline, adrenaline, and electric-field stimulation (EFS) were investigated. The selective β1-adrenergic receptor antagonists atenolol (0.1 and 1 µM), betaxolol (1 µM), and metoprolol (1 µM) and the unselective β1/β2-adrenergic receptor antagonists propranolol (1 and 10 µM) and pindolol (10 µM) caused significant rightward shifts of the concentration–response curve to 6-ND (pA2 6.41, 6.91, 6.75, 6.47, and 5.74; for atenolol, betaxolol, metoprolol, propranolol, and pindolol), but had no effect on dopamine-, noradrenaline-, and adrenaline-induced contractions. The effects of selective β1- and β1/β2-adrenergic receptor antagonists at a higher concentration (atenolol 1 µM, betaxolol 1 µM, metoprolol 1 µM, propranolol 10 µM, and pindolol 10 µM) also reduced the EFS-induced RIEVD contractions in control, but not in RIEVD obtained from L-NAME-treated animals. The selective β1-adrenoceptor agonist RO-363, the selective β2-adrenoceptor agonist salbutamol, and the selective β3-adrenoceptor agonist mirabegron, up to 300 µM, had no effect on the RIEVD tone. The results demonstrate that β1- and β1-/β2-adrenoceptor receptor antagonists act as 6-ND receptor antagonists in RIEVD, further confirming the main role of 6-ND in the RIEVD contractility.
Similar content being viewed by others
Data availability
The authors authorize the availability of any data used in this study.
References
Ahlenius S, Larsson K (1991) Opposite effects of 5-methoxy-N, N-di-methyl-tryptamine and 5-hydroxytryptophan on male rat sexual behavior. Pharmacol Biochem Behav 38(1):201–205. https://doi.org/10.1016/0091-3057(91)90611-5
Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol Chemother 14(1):48–58. https://doi.org/10.1111/j.1476-5381.1959.tb00928.x
Başar MM, Yilmaz E, Ferhat M, Başar H, Batislam E (2005) Terazosin in the treatment of premature ejaculation: a short-term follow-up. Int Urol Nephrol 37(4):773–777. https://doi.org/10.1007/s11255-005-3616-4 (PMID: 16362597)
Beaumont G (1977) Sexual side-effects of clomipramine (Anafranil). J Int Med Res 5(Suppl. 1):37–44
Belevych AE, Zima AV, Vladimirova IA, Hirata H, Jurkiewicz A, Jurkiewicz NH, Shuba MF (1999) TTX-sensitive Na(+) and nifedipine-sensitive Ca(2+) channels in rat vas deferens smooth muscle cells. Biochim Biophys Acta 15;1419(2):343–52. https://doi.org/10.1016/s0005-2736(99)00075-9
Britto-Júnior J, Coelho-Silva WC, Murari GF, Serpellone-Nash CE, Mónica FZ, Antunes E, De Nucci G (2021a) 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, Ximenes L, Ribeiro A, Fregonesi A, Campos R, Kiguti LRA, Mónica FZ, Antunes E, De Nucci G (2021b) 6-Nitrodopamine is an endogenous mediator of rat isolated epididymal vas deferens contractions induced by electric-field stimulation. Eur J Pharmacol 1(911):174544. https://doi.org/10.1016/j.ejphar.2021.174544
Britto-Júnior J, Ribeiro A, Ximenes L, Lima AT, Jacintho FF, Fregonesi A, Mónica FZ, Antunes E, De Nucci G (2022) Alpha1-adrenergic antagonists block 6-nitrodopamine contractions on the rat isolated epididymal vas deferens. Eur J Pharmacol 15(915):174716. https://doi.org/10.1016/j.ejphar.2021.174716
Burnstock G, Verkhratsky A (2010) Vas deferens—a model used to establish sympathetic cotransmission. Trends Pharmacol Sci 31(3):131–139. https://doi.org/10.1016/j.tips.2009.12.002
Campos R, Pinheiro DHA, Britto-Júnior J, de Castro HA, Mendes GD, Moraes MO, Moraes MEA, Lopes-Martins RÁB, Antunes NJ, De Nucci G (2020) 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 Analyt Technol Biomed Life Sci 22(1173):122668. https://doi.org/10.1016/j.jchromb.2021.122668
Cavallini G (1995) (1995) Alpha-1 blockade pharmacotherapy in primitive psychogenic premature ejaculation resistant to psychotherapy. Eur Urol 28(2):126–130. https://doi.org/10.1159/000475036
Chang RS, Lotti VJ (1983) Characterization of beta-adrenergic receptors in the rat vas deferens using [3H]-dihydroalprenolol binding. Life Sci 30;32(22):2603–9. https://doi.org/10.1016/0024-3205(83)90245-x
Cusack B, Nelson A, Richelson E (1994) Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology 114(4):559–565. https://doi.org/10.1007/BF02244985
Debruyne FM (2000) Alpha blockers: are all created equal? Urology 1;56(5 Suppl 1):20–2. https://doi.org/10.1016/s0090-4295(00)00744-5
Djavan B, Chapple C, Milani MM (2004) State of the art on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology 64(6):1081–1088
Dunn CJ, Matheson A, Faulds DM (2002) Tamsulosin: a review of its pharmacology and therapeutic efficacy in the management of lower urinary tract symptoms. Drugs Aging 19(2):135–161. https://doi.org/10.2165/00002512-200219020-00004
Elliott HL, Meredith PA, Sumner DJ, McLean K, Reid JL (1982) A pharmacodynamic and pharmacokinetic assessment of a new alpha-adrenoceptor antagonist, doxazosin (UK33274) in normotensive subjects. Br J Clin Pharmacol 13(5):699–703. https://doi.org/10.1111/j.1365-2125.1982.tb01439.x
Frishman WH, Eisen G, Lapsker J (1988) Terazosin: a new long-acting alpha 1-adrenergic antagonist for hypertension. Med Clin North Am 72(2):441–448. https://doi.org/10.1016/s0025-7125(16)30778-7
Furness JB, Iwayama T (1971) Terminal axons ensheathed in smooth muscle cells of the vas deferens. Z Zellforsch Mikrosk Anat 19 113(2):259–70. https://doi.org/10.1007/BF00339420
Hellstrom WJ, Sikka SC (2006) Effects of acute treatment with tamsulosin versus alfuzosin on ejaculatory function in normal volunteers. J Urol 176(4 Pt 1):1529–1533. https://doi.org/10.1016/j.juro.2006.06.004
Höfner K, Claes H, De Reijke TM, Folkestad B, Speakman MJ (1999) Tamsulosin 0.4 mg once daily: effect on sexual function in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 36(4):335–41. https://doi.org/10.1159/000019996
Hsieh JT, Liu SP, Hsieh CH, Cheng JT (1999) An in vivo evaluation of the therapeutic potential of sympatholytic agents on premature ejaculation. BJU Int 84(4):503–506. https://doi.org/10.1046/j.1464-410x.1999.00173.x
Iakovidis D, Malta E, McPherson GA, Raper C (1980) In vitro activity of RO363, a beta1-adrenoceptor selective agonist. Br J Pharmacol 68(4):677–685. https://doi.org/10.1111/j.1476-5381.1980.tb10860.x
Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM (2002) Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 17;288(3):351–7. https://doi.org/10.1001/jama.288.3.351
Lee CH, Ruben PC (2008) Interaction between voltage-gated sodium channels and the neurotoxin, tetrodotoxin. Channels (austin) 6:407–412. https://doi.org/10.4161/chan.2.6.7429
Lepor H, Baumann M, Shapiro E (1988) The stereospecificity of LY253352 for alpha 1-adrenoceptor binding sites in the brain and prostate. Br J Pharmacol 95(1):139–144. https://doi.org/10.1111/j.1476-5381.1988.tb16557.x
May JM, Abel PW, Minneman KP (1985) Binding of agonists and antagonists to beta-adrenoceptors in rat vas deferens: relationship to functional response. Naunyn Schmiedebergs Arch Pharmacol 331(4):324–333. https://doi.org/10.1007/BF00500814
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
Millan MJ, Dekeyne A, Papp M, La Rochelle CD, MacSweeny C, Peglion JL, Brocco M (2001) S33005, a novel ligand at both serotonin and norepinephrine transporters: II. Behavioral profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J Pharmacol Exp Ther 298(2):581–91
Motulsky HJ (2014) Common misconceptions about data analysis and statistics. Naunyn Schmiedebergs Arch Pharmacol 387(11):1017–1023. https://doi.org/10.1007/s00210-014-1037-6
Narahashi T, Moore JW, Poston RN (1967) Tetrodotoxin derivatives: chemical structure and blockage of nerve membrane conductance. Science 19;156(3777):976–9. https://doi.org/10.1126/science.156.3777.976
O’Leary MP (2001) Tamsulosin: current clinical experience. Urology 58(6 Suppl 1):42–8. https://doi.org/10.1016/s0090-4295(01)01346-2 (discussion 48)
O’Meara J, White WB (1988) Ejaculatory failure and urinary dysfunction secondary to labetalol. J Urol 139(2):371–2. https://doi.org/10.1016/s0022-5347(17)42420-7
Percie du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, Garner P, Holgate ST, Howells DW, Hurst V, Karp NA, Lazic SE, Lidster K, MacCallum CJ, Macleod M, Pearl EJ, Petersen OH, Rawle F, Reynolds P, Rooney K, Sena ES, Silberberg SD, Steckler T, Würbel H (2020) Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol 14;18(7):e3000411. https://doi.org/10.1371/journal.pbio.3000411
Ramsay JW, Scott GI, Whitfield HN (1988) A double-blind controlled trial of a new alpha-1 blocking drug in the treatment of bladder outflow obstruction. Br J Urol 57(6):657–659. https://doi.org/10.1111/j.1464-410x.1985.tb07026.x
Ribeiro MO, Antunes E, de Nucci G, Lovisolo SM, Zatz R (1992) Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension 20(3):298–303. https://doi.org/10.1161/01.hyp.20.3.298
Safarinejad MR (2008) Once-daily high-dose pindolol for paroxetine-refractory premature ejaculation: a double-blind, placebo-controlled and randomized study. J Clin Psychopharmacol 28(1):39–44. https://doi.org/10.1097/jcp.0b013e31816073a5
Sánchez C, Hyttel J (1999) Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 19(4):467–489. https://doi.org/10.1023/a:1006986824213
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 271(23):13561–13565. https://doi.org/10.1074/jbc.271.23.13561
Srilatha B, Adaikan PG, Arulkumaran S, Ng SC (1999) Sexual dysfunction related to antihypertensive agents: results from the animal model. Int J Impot Res 11(2):107–113. https://doi.org/10.1038/sj.ijir.3900393
Vohra MM (1979) Evidence for the presence of beta 2-inhibitory adrenoceptors in the rat vas deferens. Gen Pharmacol 10(3):221–225. https://doi.org/10.1016/0306-3623(79)90093-4
Wilt TJ, MacDonald R (2006) Doxazosin in the treatment of benign prostatic hypertrophy: an update. Clin Interv Aging 1(4):389–401. https://doi.org/10.2147/ciia.2006.1.4.389
Funding
ATL thanks FAPESP for PhD fellowship (2021/13593–6).
ACA thanks CAPES for master’s fellowship (001).
JBJ thanks CAPES for PhD fellowship (001).
RRC thanks FAPESP for scientific initiation fellowship (2021/14120–4).
EA and FM thank FAPESP (2017/15175–1).
GDN thanks FAPESP (2019/16805–4) and CNPq (303,839/2019–8).
Author information
Authors and Affiliations
Contributions
Conceptualization: JBJ, GDN.
Data curation: JBJ, GDN.
Formal analysis: GDN.
Funding acquisition: EA, GDN.
Investigation: ATL, ACA, JBJ, RRC, GDN.
Methodology: ATL, ACA, JBJ, RRC, AF, EA, FZM, GDN.
Project administration: GDN.
Supervision: FZM, EA.
Visualization: AF, EA, GDN.
Writing—original draft: JBJ, AF, EA, GDN.
The authors declare that all data were generated in-house and that no paper mill was used.
Corresponding author
Ethics declarations
Ethics approval
All experimental protocols were authorized by the Ethics Committee in Animal Use of UNICAMP (CEUA/UNICAMP, protocol numbers 5952–1/2022 and 5831–1/2021).
Consent to participate
Not applicable.
Consent for publication
The authors authorize the submission and publication of this article in Naunyn–Schmiedeberg’s Archives of Pharmacology.
Competing interests
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Lima, A.T., Amorim, A.C., Britto-Júnior, J. et al. β1- and β1/β2-adrenergic receptor antagonists block 6-nitrodopamine-induced contractions of the rat isolated epididymal vas deferens. Naunyn-Schmiedeberg's Arch Pharmacol 395, 1257–1268 (2022). https://doi.org/10.1007/s00210-022-02268-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-022-02268-6